Incidence, Risk Factors and Outcomes of Veno-Occlusive Disease / Sinusoidal Obstruction Syndrome (VOD/SOS) in Children with Severe Thalassemia (ST) Conditioned with Busulfan- Cyclophosphamide (Bu-Cy) Based Regimen
Authors: Ramprakash Stalin , Agarwal Rajat Kumar , Raghuram C P , Mehta Pallavi , Trivedi Deepa , Marwah Priya , Soni Rajpreet , Dhanya Rakesh , Faulkner Lawrence 
Published: November 2019

Introduction

Sinusoidal obstruction syndrome / Veno-occlusive disease (VOD/SOS) is one of the major complication which increases morbidity and mortality following allogeneic stem cell transplant. Busulfan-cyclophosphamide (Bu-Cy) based conditioning regimen, use of busulfan and patients with thalassaemia are considered to be among the important risk factors for development of VOD/SOS (Barker et al. Bone Marrow Transplantation (2003) 32, 79-87, Dix et al Bone Marrow Transplantation 1996 Feb;17(2):225-30). We routinely use oral busulfan in our low and intermediate risk thalassemia transplant conditioning regimen. We summarize the incidence, risk factors, severity and outcomes of VOD/SOS in our patient population.

Methods

We studied the incidence of VOD/SOS defined by EBMT criteria (Corbacioglu et al. Bone marrow transplantation 2018 Feb;53(2):138-145) in 121 consecutive patients with ST (thalassemia syndrome with the inability to spontaneously maintain hemoglobin levels ≥ 7 g/dl) on a single uniform protocol across three collaborating centers from India - People Tree hospitals, Bangalore (PTH), Care Institute of Medical sciences, Ahmedabad (CIMS), South- East Asia Institute of Thalassaemia (SEAIT). Our conditioning regimen comprised of Fludarabine (150 mg/m2, days -17 to -13), anti-thymocyte globulin (ATG) (Genzyme 4 mg/kg, days -12 to -10, dose was increased to 7 mg/kg in case of splenomegaly and or sex mismatched transplants), busulfan (14 mg/kg oral, not adjusted to serum levels over days -9 to -6) and cyclophosphamide (200 mg/kg, days -5 to -2). G-CSF-primed bone marrow (5 μg/kg/dose twice daily for 5 days prior to harvest) was the source of hematopoietic stem cells in all cases. The majority of patients (111) were low - intermediate risk based on liver size < 2 cm from costal margin and age less than 15 years (median 6.9 years, range 1.1 to 14.5) while 10 patients might have been high-risk based on Pesaro classification due to liver >3 cm by palpation at transplant. In fact, liver biopsies were not performed. All matched related donors were HLA-compatible by high resolution typing. None of the patients received routine defibrotide prophylaxis and all patients have at least one year follow up.

Results

Out of the 121 patients studied, 18 developed VOD/SOS (14.9%). One patient developed massive intracranial haemorrhage (ICH) on day 9 and subsequently died on day 11, had some features of VOD/SOS which may have contributed to the ICH. Another patient needed admission in intensive care with respiratory distress was treated with defibrotide for 5 days and recovered. In all others VOD/SOS resolved spontaneously with supportive care only. There was a trend towards decreased overall (94% vs 97%) and disease-free survival (83% vs 89%) in the VOD/SOS group, both did not reach statistical significance (Fig 1 and 2). None of the previously known risk factors studied such as age at BMT (p =0.16), Ferritin level at BMT (p = 0.2), hepatitis C status (p = 0.28) and raised pre-transplant ALT levels (> 3 times normal upper limit) (p = 0.7) showed significant variation between VOD/SOS group and unaffected group. Factors which showed significant difference were Major ABO mismatch (p = 0.041), presence of splenomegaly at BMT (p = 0.0015) and duration of Hydroxyurea (HU) treatment pre-transplant for more than 12 months (p = 0.04). Longer duration of HU may be related to the prolonged down-staging process for poorly managed ST patient pre-transplant. As expected, the VOD/SOS group required increased blood product support (Table 1).

Conclusion

Our results suggest that even though about 15% of low/intermediate risk thalassaemia transplants using Bu-Cy may develop VOD/SOS, in the great majority of cases this complication is mild and resolves spontaneously with supportive care alone. Many of the known risk factors did not seem to be relevant in our patient population. The possible role of splenomegaly at BMT and major ABO mismatch as risk factors for VOD/SOS may warrant further studies.

Disclosures

No relevant conflicts of interest to declare.