• cord blood transplantation;
  • reduced-intensity chemotherapy;
  • haemophagocytic syndrome;
  • engraftment failure


  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References

Umbilical cord blood transplantation (CBT) is widely accepted, but one critical issue for adult patients is a low engraftment rate, of which one cause is haemophagocytic syndrome (HPS). We aimed to identify the contribution of HPS to engraftment failure after CBT, following preparative regimens containing fludarabine phosphate, in 119 patients (median age, 55 years; range; 17–69 years) with haematological diseases. Graft-versus-host disease prophylaxis comprised continuous infusion of a calcineurin inhibitor with or without mycophenolate mofetil. Of the 119 patients, 20 developed HPS within a median of 15 d (cumulative incidence; 16·8%) and 17 of them did so before engraftment. Donor-dominant chimaerism was confirmed in 16 of 18 evaluable patients with HPS. Despite aggressive interventions including corticosteroid, ciclosporin, high-dose immunoglobulin and/or etoposide, engraftment failed in 14 of 18 patients. Of these 14 patients, four received second rescue transplantation and all resulted in successful engraftment. Overall survival rates significantly differed between patients with and without HPS (15·0% vs. 35·4%; P < 0·01). Univariate and multivariate analysis identified having fewer infused CD34+ cells as a significant risk factor for the development of HPS (P = 0·01 and 0·006, respectively). We concluded that engraftment failure closely correlated with HPS in our cohort, which negatively impacted overall survival after CBT.

Umbilical cord blood transplantation (CBT) is an alternative allogeneic haematopoietic stem cell transplantation (HSCT) strategy for patients with haematological diseases who do not have a matched related or unrelated donor and who need urgent transplantation. The value of CBT using myeloablative preparative regimens has already been confirmed among paediatric and adult patients (Laughlin et al, 2004; Rocha et al, 2004; Takahashi et al, 2004). However, conventional myeloablative preparative regimens are associated with significant morbidity and mortality, particularly in older patients or in those who have experienced extensive prior therapy or organ dysfunction associated with transplantation-related mortality. Various reduced-intensity preparative regimens that have been applied to such patients by several groups, including the authors of the present study, have proven feasible (Barker et al, 2003, 2005; Chao et al, 2004; Jacobsohn et al, 2004; Miyakoshi et al, 2004, 2007; Yuji et al, 2005; Misawa et al, 2006; Ballen et al, 2007; Brunstein et al, 2007; Komatsu et al, 2007; Uchida et al, 2008).

Engraftment failure is a critical problem that can arise after CBT. The limited doses of infused total nucleated and CD34+ cells contained in umbilical cord blood are thought to influence the rate and kinetics of haematopoietic recovery. In order to overcome engraftment failure, various kinds of strategies, such as multiple unit or ex-vivo expanded CBT, and co-infusion of peripheral blood stem cells, have been employed (Shpall et al, 2002; Fernandez et al, 2003; Barker et al, 2005).

Several recent reports have described HPS that arose after autologous and allogeneic HSCT followed by engraftment failure (Sokal et al, 1987; Levy et al, 1990; Reardon et al, 1991; Nagafuji et al, 1998; Sato et al, 1998; Takahashi et al, 1998; Ishikawa et al, 2000; Fukuno et al, 2001; Abe et al, 2002; Tanaka et al, 2004, 2007; Kishi et al, 2005a; Boelens et al, 2006; Ostronoff et al, 2006; Ishida et al, 2007; Koyama et al, 2007). In a reduced-intensity conditioned CBT (RI-CBT) setting, we experienced one patient who failed to achieve engraftment due to HPS following HSCT (HSCT–HPS). Following this case, several similar cases were observed in our institute. We postulated that HPS could play a critical role in engraftment failure after CBT. This report describes the characteristics of 20 patients with HSCT–HPS among 119 who underwent CBT.

Materials and methods

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References


The study population consisted of 119 adult patients with haematological diseases, who underwent CBT as the first allogeneic HSCT at Toranomon Hospital, Tokyo, Japan between January 2004 and December 2006. All the patients were incurable using conventional approaches, lacked a human leucocyte antigen (HLA)-identical sibling or a suitable unrelated donor from Japan Marrow Donor Program. Most of the patients were considered inappropriate for conventional myeloablative allogeneic HSCT due to being >50 years and/or having organ dysfunction (cardiac ejection fraction <50%, forced expiratory volume 1·0 s % <80%, or serum creatinine > 1·5× upper limit of normal range). Written informed consent was provided by all patients in accordance with the Declaration of Hersinki. The Institutional Review Board of Toranomon Hospital approved the study.

Transplantation procedures

Cord blood units that were serologically matched for ≥4 of six HLA antigens and which contained at least 1·8 × 107 nucleated cells/kg of recipient body weight before freezing were obtained from the cord blood bank at the Japan Cord Blood Bank Network (Nishihira et al, 2003). The units were not depleted of T lymphocytes. All patients received purine analogue-based preparative regimens comprising fludarabine phosphate (125–180 mg/m2), melphalan (80–140 mg/m2) or busulfan (BU; 8–16 mg/kg) and 0–8 Gy of total body irradiation (TBI), as decided by the treating physician. Graft-versus-host disease (GVHD) prophylaxis comprised a continuous intravenous infusion of either 0·03 mg/kg of tacrolimus (TAC) or 3 mg/kg of ciclosporin (CsA), starting on day-1, except eight patients who received 2 g/d of mycophenolate mofetil (MMF) starting on day-1 in addition to TAC.

Supportive cares

All the patients were treated in reverse isolation in laminar airflow-equipped rooms and received trimethoprim/sulfamethoxazole for Pneumocystis jirovecii prophylaxis. Fluoro-quinolone and azole and acyclovir were administered to prevent bacterial, fungal and herpes virus infection, respectively. Neutropenic fever was managed according to the guidelines (Hughes et al, 2002). Cytomegalovirus pp65 antigenaemia was monitored weekly and preemptive therapy with foscarnet was initiated in the event of a positive result (Matsumura et al, 2007; Narimatsu et al, 2007a). Haemoglobin and platelet counts were maintained at >70 g/l and 10 × 109/l, respectively. Granulocyte colony-stimulating factor was administered intravenously from day 1 until neutrophil recovery became durable.

Assessment of engraftment, chimaerism, pre-engraftment immune reactions, disease risk and survival

Engraftment was defined as the first of three consecutive days in which white blood cell counts were >1·0 × 109/l or the absolute neutrophil counts were >0·5 × 109/l. When the above definition was not met by day 28 without subsequent neutrophil recovery, the patient was considered to have primary engraftment failure. Delayed engraftment was defined as neutrophil engraftment after day 29. Secondary engraftment failure was defined as a decrease in the neutrophil count to <0·5 × 109/l for three consecutive days after successful engraftment. The date of platelet recovery was defined as the first of seven consecutive days during which the non-transfused platelet count was at least 20 × 109/l.

Chimaerism was assessed using fluorescent in situ hybridization (FISH) in sex-mismatched donor–recipient pairs. In sex-matched pairs, chimaerism was assessed using the polymerase chain reaction for variable numbers of tandem repeats with donor cells detected at 10% sensitivity (Thiede et al, 1999).

Pre-engraftment immune reactions (PIR) were diagnosed when febrile patients (body temperature ≥38·0°C) developed skin eruption, diarrhoea, jaundice (serum total bilirubin >34·2 μmol/l) or body weight gain of >10% of baseline, with no direct evidence of infection or adverse effects of medication, developing ≥6 d before engraftment (Kishi et al, 2005b).

Patients with acute myeloid leukaemia in first or second complete remission (CR) at the time of transplant, with acute lymphoblastic leukaemia in first or second CR, with chronic myeloid leukaemia in the chronic phase, with refractory anaemia or refractory anaemia with ringed sideroblasts of myelodysplastic syndrome and with non-malignant diseases were defined as being at standard risk. All other patients were defined as being at high risk.

The overall survival (OS) of all of the patients was measured from the date of transplantation to the date of death from any cause.

Definition of haemophagocytic syndrome following haematopoietic stem cell transplantation

We modified the criteria proposed by others for diagnosing HPS after transplantation (Henter et al, 1991; Imashuku, 1997; Tsuda, 1997) and selected two major and four minor criteria. A diagnosis of HSCT–HPS required both major criteria, or one major and all four minor criteria. The first major criterion comprised engraftment failure, delayed engraftment, or secondary engraftment failure after HSCT and the second was histopathological evidence of haemophagocytosis. The four minor criteria comprised high grade fever, hepato-splenomegaly, elevated ferritin and elevated serum lactate dehydrogenase (LDH). Although progressive cytopenia has formed the backbone of the previous criteria, we excluded it considering the post-HSCT setting.

Statistical analysis

The cumulative incidences were estimated for neutrophil engraftment and the development of HSCT–HPS (Gooley et al, 1999). The probability of OS was estimated from the time of transplantation according to the Kaplan–Meier product limit method and outcomes were compared using the log-rank test. The following patient or transplant characteristics (baseline factors) were analysed using the Cox regression model to determine their impact on the development of HSCT–HPS: patient age, gender (matched or mismatched), blood type (matched or mismatched), disease (lymphoma or not), disease risk (standard or high), preparative regimen (reduced-intensity or myeloablative), GVHD prophylaxis (TAC alone or others), disparity of HLA-A, -B, -DR antigen (one or two mismatched antigens), and numbers of infused nucleated and CD34+ cells. A value of P < 0·05 was considered statistically significant. All data were statistically analysed using Stat-View 5.0 and S-Plus 2000 (Mathsoft, Seattle, WA, USA).


  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References

Patient’s characteristics

Table I summarizes the characteristics of the 119 patients and cord blood grafts. The median age was 55 years (range, 17–69); 103 patients (87%) had high risk diseases. The preparative regimen comprised fludarabine phosphate, melphalan and TBI in 91 patients (76%) and 106 patients (89%) received TAC alone as GVHD prophylaxis. MMF was administered in addition to TAC for eight patients (7%). The median numbers of infused total nucleated and CD34+ cells were 2·52 × 107 (range, 1·85–5·13) and 0·766 × 105 cells/kg (range, 0·110–3·16), respectively. The donor–recipient pairs had serological mismatches at two HLA loci, a gender mismatch and an ABO blood-type mismatch in 103 (87%), 95 (80%) and 83 (70%) patients, respectively. Among 103 patients who survived beyond 28 d after CBT, neutrophil engraftment was achieved in 89 of them at a median of day 20 (range, 11–45). The cumulative incidence of neutrophil engraftment at day 60 was 85·6%. Secondary engraftment failure occurred in four of these 89 patients. Eleven patients were diagnosed with ‘delayed engraftment’ according to our definition. The direct causes of death in 16 patients who died within 28 d of CBT included sepsis (n = 10), haemorrhage (n = 2), relapse of primary disease (n = 2), thrombotic microangiopathy (TMA) (n = 1), and central nervous system complication (n = 1). Chimaerism data was obtained from 111 patients. Chimaerism analysis was performed in 58 patients in the peripheral blood and in 53 patients in the bone marrow. One hundred (90·1%) of them had achieved complete donor chimaerism by day 60. The median length of time required to complete donor chimaerism was 18 d (range, 9–93). Chimaerism was analysed in 10 of 16 patients who died within 28 d of CBT. All except one had complete donor chimaerism before neutrophil engraftment. Seventy-three (61·3%) of the 119 patients developed PIR. By day 100 after CBT, 55 patients had developed bacteraemia at a median of 10 d (range, 3–89 d). Of these 55 patients, 33 developed bacteraemia within 14 d of transplantation. Cytomegarovirus (CMV) was reactivated in 60 patients at a median of 33 d (range, 3–101 d). Ten patients developed histologically confirmed CMV enterocolitis. Eleven patients developed limbic encephalitis caused by human herpes virus 6 (HHV-6) at a median of 20 d of transplantation (range, 13–33 d).

Table I.   Patients’ characteristics and transplantation procedures.
  1. GVHD, graft-versus-host disease; BU, busulfan; CsA, ciclosporin; Flu, fludarabine phosphate; Mel, melphalan; MMF, mycophenolate mofetil; TAC, tacrolimus; TBI, total body irradiation; HLA, human leucocyte antigen.

Age (years), median (range)55 (17–69)
Gender (male/female)78/41
Primary diseases
Acute lymphoblastic leukaemia10
Acute myeloid leukaemia52
Chronic myeloid leukaemia5
Adult T-cell leukaemia/lymphoma11
Myelodysplastic syndrome6
Malignant lymphoma32
Aplastic anaemia1
Chronic idiopathic myelofibrosis1
Acute leukaemia of ambiguous lineage1
Preparative regimens
Flu (125–180 mg/m2)/Mel (80–140 mg/m2)/TBI (2–8 Gy)91
Flu (125–180 mg/m2)/Mel (80–140 mg/m2)7
Flu (125–180 mg/m2)/BU (8–16 mg/kg)/TBI (4–8 Gy)14
Flu (150–180 mg/m2)/BU (8–16 mg/kg)3
GVHD prophylaxis
CsA alone5
TAC alone106
TAC and MMF8
Cord blood cells
Number of infused nuclear cells, median (range), ×107/kg2·52 (1·85–5·13)
Number of infused CD34+ cells, median (range), ×105/kg0·766 (0·110–3·16)
Sex match
HLA match
ABO-blood type match
Minor mismatched31
Major mismatched38
Bidirectional mismatched14
Disease risk

HSCT–HPS patients’ characteristics

Table II shows the characteristics of the 20 of 119 patients who had clinical features of HPS according to our diagnostic criteria. The cumulative incidence of HPS after CBT was 16·8% (Fig 1). HPS occurred within 4 weeks of transplantation and the median day of diagnosis was 15 d post-transplant (range, 10–27 d). The 20 patients comprised 13 men and seven women, with a median age of 52 years (range, 23–69 years); 17 patients had high risk disease. None of them had evidence of HPS before transplantation. The preparative regimen comprised fludarabine phosphate, melphalan and TBI for 15 patients and 19 patients received TAC alone as GVHD prophylaxis. MMF was administered in addition to TAC for one patient. The median numbers of infused total nucleated and CD34+ cells were 2·40 × 107 cells/kg (range, 1·98–5·13) and 0·52 × 105 cells/kg (range, 0·18–3·10), respectively. The donor–recipient pairs had serological mismatches at two HLA loci, a gender mismatch and an ABO blood type mismatch in 17, 15 and 17 patients, respectively.

Table II.   Characteristics of HSCT–HPS patients.
PatientAge (years)/ genderDiseaseStatus TNC (×107/kg) CD34+ (×105/kg)Gender matchHLA matchBlood type matchPreparative regimenGVHD prophylaxis
  1. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; AML/MDS, acute myeloid leukaemia with multilineage dysplasia; ATLL, adult T-cell leukaemia/lymphoma; B, oral busulfan, mg/kg; BC, blastic crisis; BD, bidirectional; CML, chronic myeloid leukaemia; CR, complete response; F, fludarabine; GVHD, graft-versus-host disease; HLA, human leucocyte antigen; M, melphalan, mg/m2; MDS, myelodysplastic syndrome; MM, mismatch; MMF, mycophenolate mofetil; NHL, non-Hodgkin lymphoma; NT, not treated; pASCT, post autologous stem-cell transplantation; PD, progressive disease; PIF, primary induction failure; PR, partial response; RL, relapse; TAC, tacrolimus; TBI, total body irradiation; TNC, total nucleated cell count; TSP, tespamine.

11768/MALLRL12·640·74Match4/6BD MMF125/M80/TBI4TAC
15738/MAMLPIF2·390·31MM4/6Minor MMF125/M80/TBI4TAC
16169/MNHLRL12·540·99Match4/6Major MMF125/M80/TBI4TAC
16448/FATLLPR5·133·10MM4/6Minor MMF125/M80/TBI4TAC
17123/MAMLRL22·300·52MM5/6Minor MMF180/B8/TBI8TAC
18162/MAMLCR21·940·18MM4/6Major MMF125/M80/TSPTAC
19856/FATLLPR3·990·20MM4/6BD MMF125/B8/TBI4TAC
20852/MNHLPD2·410·52MM4/6Minor MMF125/M80/TBI4TAC
20952/MAML/MDSCR12·520·58Match4/6Major MMF125/M80/TBI4TAC
21257/MAML/MDSNT2·080·57MM4/6Minor MMF125/M80/TBI4TAC
21547/FNHLPD3·160·45MM4/6Major MMF180/B8TAC
24039/MAMLRL12·620·29MM4/6Minor MMF125/M140/TBI4TAC
24233/FAMLRL12·570·39MM4/6Minor MMF125/M160/TBI4TAC
24666/MAML/MDSPIF2·370·65MM4/6Major MMF125/M80/TBI4TAC
27431/FNHLRL pASCT2·720·22MM4/6MatchF180/M140TAC
27859/MAML/MDSPIF1·980·50MM4/6Major MMF125/M80/TBI4TAC
28040/FNHLRL12·350·90Match4/6Minor MMF125/M80/TBI4TAC
28262/MAMLCR22·050·70Match4/6Minor MMF125/M80/TBI4TAC/MMF

Figure 1.  Cumulative incidence of HPS following CBT.

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Clinical features of HSCT–HPS patients

Table III shows the clinical features and outcome of HSCT–HPS patients. All patients, except for one, presented with high grade fever. Hepatosplenomegaly was found in four patients and 11 had clinical manifestations of PIR. Serum aminotransferases (predominantly aspartate, rather than alanine aminotransferase) and bilirubin were elevated in 12 patients each. None of them had acute hepatic failure. Serum LDH and ferritin levels were elevated in 16 and 19 patients respectively [median value (range) of highest LDH, 340 (65–2444) i/u per litre and ferritin, 9397 (1423–568500) μg/l]. The highest values of serum ferritin by day 30 after CBT significantly differed between patients with and without HPS (P < 0·0094) (Fig 2). The diagnosis of HPS was confirmed by cytological or pathological assessment of all patients, except for one with extremely elevated serum ferritin who rapidly developed secondary engraftment failure, which was strongly indicative for HSCT–HPS. Bone marrow aspirates from 18 of 19 patients exhibited haemophagocytosis (the remaining one was diagnosed by a bone marrow biopsy post-mortem). This test was performed between day 10 and 27 d after transplantation to determine the cause of delayed neutrophil recovery or to predict the development of HPS. Bone marrow aspiration smear showed very hypocellular marrow with a prominent increase of activated macrophages phagocytosing red cells and myeloid precursors.

Table III.   Clinical features and outcome of HSCT–HPS patients.
PatientEngraftment (d)M in BM (%)Day of DxChimaerism (% donor)PIRFeverHSMLDH (i/u per litre)Ferritin (μg/l)InterventionResponse
  1. BM, bone marrow; CBT, cord blood transplantation; CS, corticosteroid; CsA, ciclosporin; Dx, diagnosis; HSM, hepatosplenomegaly; IVIG, intravenous immunoglobulin; M, macrophage; NA, not available; NE, not evaluated; PIR, pre-engraftment immune reactions; sEF, secondary engraftment failure.

  2. *Haemophagocytosis confirmed by post-mortem bone marrow biopsy.

117Not engrafted29·019NANoYesNo65NANoneNot engrafted
157Not engrafted66·019 98·4YesYesYes1255  1423CS/CsANot engrafted
161Day 19, sEFNA*NA*NA*YesYesNo1372  9397CSNot engrafted
164Day 13, sEF 1·025 96·2NoYesYes2444568500CS/CsAEngrafted
171Not engrafted43·027  0·2NoYesNo166  6434CSNot engrafted
181Not engrafted53·012 94·0NoYesYes587 18150CSNot engrafted
194Not engrafted24·013 98·8YesYesNo664 34200CSNot engrafted
198Not engrafted17·020 94·6YesYesNo208  2719CSNot engrafted
208Not engrafted21·513 99·6YesYesNo994 18640CS/VP16Not engrafted
209Not engrafted51·012 64·0NoYesNo174  1946IVIG/second CBTEngrafted
212Day 3030·511 63·6YesYesNE261  9339IVIGEngrafted
215Day 3318·521 99·8YesYesNo216  9808CSEngrafted
239Day 3025·022 96·4YesYesNE313  5212CSEngrafted
240Not engrafted15·011 99·0YesYesNE268 58824CSNot engrafted
242Not engrafted10·010 96·4YesYesNo143  3439IVIG/second CBTEngrafted
246Not engrafted15·021 18·2NoYesNo800  7740Second CBTEngrafted
274Not engrafted90·011 68·4YesYesNE367 20304Second CBTEngrafted
278Not engrafted34·010 99·4YesYesNo891111800NoneNot engrafted
280Not engrafted11·513100NoYesYes1634 67600CS/VP16Not engrafted
282Day 24, sEF58·020 92·6NoNoNo276  2464CSNot engrafted

Figure 2.  Comparison of highest value of serum ferritin by day 30 of CBT (with versus without HPS).

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Engraftment and chimaerism of HSCT–HPS patients

Of 14 patients with HPS who failed to engraft (primary engraftment failure), eight died within 28 d of CBT. Three patients achieved engraftment after day 29 of CBT (delayed engraftment). Secondary engraftment failure occurred in three patients. Chimaerism data were obtained from 18 out of 20 patients. Donor chimaerism was complete at the time of HPS diagnosis in 13 patients. Three and two patients had donor- and recipient-dominant chimaerism, respectively. An examination of bone marrow clot specimens using XY-FISH method (Ishida et al, 2007) confirmed that the activated macrophages in two patients with HPS who achieved complete donor chimaerism (patients 157 and 181; Table II) were donor-derived.

Concomitant clinical conditions of HSCT–HPS patients

Concomitant clinical conditions might be relevant to the development of HPS. Twelve of 20 patients had extant infections, most of which were bacteraemia (n = 10). The pathogens in eight patients were Gram-positive cocci, namely coagulase-negative Staphylococcus (n = 5), Enterococcus faecalis (n = 2) and Enterococcus faecium (n = 1), and Gram-negative rods, Stenotrophomonous maltophilia (n = 1) and Pseudomonous aeruginosa (n = 1) in two. Three patients were infected with CMV. Two had simultaneous bacteraemia and HHV-6 infection was found in one patient who developed limbic encephalitis. Among eight patients who had no documented infections, five developed transient atypical lymphocytosis soon after transplantation, two had PIR, and the remaining patient developed HPS without any concomitant clinical conditions.

Therapeutic interventions for HSCT–HPS and outcome

Corticosteroid (CS) was administered in 13 of 20 patients to reduce macrophage activation, CsA was administered in addition to CS in two patients and etoposide (VP-16) was also administered in addition to CS in two others. Four patients underwent a second rescue CBT, two of which were after the administration of high-dose intravenous immunoglobulin (IVIG). One patient was treated with IVIG alone. Two patients could not undergo specific treatments due to severe infections and/or severe organ damage. These efforts finally resolved the failed engraftment in eight patients. The prognosis was poor; 17 of 20 patients died (85%) and eight had died by 28 d after CBT. The causes of death were sepsis (n = 7), relapse of primary disease (n = 3), haemorrhage (n = 2), TMA (n = 2), GVHD (n = 2) and central nervous system complication (n = 1). As of December 2007, the median follow-up after CBT for surviving patients was 598 d (range, 26–1426 d). The Kaplan–Meier probability of overall survival at 4 years was 31·4% (95% confidence interval, 20·0–42·8%). The overall survival was significantly poorer for patients with HPS than without HPS (15·0% vs. 35·4%; P = 0·0002, Fig 3).


Figure 3.  Comparison of overall survival (with versus without HPS).

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Risk factors for HSCT–HPS

Univariate and multivariate analysis identified having fewer infused CD34+ cells as a significant risk factor for the development of HPS (P = 0·01 and 0·006 respectively, Table IV). Patients were subdivided into two groups according to the intensity of preparative regimen; those who received 16 mg/kg of BU or 8 Gy of TBI were categorized as ‘myeloablative’ (n = 18), and the others who received less intensive regimens were classified as ‘reduced-intensity’ (n = 101). The incidence of HPS was higher in the ‘reduced-intensity’ group, although it did not reach statistical significance (P = 0·17).

Table IV.   Risk factors of HPS development.
Univariate factors Cumulative incidenceP value
Age (<55 vs. ≥55 years) 19·3% vs. 14·5%0·50
Gender (mismatch versus match) 18·3% vs. 11·5%0·41
Blood type (mismatch versus match) 20·8% vs. 8·1%0·09
Underlying disease (non-lymphoma versus lymphoma) 17·1% vs. 16·3%0·85
Risk of underlying disease (standard versus high) 18·8% vs. 16·5%0·80
Preparative regimen (reduced-intensity versus myeloablative) 19·4% vs. 5·6%0·17
GVHD prophylaxis (TAC alone versus others) 18·4% vs. 7·7%0·35
Disparity of HLA-A, -B, -DR antigen (1 or 0 vs. 2-antigen mismatch) 18·8% vs. 16·5%0·89
GVH vector (2 vs. 1 or 0-mismatch) 18·4% vs. 12·5%0·41
HVG vector (1 or 0 vs. 2-antigen mismatch) 21·1% vs. 15·1%0·53
Number of infused total nucleated cells (<2·52 vs. ≥2·52 × 107/kg) 18·6% vs. 15·0%0·60
Number of infused CD34+ cells (<0·766 vs. ≥0·766 × 105/kg) 27·1% vs. 6·8%0·01
Multivariate factorsHazard ratio95% Confidence intervalP value
  1. GVH, graft-versus-host; HVG, host-versus-graft.

Blood type (mismatch versus match)2·800·79–9·860·11
Preparative regimen (reduced-intensity versus myeloablative)2·760·43–17·80·29
GVHD prophylaxis (TAC alone versus others)2·710·41–17·90·30
Number of infused CD34+ cells (<0·766 vs. ≥0·766 × 105/kg)4·481·54–13·10·006
GVH vector (1 or 0 vs. 2-antigen mismatch)1·480·52–4·210·46


  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References

This study of clinical manifestations, therapeutic management, outcome and risk factors for HPS after CBT is the largest to date. Our results demonstrated that HPS is an aggressive and devastating complication after CBT that closely correlates with delayed engraftment or failure, resulting in a poor OS. As far as we understand from the English medical literature (Table V), only 23 patients in 16 case reports appear to have developed HPS after autologous (n = 5) and allogeneic (n = 18) HSCT (Sokal et al, 1987; Levy et al, 1990; Reardon et al, 1991; Nagafuji et al, 1998; Sato et al, 1998; Takahashi et al, 1998; Ishikawa et al, 2000; Fukuno et al, 2001; Abe et al, 2002; Tanaka et al, 2004, 2007; Kishi et al, 2005a; Boelens et al, 2006; Ostronoff et al, 2006; Ishida et al, 2007; Koyama et al, 2007). Among 18 patients who received allogeneic HSCT, reduced-intensity preparative regimens were employed in nine patients and three underwent CBT. Thus, HPS has been considered a rare event after HSCT. The incidence of HPS following CBT in our study, however, was strikingly higher than previous reports have indicated.

Table V.   Occurrence of haemophagocytic syndrome among autologous and allogeneic haematopoietic stem cell transplantation reported in English medical literature.
Ref.Age (years)/ genderDisease Stem cell HLA matchPreparative regimenGVHD prophylaxisDay of DxPrincipal causeInterventionResponse
  1. ADM, adriamycin; ADV, adenovirus; ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; AML/MDS, acute myeloid leukaemia with multilineage dysplasia; Ara-C, cytosine arabinoside; ATG, anti-thymoglobulin; Auto, autologous; BM, bone marrow; BU, busulfan; CB, cord blood; CBDCA, carboplatin; CMV, cytomegalovirus; CS, corticosteroid; CsA, ciclosporin; CY, cyclophosphamide; Dx, diagnosis; (D), donor-derived; EBV-LPD, Epstein–Barr virus associated lymphoproliferative disorder; F, female; FA, Fanconi anaemia; Flu, fludarabine; HS, Hurler syndrome; HSV, herpes virus; ID, immunodeficiency; IVIG, intravenous immunoglobulin; JMML, juvenile myelomonocytic leukaemia; M, male; MCNU, ranimustine; Mel, melphalan; MM, multiple myeloma; MMF, mycophenolate mofetil; MRCNS, methicillin-resistant coagulase negative Staphylococcus; MRSA, methicillin-resistant Staphylococcus aureus; ND, not detected; NHL, non-Hodgkin lymphoma; NR, not referred; PBSC, peripheral blood stem cell; r, related; (R), recipient-derived; Ref, reference; RT, radiation therapy; ur, unrelated; sEF, secondary engraftment failure; sMTX, short-term methotrexate; TAC, taclorimus; TBI, total body irradiation; TSP, tespamine; VP16, etoposide.

(A) After autologous haematopoietic stem cell transplantation
Levy et al (1990) 6/FWilm tumourAuto BMLocal RT/Mel/ADM 28ADV-11IVIGNot engrafted
Nagafuji et al (1998)52/FAMLAuto PBSCBU/VP16/Ara-C 25CMVCS/IVIGNot resolved
Takahashi et al (1998)43/FNHLAuto PBSCCY/VP16/MCNU/CBDCA130LymphomaCS/IVIGNot resolved
Fukuno et al (2001)67/FNHLAuto PBSCCY/VP16/MCNU 12MRSACS/CsANot engrafted
Ostronoff et al (2006)54/FMMAuto PBSCMel 16NDCS/IVIGEngrafted
(B) After allogeneic haematopoietic stem cell transplantation
Sokal et al (1987) 8/MFAur-BM, 6/6CY/TBI 4CsA300HSV-1Resolved
Reardon et al (1991) 8/FALLr-BM, 6/6BU/CYCsA/CS 38ADVNot resolved
Sato et al (1998)40/FAMLur-BM, 6/6VP16/TBI 12CsA/sMTX 59CMVIVIG/VP16Not resolved
Ishikawa et al (2000)40/MAMLr-BM, 6/6CY/TBI 12CsA/sMTX 16 (D)NDCSEngrafted
Abe et al (2002)39/MNHLr-PBSC, 6/6TBI 2CsA/MMF 15 (D)NDCS/VP16Not engrafted
Abe et al (2002)50/FNHLr-PBSC, 5/6TBI 2CsA/MMF 56 (D)NDCSNot engrafted
Tanaka et al (2004) 7/FAML/MDSur-CB, 5/6CY/TBI 12/Ara-CCsA/sMTX 20 (D)MRCNSCS/second PBSCTEngrafted
Kishi et al (2005a)30/MAMLr-PBSC, 5/6BU/CYTAC 11NDCSNot resolved
Boelens et al (2006) 2/FHSr-BM/PBSC, 3/6Flu/Mel/TSP/ATGNR 35, sEF (D)EBV-LPDCSResolved
Ishida et al (2007) 2/MJMMLur-BM, 6/6Flu/Mel/BUTAC/sMTX 39, sEF (R)NRIVIG/second CBTEngrafted
Ishida et al (2007) 2/MJMMLur-CB, –Flu/Mel/VP16TAC 11 (R)NRIVIG/VP16Engrafted
Tanaka et al (2007)54/MAMLur-CB, 5/6CY/TBI 12/Ara-CCsA/sMTX 33, sEFNRCS/second CBTEngrafted
Koyama et al (2007) 9/–IDur-BM, 6/6Mel/TBI 6/ATGTAC/sMTX 10NRCS/IVIG/VP16Engrafted
Koyama et al (2007) 3/–AMLr-BM, 4/6Flu/TBI 12/Ara-C/VP16TAC/sMTX 10NRCS/IVIGEngrafted
Koyama et al (2007) 2/–ALLr-PBSC, –TBI 10/TSPTAC  8NRIVIG/VP16Not engrafted
Koyama et al (2007)16/–EBV-LPDr-PBSC, –Flu/Mel/ATGTAC  7NRCS/VP16Not engrafted
Koyama et al (2007) 9/–AMLur-BM, 6/6CY/TBI 12/TSPTAC/sMTX 12NRCS/VP16Engrafted
Koyama et al (2007) 3/–NHLr-BM, 3/6TBI 12/VP16/TSPTAC/sMTX/CS  5NRCS/VP16Engrafted

Multivariate analyses identified the dose of CD34+ cells as the only statistically significant risk factor. Given that a low dose of CD34+ cells can negatively affect the rate of engraftment and duration to neutrophil recovery, more infectious complications accompanying low CD34+ cell counts might be directly related to the onset of HPS. In our study cohort, the incidence of infectious complications arising during the early phase after transplant (by day 28) was higher in those with HPS than those without HPS (12/20 vs. 37/99; P = 0·027), suggesting that infections are associated with the likelihood of developing HPS. The high prevalence of elderly patients and of those with high-risk disease status might explain this high incidence of infections. Consequently, the poor outcome following development of HPS was mainly due to the engraftment failure and following exacerbation of infections.

The intriguing finding of our chimaerism analysis of patients with HPS was that of donor-dominancy in 16 of 18 patients. XY-FISH determined that the phagocytosing macrophages were also of the donor type in the two evaluated patients. These findings indicated that HPS after CBT might be mediated by donor-derived macrophages rather than host-derived, and that engraftment failure is not due to a simple rejection mechanism, but to factors and events that activates donor-derived macrophages and leads to the cascade of HPS. The incidence of HPS may have been underestimated in previous reports, as the reason for graft failure after transplantation had often not been described, especially for graft failure with donor-dominant chimaerism.

The postulated pathophysiology of HPS is that excessive cytokine production from T cells activate macrophages, leading to a substantial loss of haematopoietic cells. Although of great interest, the role of cytokine levels in the precise mechanism of HPS needs further study in the future. We previously described unique early immune reactions after CBT and termed them PIR (pre-engraftment immune reactions), i.e. non-infectious high-grade fever concomitant with eruption, diarrhoea and weight gain, starting on a median of day 9 after CBT (Kishi et al, 2005b). In the present study, 61% of the patients developed this syndrome, suggesting that immune cells became activated soon after transplantation. We regarded this syndrome as early onset of acute GVHD, where activated donor T cell secreted various cytokines (Reddy & Ferrara, 2003).

We also recently reported that the degree of HLA mismatch in the graft-versus-host direction was inversely associated with engraftment kinetics after RI-CBT (Matsuno et al, 2009). Paradoxically to the former notion of graft failure, the degree of HLA mismatch in the host-versus-graft direction had no impact on the engraftment kinetics. These findings propose a novel mechanism responsible for engraftment failure after CBT and HPS might be one of the relevant mechanisms. HLA disparity in the graft-versus-host direction may augment allo-immune reactions, which evoke hypercytokinaemia, macrophage activation, and occasionally result in establishment of HPS. Indeed, most of our patients received cord blood units with an HLA mismatch due to the limited availability of cord blood units with a sufficient cell dose, and received relatively less intensive GVHD prophylaxis using calcineurin inhibitor alone. Thus, the donor T cells in the grafts were more susceptible to stimuli of cytokines triggered by infections and tissue damage from preparative regimens. In most of the other reported series, methotrexate (MTX), anti-thymocyte globulin (ATG), steroid, or MMF was used along with calcineurin inhibitor for GVHD prophylaxis and there are little reports about HPS. More intensive immunosuppression may have a positive effect on preventing post-transplant immune reactions (Narimatsu et al, 2007b) and the development of HPS.

An optimal strategy has not been established to treat HPS, especially after HSCT. Although CS was administered at the discretion of the primary physician to 13 HPS patients to reduce macrophage activation, HPS was resolved in only three patients and all four who could tolerate a second rescue CBT achieved durable engraftment.

In conclusion, HPS is a significant complication associated with engraftment delay and failure following CBT. The development of HPS increased mortality rates after CBT, worsening the prognosis. The precise mechanism of HPS development after HSCT remains unknown, although several lines of evidence suggest that donor immune cells are critically involved and therefore a key. The identification of high risk patients, more intensified GVHD prophylaxis, close and careful follow-up and prompt differential diagnosis are important for managing HSCT–HPS and avoiding engraftment failure. More detailed data from patients who have undergone CBT as well as other types of transplantation are warranted to further understand the mechanisms behind the development of HSCT–HPS and to develop more effective prophylaxis and treatment for this complication.


  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References

The authors also wish to thank all physicians, nurses, pharmacists, data-managers and support personnel for their care of patients in this study. This work was also supported (in part) by a Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japanese Ministry of Health, Labour and Welfare.

Authors’ contribution

  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References

S. Takagi and K.M. performed research and extracted data; Y.O., K.O. and A.Y. reviewed histopathological findings; N.M. and S. Takagi performed statistical analysis; N.U. and S. Taniguchi reviewed study design and methods; K.I., A.H., M.T., H.Y., D.K., Y.M., E.K., S.S., T.M., S. Miyakoshi and S. Makino contributed to writing the paper.


  1. Top of page
  2. Summary
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Authors’ contribution
  8. Conflict-of-interest disclosure
  9. References
  • Abe, Y., Choi, I., Hara, K., Matsushima, T., Nishimura, J., Inaba, S., Nawata, H. & Muta, K. (2002) Hemophagocytic syndrome: a rare complication of allogeneic nonmyeloablative hematopoietic stem cell transplantation. Bone Marrow Transplantation, 29, 799801.
  • Ballen, K.K., Spitzer, T.R., Yeap, B.Y., McAfee, S., Dey, B.R., Attar, E., Haspel, R., Kao, G., Liney, D., Alyea, E., Lee, S., Cutler, C., Ho, V., Soiffer, R. & Antin, J.H. (2007) Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biology of Blood and Marrow Transplantation, 13, 8289.
  • Barker, J.N., Weisdorf, D.J., DeFor, T.E., Blazar, B.R., Miller, J.S. & Wagner, J.E. (2003) Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood, 102, 19151919.
  • Barker, J.N., Weisdorf, D.J., DeFor, T.E., Blazar, B.R., McGlave, P.B., Miller, J.S., Verfaillie, C.M. & Wagner, J.E. (2005) Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood, 105, 13431347.
  • Boelens, J.J., Lazo, G., Gaiser, J.F. & Wulffraat, N.M. (2006) Epstein–Barr virus-associated haemophagocytic lympho-histiocytosis after stem cell transplantation. Bone Marrow Transplantation, 38, 709710.
  • Brunstein, C.G., Barker, J.N., Weisdorf, D.J., DeFor, T.E., Miller, J.S., Blazar, B.R., McGlave, P.B. & Wagner, J.E. (2007) Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood, 110, 30643070.
  • Chao, N.J., Koh, L.P., Long, G.D., Gasparetto, C., Horwitz, M., Morris, A., Lassiter, M., Sullivan, K.M. & Rizzieri, D.A. (2004) Adult recipients of umbilical cord blood transplants after nonmyeloablative preparative regimens. Biology of Blood and Marrow Transplantation, 10, 569575.
  • Fernandez, M.N., Regidor, C., Cabrera, R., Garcia-Marco, J.A., Fores, R., Sanjuan, I., Gayoso, J., Gil, S., Ruiz, E., Little, A.M., McWhinnie, A. & Madrigal, A. (2003) Unrelated umbilical cord blood transplants in adults: early recovery of neutrophils by supportive co-transplantation of a low number of highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor. Experimental Hematology, 31, 535544.
  • Fukuno, K., Tsurumi, H., Yamada, T., Oyama, M. & Moriwaki, H. (2001) Graft failure due to hemophagocytic syndrome after autologous peripheral blood stem cell transplantation. International Journal of Hematology, 73, 262265.
  • Gooley, T.A., Leisenring, W., Crowley, J. & Storer, B.E. (1999) Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Statistics in Medicine, 18, 695706.
  • Henter, J.I., Elinder, G. & Ost, A. (1991) Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Seminars in Oncology, 18, 2933.
  • Hughes, W.T., Armstrong, D., Bodey, G.P., Bow, E.J., Brown, A.E., Calandra, T., Feld, R., Pizzo, P.A., Rolston, K.V., Shenep, J.L. & Young, L.S. (2002) 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clinical Infectious Diseases, 34, 730751.
  • Imashuku, S. (1997) Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. International Journal of Hematology, 66, 135151.
  • Ishida, H., Yoshida, H., Yoshihara, T., Ito, M. & Morimoto, A. (2007) Origin of macrophages involved in the development of allogeneic hematopoietic stem cell transplantation-associated hemophagocytic syndrome: observations on a patient with juvenile myelomonocytic leukemia. Bone Marrow Transplantation, 40, 701703.
  • Ishikawa, J., Maeda, T., Miyazaki, T., Manabe, N., Honda, S., Nishiura, T., Tomiyama, Y. & Matsuzawa, Y. (2000) Early onset of hemophagocytic syndrome following allogeneic bone marrow transplantation. International Journal of Hematology, 72, 243246.
  • Jacobsohn, D.A., Duerst, R., Tse, W. & Kletzel, M. (2004) Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children. Lancet, 364, 156162.
  • Kishi, Y., Kami, M., Murashige, N., Tanaka, Y., Haraguchi, K., Fujisaki, G., Kusumoto, S., Mori, S.I., Takaue, Y. & Tanosaki, R. (2005a) Hyperacute GVHD and emergence of peripheral CD3+ CD56+ T cells and activated natural killer cells are useful markers for early diagnosis of post-transplant hemophagocytic syndrome. Bone Marrow Transplantation, 35, 415417.
  • Kishi, Y., Kami, M., Miyakoshi, S., Kanda, Y., Murashige, N., Teshima, T., Kusumi, E., Hara, S., Matsumura, T., Yuji, K., Masuoka, K., Wake, A., Morinaga, S., Kanemaru, M., Hayashi, T., Tanaka, Y. & Taniguchi, S. (2005b) Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation, 80, 3440.
  • Komatsu, T., Narimatsu, H., Yoshimi, A., Kurita, N., Kusakabe, M., Hori, A., Murashige, N., Matsumura, T., Kobayashi, K., Yuji, K., Tanaka, Y. & Kami, M. (2007) Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan. Annals of Hematology, 86, 4954.
  • Koyama, M., Sawada, A., Yasui, M., Inoue, M. & Kawa, K. (2007) Encouraging results of low-dose etoposide in the treatment of early-onset hemophagocytic syndrome following allogeneic hematopoietic stem cell transplantation. International Journal of Hematology, 86, 466467.
  • Laughlin, M.J., Eapen, M., Rubinstein, P., Wagner, J.E., Zhang, M.J., Champlin, R.E., Stevens, C., Barker, J.N., Gale, R.P., Lazarus, H.M., Marks, D.I., Van Rood, J.J., Scaradavou, A. & Horowitz, M.M. (2004) Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. New England Journal of Medicine, 351, 22652275.
  • Levy, J., Wodell, R.A., August, C.S. & Bayever, E. (1990) Adenovirus-related hemophagocytic syndrome after bone marrow transplantation. Bone Marrow Transplantation, 6, 349352.
  • Matsumura, T., Narimatsu, H., Kami, M., Yuji, K., Kusumi, E., Hori, A., Murashige, N., Tanaka, Y., Masuoka, K., Wake, A., Miyakoshi, S., Kanda, Y. & Taniguchi, S. (2007) Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients. Biology of Blood and Marrow Transplantation, 13, 577583.
  • Matsuno, N., Wake, A., Uchida, N., Ishiwata, K., Araoka, H., Takagi, S., Tsuji, M., Yamamoto, H., Kato, D., Matsuhashi, Y., Seo, S., Masuoka, K., Miyakoshi, S., Makino, S., Yoneyama, A., Kanda, Y. & Taniguchi, S. (2009) Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation. Blood, doi:DOI: 10.1182/blood-2008-12-194696.
  • Misawa, M., Kai, S., Okada, M., Nakajima, T., Nomura, K., Wakae, T., Toda, A., Itoi, H., Takatsuka, H., Itsukuma, T., Nishioka, K., Fujimori, Y., Ogawa, H. & Hara, H. (2006) Reduced-intensity conditioning followed by unrelated umbilical cord blood transplantation for advanced hematologic malignancies: rapid engraftment in bone marrow. International Journal of Hematology, 83, 7479.
  • Miyakoshi, S., Yuji, K., Kami, M., Kusumi, E., Kishi, Y., Kobayashi, K., Murashige, N., Hamaki, T., Kim, S.W., Ueyama, J., Mori, S., Morinaga, S., Muto, Y., Masuo, S., Kanemaru, M., Hayashi, T., Takaue, Y. & Taniguchi, S. (2004) Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases. Clinical Cancer Research, 10, 35863592.
  • Miyakoshi, S., Kami, M., Tanimoto, T., Yamaguchi, T., Narimatsu, H., Kusumi, E., Matsumura, T., Takagi, S., Kato, D., Kishi, Y., Murashige, N., Yuji, K., Uchida, N., Masuoka, K., Wake, A. & Taniguchi, S. (2007) Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases. Transplantation, 84, 316322.
  • Nagafuji, K., Eto, T., Hayashi, S., Tokunaga, Y., Gondo, H. & Niho, Y. (1998) Fatal cytomegalovirus interstitial pneumonia following autologous peripheral blood stem cell transplantation. Fukuoka Bone Marrow Transplantation Group. Bone Marrow Transplantation, 21, 301303.
  • Narimatsu, H., Kami, M., Kato, D., Matsumura, T., Murashige, N., Kusumi, E., Yuji, K., Hori, A., Shibata, T., Masuoka, K., Wake, A., Miyakoshi, S., Morinaga, S. & Taniguchi, S. (2007a) Reduced dose of foscarnet as preemptive therapy for cytomegalovirus infection following reduced-intensity cord blood transplantation. Transplant Infectious Disease, 9, 1115.
  • Narimatsu, H., Terakura, S., Matsuo, K., Oba, T., Uchida, T., Iida, H., Hamaguchi, M., Watanabe, M., Kohno, A., Murata, M., Sawa, M., Miyamura, K. & Morishita, Y. (2007b) Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults. Bone Marrow Transplantation, 39, 3139.
  • Nishihira, H., Kato, K., Isoyama, K., Takahashi, T.A., Kai, S., Kato, S., Takanashi, M., Sato, N., Sato, H., Kitajima, K., Naoe, T. & Saito, H. (2003) The Japanese cord blood bank network experience with cord blood transplantation from unrelated donors for haematological malignancies: an evaluation of graft-versus-host disease prophylaxis. British Journal of Haematology, 120, 516522.
  • Ostronoff, M., Ostronoff, F., Coutinho, M., Calixto, R., Souto Maior, A.P., Sucupira, A., Florencio, R. & Tagliari, C. (2006) Hemophagocytic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma; successful treatment with high-dose intravenous immunoglobulin. Bone Marrow Transplantation, 37, 797798.
  • Reardon, D.A., Roskos, R., Hanson, C.A. & Castle, V. (1991) Virus-associated hemophagocytic syndrome following bone marrow transplantation. The American Journal of Pediatric Hematology/Oncology, 13, 305309.
  • Reddy, P. & Ferrara, J.L. (2003) Immunobiology of acute graft-versus-host disease. Blood Reviews, 17, 187194.
  • Rocha, V., Labopin, M., Sanz, G., Arcese, W., Schwerdtfeger, R., Bosi, A., Jacobsen, N., Ruutu, T., De Lima, M., Finke, J., Frassoni, F. & Gluckman, E. (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. New England Journal of Medicine, 351, 22762285.
  • Sato, M., Matsushima, T., Takada, S., Hatsumi, N., Kim, K., Sakuraya, M., Saito, T., Tamura, J., Karasawa, M., Murakami, H. & Naruse, T. (1998) Fulminant, CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation. Bone Marrow Transplantation, 22, 12191222.
  • Shpall, E.J., Quinones, R., Giller, R., Zeng, C., Baron, A.E., Jones, R.B., Bearman, S.I., Nieto, Y., Freed, B., Madinger, N., Hogan, C.J., Slat-Vasquez, V., Russell, P., Blunk, B., Schissel, D., Hild, E., Malcolm, J., Ward, W. & McNiece, I.K. (2002) Transplantation of ex vivo expanded cord blood. Biology of Blood and Marrow Transplantation, 8, 368376.
  • Sokal, E., Michel, M., Ninane, J., Latinne, D., De Bruyere, M. & Cornu, G. (1987) Bone marrow transplantation from an unrelated donor for Fanconi’s anaemia: two unusual complications. Bone Marrow Transplantation, 2, 99102.
  • Takahashi, T., Kanda, Y., Mori, M., Saito, T., Chiba, S., Mitani, K., Hirai, H. & Yazaki, Y. (1998) B cell lymphoma-associated hemophagocytic syndrome after PBSCT. Bone Marrow Transplantation, 21, 623625.
  • Takahashi, S., Iseki, T., Ooi, J., Tomonari, A., Takasugi, K., Shimohakamada, Y., Yamada, T., Uchimaru, K., Tojo, A., Shirafuji, N., Kodo, H., Tani, K., Takahashi, T., Yamaguchi, T. & Asano, S. (2004) Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood, 104, 38133820.
  • Tanaka, T., Matsubara, H., Adachi, S., Chang, H., Fujino, H., Higashi, Y., Yasumi, T., Kobayashi, M., Watanabe, K., Takahashi, M., Kobayashi, Y., Maruya, E., Saji, H. & Nakahata, T. (2004) Second transplantation from HLA 2-loci-mismatched mother for graft failure due to hemophagocytic syndrome after cord blood transplantation. International Journal of Hematology, 80, 467469.
  • Tanaka, H., Ohwada, C., Sakaida, E., Takeda, Y., Abe, D., Oda, K., Ozawa, S., Shimizu, N., Masuda, S., Cho, R., Nishimura, M., Saito, Y. & Nakaseko, C. (2007) Successful engraftment by second cord blood transplantation with reduced-intensity conditioning after graft rejection due to hemophagocytic syndrome following initial CBT. Bone Marrow Transplantation, 40, 995996.
  • Thiede, C., Florek, M., Bornhauser, M., Ritter, M., Mohr, B., Brendel, C., Ehninger, G. & Neubauer, A. (1999) Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transplantation, 23, 10551060.
  • Tsuda, H. (1997) Hemophagocytic syndrome (HPS) in children and adults. International Journal of Hematology, 65, 215226.
  • Uchida, N., Wake, A., Takagi, S., Yamamoto, H., Kato, D., Matsuhashi, Y., Matsumura, T., Seo, S., Matsuno, N., Masuoka, K., Kusumi, E., Yuji, K., Miyakoshi, S., Matsuzaki, M., Yoneyama, A. & Taniguchi, S. (2008) Umbilical cord blood transplantation after reduced-intensity conditioning for elderly patients with hematologic diseases. Biology of Blood and Marrow Transplantation, 14, 583590.
  • Yuji, K., Miyakoshi, S., Kato, D., Miura, Y., Myojo, T., Murashige, N., Kishi, Y., Kobayashi, K., Kusumi, E., Narimatsu, H., Hamaki, T., Matsumura, T., Kami, M., Fukuda, T., Masuo, S., Masuoka, K., Wake, A., Ueyama, J., Yoneyama, A., Miyamoto, K., Nagoshi, H., Matsuzaki, M., Morinaga, S., Muto, Y., Takeue, Y. & Taniguchi, S. (2005) Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma. Biology of Blood and Marrow Transplantation, 11, 314318.