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Sinusoidal obstructive syndrome prophylaxis with recombinant human soluble thrombomodulin is feasible in gemtuzumab ozogamicin-treated patients undergoing allogeneic hematopoietic cell transplantation

Bone Marrow Transplantation volume 52, pages 1068–1070 (2017)Cite this article

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Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT). SOS is characterized by painful hepatomegaly, jaundice, ascites, fluid retention and weight gain.1 Prior exposure to gemtuzumab ozogamicin (GO) is recognized as a significant pre-transplant risk factor for the development of severe SOS after HSCT.2 It has also been shown that patients who undergo HSCT shortly after being treated with GO (within 3.5 months) are at greatest risk of SOS.2 Although defibrotide (DF) has been shown to be effective as a prophylaxis against and treatment for SOS,3 it is not yet available for routine clinical use in Japan. Recombinant human soluble thrombomodulin (rTM), which comprises the active extracellular domain of thrombomodulin, inactivates coagulation by binding to thrombin.4 A recent phase III trial examining the efficacy and safety of rTM showed that it significantly improved disseminated intravascular coagulation (DIC) associated with hematological malignancies or infections.5 rTM also exhibits anti-inflammatory activity due to its ability to dampen proinflammatory mediator activity.6 Recently, a few case reports have described that rTM is effective against SOS in adult patients.7, 8 However, little is known about its usefulness for prophylaxis of rTM in the patients who are at high risk of SOS. Here, we report the cases of four patients who received HSCT shortly after GO treatment with or without prophylactic rTM.

Between April 2010 and December 2015, two males and two females (median age, 3 years; range, 1–13 years) with relapsed or refractory AML were treated with fludarabine, cytarabine, G-CSF and GO [FLAG-IDA-GO] as re-induction therapy prior to HSCT (Table 1). The protocol involved 30 mg/m2 of fludarabine and 2 g/m2 of cytarabine (days 2–6), 10 mg/m2 of idarubicin (day 6) and 300 μg/m2 of G-CSF (days 1–6). GO was administered at a dose of 3 mg/m2 on day 7 of treatment. All patients except patient 1 (M7) had AML subtype M2 according to the French-American-British classification. Of these patients, patient 2 had primary refractory AML, and the other three patients (patients 1, 3 and 4) relapsed <12 months after the initial diagnosis. All patients achieved CR after the FLAG-IDA-GO treatment. The median interval between the GO treatment and day 0 of the HSCT was 51 days (range, 36–79 days). Patient 1 underwent a haploidentical HSCT from his father. The other three patients (patients 2, 3 and 4) underwent unrelated cord blood transplants from HLA-2 or -3 locus-mismatched donors. All of the patients except patient 1 received full-intensity conditioning cyclophosphamide (120 mg/kg) per TBI (12 Gy) (patients 2, 3 and 4). Patient 1 received busulfan (19.2 mg/kg), melphalan (6 mg/kg) and fludarabine (4 mg/kg) due to his age (1 year). The prophylaxis for GvHD consisted of tacrolimus (0.02 mg/kg/day) and short-term methotrexate (days 1, 3 and 6: 7.5, 5 and 5 mg/m2, respectively). Ursodeoxycholic acid and low MW heparin (LMWH) were administered as prophylactic treatments against SOS in cases 1 and 2. The other patients received prophylactic rTM (380 U/kg per day for 7 days, from days 7 to 13) as well as ursodeoxycholic acid and LMWH as prophylactic treatments against SOS because patients 1 and 2 developed SOS around day 10. SOS was defined according to the modified Seattle criteria.9 The severity grading of a suspected SOS (mild, moderate, severe and very severe) was determined based on new EBMT criteria.10

Table 1 Summary of patients and treatment characteristics
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Acknowledgements

Author contributions

SY and RM designed and performed the research, and wrote the paper; SY, RM, SY, RK, ON, KM, FS, KA, DT and KI collected and managed clinical data.

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  1. Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan

    S Yamamoto, R Matsuno, Y Sugishita, R Kaneko, N Okamoto, M Koganesawa, S Fujita, K Akiyama, D Toyama & K Isoyama

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  1. S Yamamoto
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Correspondence to S Yamamoto.

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Yamamoto, S., Matsuno, R., Sugishita, Y. et al. Sinusoidal obstructive syndrome prophylaxis with recombinant human soluble thrombomodulin is feasible in gemtuzumab ozogamicin-treated patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 52, 1068–1070 (2017). https://doi.org/10.1038/bmt.2017.65

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