Sinusoidal obstruction syndrome after allogeneic ... - Nature

Bone Marrow Transplantation (2016) 51, 403–409 © 2016 Macmillan Publishers Limited All rights reserved 0268-3369/16 www.nature.com/bmt

ORIGINAL ARTICLE

Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes K Yakushijin1, Y Atsuta2,3, N Doki4, A Yokota5, H Kanamori6, T Miyamoto7, C Ohwada8, K Miyamura9, Y Nawa10, M Kurokawa11, I Mizuno12, T Mori13, M Onizuka14, J Taguchi15, T Ichinohe16, H Yabe17, Y Morishima18, K Kato19, R Suzuki20 and T Fukuda21 This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, 2–30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P o 0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival. Bone Marrow Transplantation (2016) 51, 403–409; doi:10.1038/bmt.2015.283; published online 23 November 2015

INTRODUCTION Recently, many changes have been made to improve the outcomes of hematopoietic stem cell transplantation (HSCT), including improvements in conditioning regimen, donor selection and prophylaxis, and in the treatment of organ complications, GVHD and infection. Although HSCT outcomes are gradually improving, they are still unsatisfactory.1–5 Sinusoidal obstruction syndrome (SOS) is a well-known, potentially lethal complication of HSCT. Its reported incidence ranges from 5% to over 50%.6–9 This variability in SOS incidence may result from the use of different diagnostic criteria. SOS usually occurs within the first 3 weeks after HSCT as a result of endothelial and hepatic damage caused by the conditioning regimen.10 Because SOS is associated with low platelet count and ascites, it is usually diagnosed by clinical manifestations rather than liver biopsy. Painful hepatomegaly, jaundice, ascites and unexplained weight gain are the primary symptoms of SOS. Two major clinical diagnostic systems, proposed by groups in Seattle and Baltimore, are currently used.6–8 Recent

retrospective studies reported the incidence of SOS, according to the Seattle criteria, as 17.3 and 13.8%.11,12 SOS has a poor prognosis. Although patients with mild SOS improved with supportive care alone, the overall mortality in patients with severe SOS was 84.3%.11 There are no satisfactory drugs for prophylaxis and treatment of SOS, aside from defibrotide.13–17 Thus, SOS remains a critical problem following HSCT.18 Several studies from Western countries have reported the incidence of SOS in large patient samples, but none exist from Asian countries. To determine the incidence, risk factors and outcomes of clinically diagnosed SOS after allogeneic HSCT, we conducted a retrospective study among centers registered with the Japan Society for Hematopoietic Cell Transplantation (JSHCT). PATIENTS AND METHODS Data from 4171 patients (4290 transplants) who underwent HSCT between 1999 and 2010 in 117 participating centers registered with the JSHCT were

1 Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 2Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; 3Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan; 4Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; 5Department of Hematology, Chiba Aoba Municipal Hospital, Chiba, Japan; 6Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan; 7Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 8 Department of Hematology, Chiba University Hospital, Chiba, Japan; 9Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; 10Division of Hematology, Ehime Prefectural Central Hospital, Matsuyama, Japan; 11Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Tokyo, Japan; 12 Department of Hematology, Hyogo Cancer Center, Hyogo, Japan; 13Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; 14 Department of Hematology/Oncology, Tokai University School of Medicine, Kanagawa, Japan; 15Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Nagasaki University Hospital, Nagasaki, Japan; 16Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; 17Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Kanagawa, Japan; 18Division of Epidemiology and Prevention, Aichi Cancer Center Research, Nagoya, Japan; 19Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; 20Department of HSCT Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan and 21Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan. Correspondence: Dr K Yakushijin, Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017, Japan. E-mail: [email protected] Received 11 June 2015; revised 28 September 2015; accepted 16 October 2015; published online 23 November 2015

Sinusoidal obstruction syndrome after transplant K Yakushijin et al

404 retrospectively analyzed. Patient data were based on the Japan transplant outcomes registry database by the Transplant Registry Unified Management Program (TRUMP), confirmed in 2010.19 Additional data were collected regarding clinical presentation, diagnosis, treatment and follow-up of 618 cases that developed SOS. Treatment totals could exceed 100% because patients could have received multiple treatments. This study was approved by the institutional review boards of the National Cancer Center Hospital, Kobe University Hospital and the JSHCT.

included was 4290. The median age of the SOS patients was 43 years (range, 0–72); 346 patients (75%) received MAC and 108 (23%) reduced-intensity conditioning.

Table 1.

Characteristics of patients and transplants Total, n

Definitions of SOS The diagnosis of SOS was established clinically, based on the Seattle or Baltimore criteria. The Seattle criteria include the presence of at least two of the following, occurring within 30 days after HSCT: (i) jaundice, (ii) hepatomegaly and right upper-quadrant pain and (iii) ascites and/or unexplained weight gain (⩾2%).6 The modified Seattle criteria include the presence of at least two of the following within 20 days after HSCT: (i) hyperbilirubinemia ⩾ 2 mg/dL, (ii) hepatomegaly or right upperquadrant pain of liver origin and (iii) sudden weight gain (⩾2%).7 The Baltimore criteria include the development of hyperbilirubinemia ⩾ 2 mg/dL within 21 days after HSCT and at least two of the following: (i) hepatomegaly, (ii) ascites and (iii) weight gain (⩾5%).8 Severe SOS was defined as SOS with renal failure (serum creatinine ⩾ 3 × the upper limit of normal or dialysis dependency) and/or respiratory failure (oxygen saturation o90% in room air, requirement for oxygen supplementation or ventilator dependency) at diagnosis. Non-severe SOS was defined as SOS without renal or respiratory failure. A complete response (CR) for SOS was defined as the resolution of all signs and symptoms of the SOS diagnostic criteria.

Statistical analysis Categorical and continuous variables were compared using chi-squared tests and Student’s t-tests, respectively. The cumulative incidence of SOS was estimated by cumulative incidence functions, considering non-SOS death within 30 days after HSCT as a competing risk. Overall survival was estimated by the Kaplan–Meier method, with SOS treated as a timedependent variable, and compared using the log-rank test. In the multivariate analyses, the Fine and Gray’s model was used to identify risk factors for SOS development, and the Cox proportional hazard model was used to examine the effect of SOS on overall mortality, treating SOS as a time-dependent covariate. The variables considered were: the number of transplantations; patient’s age at transplantation (⩽15 years, 16–39 years and ⩾ 40 years); patient’s sex; donor–patient sex mismatch (matched male to female vs female to male); Eastern Cooperative Oncology Group (ECOG) performance status (PS; 0 or 1 vs 2–4); hepatitis B virus serostatus; hepatitis C virus (HCV) serostatus; disease status at conditioning (grouped as (i) standard risk disease: first or second CR of AML, first CR of ALL, first chronic phase of CML and refractory anemia or refractory anemia with ringed sideroblasts; vs (ii) advanced disease for all other AML, ALL, CML and myelodysplastic syndrome; vs (iii) other hematological malignancies; vs (iv) bone marrow failure, including aplastic anemia); the conditioning regimen (reduced-intensity conditioning vs myeloablative conditioning (MAC)) and the type of prophylaxis against GVHD (tacrolimus-based vs cyclosporine-based). Conditioning regimens were classified as myeloablative if TBI 48 Gy, oral busulfan (Bu) ⩾ 9 mg/kg, IV Bu ⩾ 7.2 mg/kg or melphalan 4140 mg/m2 was used (based on reports from the Center for International Blood and Marrow Transplant Research).20,21 SOS was maintained in the model. Other variables with P-values o0.1 were selected for the model, and were finally selected in a backward stepwise manner with a variable retention criterion of Po0.05. Statistical significance was defined as a two-tailed P-value o0.05. Statistical analyses were performed using Stata version 12 (StataCorp, College Station, TX, USA).

RESULTS Patient characteristics Characteristics of the 4290 patients who underwent HSCT are shown in Table 1, and characteristics of the SOS patients are detailed in Table 2. Overall, 747 patients received two or more transplantations. Of these, the previous HSCTs were allogeneic (n = 538), autologous (n = 188), syngeneic (n = 4) and unknown (n = 17). As some patients underwent previous transplantation before our study period, the total number of transplantations Bone Marrow Transplantation (2016) 403 – 409

Number of patients Median (range) age (years) Male: Female

4171 41 (0–76) 2524:1647

Age 0–15 years 16–39 years ⩾ 40 years

495 1429 2247

Diagnosis AML ALL MDS CML/MPD Lymphoid malignancy Plasmacytic malignancy Bone marrow failure ATL Other

1517 915 424 359 489 53 155 227 32

Number of transplants Conditioning regimen MAC (n = 2895) TBI containing Bu-containing Other

4290 2087 719 89

RIC (n = 1367) Flu-Bu-based Flu-CY-based Flu-Mel-based Other

421 137 551 258

Donor source Related (BM:PB:CB) Unrelated (BM:CB)

1166 (501:664:1) 3124 (2100:1024)

Number of transplants 1 2 or more

3543 747

ECOG PS 0–1 2–4

3049 552

GVHD prophylaxis TAC-based CSP-based Other

2268 1907 115

HBV positive negative

105 3546

HCV positive negative

45 3211

Abbreviations: ATL = adult T-cell leukemia; BM = bone marrow; Bu = busulfan; CB = cord blood; CSP = cyclosporine; CY = cyclophosphamide; ECOG = Eastern Cooperative Oncology Group; Flu = fludarabine; HBV = hepatitis B virus; HCV = hepatitis C virus; MAC = myeloablative conditioning; MDS = myelodysplastic syndrome; Mel = melphalan; MPD = myeloproliferative disease; PB = peripheral blood; PS = performance status; RIC = reduced-intensity conditioning; TAC = tacrolimus.

© 2016 Macmillan Publishers Limited


405 Table 2.

Characteristics of patients with SOS

Number of patients Median (range) age (years) Male: Female

Severe SOS

Non-severe SOS

Total SOS, n (%)

168 46 (0–72) 101:67

294 41 (0–70) 172:122

462 (10.8%) 43 (0–72) 273:189

Age 0–15 years 16–39 years ⩾ 40 years

15 52 101

58 81 155

73 (14.2%) 133 (9.0%) 256 (11.1%)

69 30 20 11 20 3 4 10 1

106 62 30 35 34 1 6 16 4

175 (11.1%) 92 (9.8%) 50 (11.5%) 46 (12.6%) 54 (11.0%) 4 (7.4%) 10 (6.4%) 26 (11.2%) 5 (13.5%)

123 81 38 4

223 139 75 9

346 (12.0%) 220 (10.5%) 113 (15.7%) 13 (14.6%)

17 5 16 5

18 3 31 13

108 (7.9%) 35 (8.3%) 8 (5.8%) 47 (8.5%) 18 (7.0%)

19:23 75:51

12:51 132:75

Number of Transplants 1 2 or more

127 41

237 64

364 (10.3%) 105 (14.1%)

ECOG PS 0–1 2–4

118 27

171 72

289 (9.5%) 99 (17.9%)

86 75 7

141 147 6

227 (10.0%) 222 (11.6%) 13 (11.3%)

5 126

7 233

12 (11.4%) 359 (10.1%)

Diagnosis AML ALL MDS CML/MPD Lymphoid malignancy Plasmacytic malignancy Bone marrow failure ATL Other Conditioning regimen MAC TBI containing Bu-containing Other RIC Flu-Bu-based Flu-CY-based Flu-Mel-based Other Donor source Related (BM:PB) Unrelated (BM:CB)

GVHD prophylaxis TAC-based CSP-based Other HBV positive negative HCV positive negative

2 0

7 332

55:74 207:126

9 (25.0%) 332 (10.4%)

Abbreviations: ATL = adult T-cell leukemia; BM = bone marrow; Bu = busulfan; CB = cord blood; CSP = cyclosporine; CY = cyclophosphamide; ECOG = Eastern Cooperative Oncology Group; Flu = fludarabine; HBV = hepatitis B virus; HCV = hepatitis C virus; MAC = myeloablative conditioning; MDS = myelodysplastic syndrome; Mel = melphalan; MPD = myeloproliferative disease; PB = peripheral blood; PS = performance status; RIC = reducedintensity conditioning; SOS = sinusoidal obstruction syndrome; TAC = tacrolimus.

Clinical presentation of SOS Among 618 patients, 156 did not meet the SOS criteria described above. The clinical diagnosis of SOS was based on the Seattle © 2016 Macmillan Publishers Limited

criteria (cumulative incidence, 10.8%; 95% confidence interval (CI), 9.9–11.7); 107 of the 462 patients also met the Baltimore criteria. The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3% (95% CI, 8.4–10.2). The incidence of SOS remained around 10% over time (10.8%, 95% CI 9.3–12.4% between 1999 and 2004, and 10.8%, 95% CI 9.6–11.9% between 2005 and 2010). Clinical characteristics of patients at the time of SOS diagnosis are shown in Table 3. The median time from transplantation to SOS diagnosis was 12 days (range, − 2 to 30). Among the 462 patients who developed SOS, 168 (36%) had severe SOS with renal (25%) and/or respiratory (23%) failure. Severe SOS patients had higher levels of total bilirubin (P = 0.005), ascites (P = 0.01) and encephalopathy (P o 0.001) at diagnosis. Risk factors predicting SOS development Multivariate analyses for SOS development are shown in Table 4. Patients who received two or more HSCTs were at an increased risk of SOS compared with those who had only one transplant (relative risk (RR), 1.32; P = 0.03). Compared with younger patients (⩽15 years), patients aged 16–39 years had a significantly lower risk of SOS (RR, 0.68; P = 0.007), and the risk for those ⩾ 40 years was not different (RR, 0.93; P = 0.62). Patients with a PS of 2–4 had almost twice the risk of SOS (RR, 1.88; P o 0.001) compared with those with a PS of 0–1. HCV-seropositivity was associated with an increased risk of SOS (RR, 2.19; P = 0.02), as was advanced disease status (RR, 1.70; P o 0.001). MAC regimens (TBI-based: RR 1.73; P o0.001 and Bu-based: RR 2.43; P o 0.001) were associated with a higher risk of SOS compared with reduced-intensity conditioning regimen. Of 719 patients who received MAC with Bu, 410 received Bu orally and 309 intravenously. Patients who received oral Bu had a relatively lower risk of SOS development compared with patients who received IV Bu in this retrospective study (RR 0.76; 95%CI, 0.49–1.19, P = 0.23). SOS treatment Questionnaire results revealed that attending physicians used the following therapeutic agents: fresh frozen plasma (37%), ursodeoxycholic acid (37%), antithrombin III (33%), low MW heparin (29%), prostaglandin E1 (16%), heparin (13%), recombinant thrombomodulin (12%), tissue plasminogen activator (10%) and others. Defibrotide, which was not approved in Japan, was used in only 5% of patients. Response to SOS treatment Table 5 shows the CR rate for SOS. Overall, the SOS CR rate was 45%, but it was lower in those who fulfilled both the Seattle and Baltimore criteria at diagnosis (23%; P o 0.001). In patients with severe SOS, the CR rate among those fulfilling both criteria was only 10%. Overall survival The median follow-up period for survivors was 1357 days (range, 2–4870). In SOS patients, survival at day 100 was 32%; in patients without SOS, it was 76% (P o 0.001; Figure 1a). Patients meeting both the Seattle and Baltimore criteria (n = 107) had a poor prognosis (Figure 1b). Overall survival at day 100 was only 15% for those fulfilling both criteria at the time of SOS diagnosis. Overall survival was significantly lower for patients with severe SOS than for those with non-severe SOS. Overall survival at day 100 was 44% for non-severe (n = 294) and 15% for severe SOS (n = 168) (P o 0.001; Figure 1c). We divided the patients into four groups according to their condition at SOS diagnosis: (i) non-severe SOS patients diagnosed by the Seattle criteria alone (‘Non-severe SOS, Seattle’; n = 245), (ii) non-severe SOS patients who fulfilled both criteria (‘Non-severe SOS, Baltimore’; n = 49), (iii) severe SOS patients diagnosed by the Bone Marrow Transplantation (2016) 403 – 409


406 Table 3.

Clinical presentation at diagnosis of SOS Adult (16 – years)

Children (0–15 years) Severe SOS (n = 15) Median time to diagnosis (range) Median T-Bil (mg/ dL, range) Weight gain Jaundice ( ⩾ 2mg/ dL) Hepatomegaly Right upper abdominal pain Ascites Encephalopathy Respiratory failure Renal failure

16 (6–26)

Non-severe SOS (n = 58)

Children total (n = 73)

Severe SOS (n = 153)


14.5 (2–30)

15 (2–30)

12 (0–28)

10.5 (−2–30)

2.9 (0.4–27.8)

2.2 (0.8–11.3)

1.5 (0.1–25.2)

1.8 (0.1–25.2)

13 (87%) 11 (73%)

46 (79%) 25 (43%)

59 (81%) 36 (49%)**

13 (87%) 11 (73%)

48 (83%) 35 (60%)

61 (84%) 46 (63%)

10 2 9 7

31 2 0 0

41 4 9 7

(67%) (13%) (60%) (47%)

(53%) (3%) (0%) (0%)

(56%) (5%) (12%) (10%)

All patients

Adult total (n = 389)

2.4 (0.4–30.1)

Total (n = 462)

12 (−2–30)

12 (−2–30)

2.5 (0.4–30.1)**

2.4 (0.1–30.1)**

139 (91%) 120 (78%)

223 (94%) 162 (69%)

362 (93%) 282 (72%)**

421 (91%) 317 (69%)*

93 (61%) 84 (55%)

127 (54%) 136 (58%)

220 (57%) 220 (57%)

281 (61%) 266 (58%)

181 51 105 101

222 55 114 108

84 41 105 101

(55%) (27%) (69%) (66%)

97 10 0 0

(41%) (4%) (0%) (0%)

(47%)* (13%)* (27%) (26%)

(48%)** (12%)* (25%) (23%)

Abbreviation: SOS = sinusoidal obstruction syndrome. *Po0.01, **Po 0.05 for the comparison of severe vs non-severe SOS.

Table 4.

Multivariate analysis of factors affecting SOS development n

RR

95% CI

3542 1 747 1.32 1.03–1.71

Age 0–15 16–39 40–

512 1 1473 0.68 0.51–0.90 2305 0.93 0.71–1.22

Performance status 0–1 2–4

3049 1 552 1.88 1.47–2.40 o0.001

HCV Negative Positive

3211 1 45 2.19 1.13–4.26

0.03


Total SOS (n = 462)

37/168 (22%) 6/58 (10%)

169/294 (57%) 19/49 (39%)

206/462 (45%) 25/107 (23%)

0.007 0.62

0.02

1 1.73 1.32–2.27 o0.001 2.43 1.83–3.22 o0.001 1.82 1.02–3.24 0.04

Abbreviations: Bu = busulfan; CI = confidence interval; HCV = hepatitis C virus; HSCT = hematopoietic stem cell transplantation; MAC = myeloablative conditioning; MDS = myelodysplastic syndrome; RIC = reducedintensity conditioning; SOS = sinusoidal obstruction syndrome.

Seattle criteria alone (‘Severe SOS, Seattle’; n = 110) and (iv) severe SOS patients who fulfilled both criteria (‘Severe SOS, Baltimore’; n = 58). Overall survival at day 100 in the four groups was 47%, 28%, 21% and 5%, respectively. The prognoses of the four groups were significantly different (P o0.001, Figure 1d). ‘Non-severe SOS, Seattle’ patients had the best prognosis and ‘Severe SOS, Baltimore’ patients had the worst prognosis. Bone Marrow Transplantation (2016) 403 – 409

Total (n = 462) Baltimore criteriaa

Severe SOS (n = 168)

Abbreviation: SOS = sinusoidal obstruction syndrome. Data are presented as CR/Total (%). aPatients who fulfilled the Baltimore criteria.

Disease status AML/ALL/CML/MDS, Standard 1416 1 risk AML/ALL/CML/MDS, High risk 1729 1.70 1.34–2.16 o0.001 Other hematological malignancy 907 1.07 0.49–2.33 0.87 Bone marrow failure 157 1.52 1.15–2.02 0.003 1367 2087 719 89

Complete response rate of SOS

P value

Number of HSCT 1 2 or more

Conditioning RIC MAC, TBI containing MAC, Bu-containing MAC, other

Table 5.

The main causes of death in all SOS patients were SOS-related mortality (49%) and disease progression (18%). The proportion of patients who died of SOS-related causes was significantly higher in severe SOS than in non-severe SOS (61% vs 41%, P o0.001). Multivariate analyses for mortality The multivariate model, adjusted for other significant variables affecting survival, revealed that SOS was highly associated with overall mortality (hazard ratio, 2.09; 95% CI, 1.84–2.36; P o0.001). DISCUSSION Here, the incidence of SOS in Japan was 10.8%, similar to that reported in Western countries.11,12 While the reported incidence of acute GVHD is lower in Japanese than in Caucasian patients,22 ethnicity was not associated with SOS incidence. Coppell et al.11 reported that the overall incidence of SOS has increased because of transplantation diversity. However, Carreras et al.12 reported a decrease because of the introduction of reduced-intensity conditioning and improvement of MAC procedures using alternative donors. We did not detect a change in SOS incidence over time. We focused on patients clinically diagnosed with SOS using representative criteria (the Seattle and Baltimore criteria6,8), because liver biopsy is difficult to conduct and SOS diagnosis is usually made on the basis of such clinical diagnostic criteria. However, the clinical findings of SOS are not specific, and physicians must differentiate SOS from other diagnoses, such as cholangitis lenta, infectious liver disease, acute GVHD or drug toxicity.23 Although our retrospective study did not include biomarker analyses, some are thought to be useful for diagnosing © 2016 Macmillan Publishers Limited


407

a

b

Overall survival

1.00

Overall survival

1.00 P < 0.001 0.75

0.75

Patients who did not develop SOS (n = 3828)

0.50

0.50

Patients who developed SOS (n = 462)

0.25

0.25 Baltimore criteria** (n = 107)

0.00

0.00 0

200

400

600

800

0

200

Days after HSCT

c

d

Overall survival

1.00

600

400

800

Days after HSCT

Overall survival

1.00 P < 0.001

P < 0.001

0.75

0.75

0.50

0.50 Non-severe SOS, Seattle* (n = 245) Non-severe SOS (n = 294)

0.25

0.25

Non-severe SOS, Baltimore** (n = 49) Severe SOS (n = 168) Severe SOS, Seattle* (n = 110)

0.00

0.00 0

200

400

600

800

Days after HSCT

Severe SOS, Baltimore** (n = 58)

0

200

400

600

800

Days after HSCT

Figure 1. The probabilities of overall survival. Overall survival in patients with SOS following HSCT was significantly lower than that in patients who underwent HSCT but did not develop SOS (a). Overall survival in SOS patients who fulfilled both the Baltimore and Seattle criteria at diagnosis was very low (b). Overall survival in severe SOS patients was significantly lower than that in non-severe SOS patients (c). When SOS patients were divided into four groups according to their condition at the time of SOS diagnosis, (i) ‘Non-severe SOS, Seattle’ (non-severe SOS patients diagnosed by the Seattle criteria alone), (ii) ‘Non-severe SOS, Baltimore’ (non-severe SOS patients who fulfilled both the Baltimore and Seattle criteria at diagnosis), (iii) ‘Severe SOS, Seattle’ (severe SOS patients diagnosed by the Seattle criteria alone) and (iv) ‘Severe SOS, Baltimore’ (severe SOS patients who fulfilled both the Baltimore and Seattle criteria at diagnosis), the prognoses of the four groups were significantly different (d). *Patients who were diagnosed with SOS by the Seattle criteria but did not fulfill the Baltimore criteria at diagnosis. **Patients who fulfilled both the Baltimore and Seattle criteria at diagnosis.

SOS. Recent research has identified plasminogen activator inhibitor type 1,24 procollagen type III,25 antithrombin and protein C26 as potential biomarker candidates for SOS. However, none appears to be SOS-specific. Further research is required to detect specific SOS biomarkers. In our study, the number of HSCTs, age, poor PS and MAC regimen, especially Bu-containing regimens, were risk factors for SOS, as previously reported.7,9,12,18,27,28 Contrary to previous reports, patients receiving oral Bu here had a relatively lower risk of SOS development than did patients receiving IV Bu. We think this difference is because: (i) this was a retrospective study, which contains biases, and (ii) we do not routinely adjust Bu dose after monitoring the drug concentration. The RR of SOS in patients aged ⩾ 40 years was similar to that in patients aged 0–15 years, but it was lower for those between 16 and 39 years of age. Our study also indicated that disease status and HCV infection were associated with an increased risk of SOS. Although we recently reported the impact of HCV infection on clinical outcomes in HSCT recipients, various criteria for SOS diagnosis were used by the attending physicians.29 In this study, SOS diagnosis was based on the Seattle criteria and verified by collecting additional data from 117 centers. Although the number of HCV-seropositive patients was small, multivariate analyses confirmed HCV-positivity as an © 2016 Macmillan Publishers Limited

independent risk factor for SOS. Pretransplantation liver disease is also a major reported risk factor.7,9,12,18,28 Because information on pretransplantation comorbidities was only recently added to the TRUMP database, we did not investigate pretransplant liver disease, to avoid bias. Use of gemtuzumab ozogamicin is also a risk factor for SOS.18,28,30,31 However, we do not have data on gemtuzumab ozogamicin use, as it is rarely used before transplantation in Japan. The overall CR rate was 45%. The CR rate of patients diagnosed by both the Seattle and the Baltimore criteria was only 23%. Richardson et al.15 reported that the CR rate for SOS diagnosed by the Baltimore criteria and treated with defibrotide was 46%. For patients with severe SOS fulfilling the Baltimore criteria at diagnosis, the CR rate was extremely low (10%) in our cohort, similar to that for historical controls without defibrotide treatment.11 However, the CR rate was 19–29% among patients with renal and/or respiratory failure treated with defibrotide,15 suggesting that defibrotide might prevent SOS progression and improve clinical outcomes. In Japan, defibrotide is not available, except for compassionate use or clinical trials,32 even though it is the only agent recommended for SOS prophylaxis and treatment by the BCSH/ BSBMT guidelines.28 No SOS patients in our cohort received Bone Marrow Transplantation (2016) 403 – 409


408 defibrotide for SOS prophylaxis. Recombinant thrombomodulin is approved and widely used to treat disseminated intravascular coagulation in Japan. Recent reports suggest that thrombomodulin is efficacious for SOS treatment,33,34 but it might be associated with intracranial hemorrhage.35 Although thrombomodulin may be a reasonable alternative SOS treatment, this should be confirmed by a prospective study. We divided the patients in our study into four groups according to SOS severity and diagnostic criteria. We found that overall survival was significantly different among the four groups (Figure 1d). Patients in the ‘Non-severe SOS, Seattle’ group had the best prognosis, while those in ‘Severe SOS, Baltimore’ group had the worst prognosis. This classification might be a useful system for grading disease severity and prognosis upon diagnosis of SOS. Multiorgan failure has been used to prospectively define the severity of SOS in clinical studies using defibrotide therapy.15 The Baltimore criteria are more stringent than the Seattle criteria, and the mortality rate due to SOS among patients diagnosed using the Baltimore criteria is high.12 Thus, our classification into these four groups is reasonable. Several grading systems have been reported.7,9,36,37 Chao36 proposed an alternative grading system based on bilirubin levels and liver function test results, as well as rate of change, amount and pace of weight gain, presence of hepatomegaly and overall symptoms. Recently, Carreras37 proposed a modified grading system and practical treatment strategies according to the grade. Although our database did not include the rate and the pace of clinical changes, renal and/or respiratory failure and meeting the Baltimore criteria suggest rapid deterioration of SOS. This study has several limitations because of its retrospective nature. First, patient background data, including details of SOS prophylaxis, history of pretransplantation liver injury, antibiotic use and prior abdominal irradiation, were not available. Second, the presence of SOS was based on the records of patients clinically diagnosed by attending physicians rather than by a central review panel. However, our results are validated by the large number of patients included in this study, as it was the largest nationwide survey of SOS in an Asian country. In conclusion, this retrospective survey showed that the cumulative incidence of SOS in the Japanese population was 10.8%, similar to previous reports from Western countries.11,12 Overall survival of these patients was quite low, and was lowest in patients with severe SOS. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.

4

5

6

7

8

9

10

11

12

13

14

15

16

17

CONFLICT OF INTEREST The authors declare no conflict of interest. 18

ACKNOWLEDGEMENTS We appreciate the contributions of all of the physicians and data managers at the centers who provided important data regarding transplantation to the JSHCT, the Japan Marrow Donor Program (JMDP) and the Japan Cord Blood Bank Network (JCBBN). We also thank all of the members of the TRUMP committees of the JSHCT, JMDP and JCBBN for their dedication and contribution to data management.

19

20

REFERENCES 1 Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101. 2 Horan JT, Logan BR, Agovi-Johnson MA, Lazarus HM, Bacigalupo AA, Ballen KK et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol 2011; 29: 805–813. 3 Remberger M, Ackefors M, Berglund S, Blennow O, Dahllof G, Dlugosz A et al. Improved survival after allogeneic hematopoietic stem cell transplantation in

Bone Marrow Transplantation (2016) 403 – 409

21

22

23

recent years. A single-center study. Biol Blood Marrow Transplant 2011; 17: 1688–1697. Kurosawa S, Yakushijin K, Yamaguchi T, Atsuta Y, Nagamura-Inoue T, Akiyama H et al. Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia. Bone Marrow Transplant 2013; 48: 1198–1204. Kurosawa S, Yakushijin K, Yamaguchi T, Atsuta Y, Nagamura-Inoue T, Akiyama H et al. Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry. Bone Marrow Transplant 2013; 48: 529–536. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116–122. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Venoocclusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783. Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998; 92: 3599–3604. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002; 22: 27–42. Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant 2010; 16: 157–168. Carreras E, Diaz-Beya M, Rosinol L, Martinez C, Fernandez-Aviles F, Rovira M. The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant 2011; 17: 1713–1720. Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 2012; 379: 1301–1309. Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100: 4337–4343. Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant 2010; 16: 1005–1017. Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111: 1122–1129. Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998; 92: 737–744. Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectivesa position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2015; 50: 781–789. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol 2007; 86: 269–274. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M et al. Reducedintensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009; 15: 367–369. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633. Morishima Y, Kawase T, Malkki M, Morishima S, Spellman S, Kashiwase K et al. Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1197–1203. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995; 85: 3005–3020.



409 24 Lee JH, Lee KH, Kim S, Seol M, Park CJ, Chi HS et al. Plasminogen activator inhibitor-1 is an independent diagnostic marker as well as severity predictor of hepatic veno-occlusive disease after allogeneic bone marrow transplantation in adults conditioned with busulphan and cyclophosphamide. Br J Haematol 2002; 118: 1087–1094. 25 Heikinheimo M, Halila R, Fasth A. Serum procollagen type III is an early and sensitive marker for veno-occlusive disease of the liver in children undergoing bone marrow transplantation. Blood 1994; 83: 3036–3040. 26 Tabbara IA, Ghazal CD, Ghazal HH. Early drop in protein C and antithrombin III is a predictor for the development of venoocclusive disease in patients undergoing hematopoietic stem cell transplantation. J Hematother 1996; 5: 79–84. 27 Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica 2005; 90: 1396–1404. 28 Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A et al. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol 2013; 163: 444–457. 29 Nakasone H, Kurosawa S, Yakushijin K, Taniguchi S, Murata M, Ikegame K et al. Impact of hepatitis C virus infection on clinical outcome in recipients after allogeneic hematopoietic cell transplantation. Am J Hematol 2013; 88: 477–484. 30 Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive


31

32

33

34

35

36 37

disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003; 102: 1578–1582. McKoy JM, Angelotta C, Bennett CL, Tallman MS, Wadleigh M, Evens AM et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res 2007; 31: 599–604. Yakushijin K, Matsui T, Okamura A, Yamamoto K, Ito M, Chihara K. Successful treatment with defibrotide for sinusoidal obstruction syndrome after hematopoietic stem cell transplantation. Kobe J Med Sci 2005; 51: 55–65. Ikezoe T, Takeuchi A, Taniguchi A, Togitani K, Yokoyama A. Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome. Bone Marrow Transplant 2011; 46: 616–618. Nakamura D, Yoshimitsu M, Kawada H, Inoue H, Kuroki T, Kaieda T et al. Recombinant human soluble thrombomodulin for the treatment of hepatic sinusoidal obstructive syndrome post allogeneic hematopoietic SCT. Bone Marrow Transplant 2012; 47: 463–464. Tsubokura M, Yamashita T, Inagaki L, Kobayashi T, Kakihana K, Wakabayashi S et al. Fatal intracranial hemorrhage following administration of recombinant thrombomodulin in a patient after cord blood transplantation. Bone Marrow Transplant 2011; 46: 1030–1031. Chao N. How I treat sinusoidal obstruction syndrome. Blood 2014; 123: 4023–4026. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol 2015; 168: 481–491.

Bone Marrow Transplantation (2016) 403 – 409