Background and Methods: Sinusoidal obstruction syndrome/veno-occlusive disease (VOD) is a severe complication of allogeneic stem cell transplant (SCT). Given the increased use of SCT, cases from two transplant centers in Ontario, Canada (2019 - 2021) were reviewed to identify risk factors prognostic for VOD onset and outcomes.
Results: There were 536 SCT cases; mean age 53.4 years [range: 17-76], 322 males and 214 females. The most common indication was acute myelogenous leukemia (AML) [32%] categorized as favourable [19%], intermediate [44%] and adverse [37%] as per the European LeukemiaNet (ELN). Other common indications were myelodysplastic syndrome (MDS) [16%], acute lymphoblastic leukemia (ALL) [14%], secondary AML [9%], and non Hodgkin's lymphoma [7%]. A majority achieved complete remission (CR) [63%] or partial remission [19%] at transplant. Twelve patients received inotuzumab and five received gemtuzumab.
A Karnofsky Performance Scale (KPS) Index > 90% [range: 60-100] was reported in 38% of cases. Regimen intensities were as follows: myeloablative (MA) [48%], reduced intensity (RI) [34%], haploidentical (haplo) [11%], and non-MA [7%]. Stem cell sources included matched unrelated donors (MUD) [68%], matched related donors (MRD) [21%] and haplo donors [11%]. Intravenous (i.v.) busulfan (Bu) was administered to 330 patients; median dose 860 mg. Total body irradiation was delivered to 156 patients; median dose of 200 cGy. Treatment with ursodeoxycholic acid was used in 93% of cases. Graft versus host prophylaxis included i.v. methotrexate [65%], calcineurin inhibitor [99%] and anti-thymocyte globulin [85%].
Of the entire cohort the average length of hospital stay was 37 days [4 - 385] and 73 patients were admitted to the Intensive Care Unit (ICU). The average ICU stay for the entire cohort was 1 day [0 - 49]. There were six COVID-19 cases. Fifty-one patients [10%] died by day 100 [range: 3 -100] with no COVID-19 related deaths.
There were 16 diagnosed VOD cases representing 3% of SCT cases. Review of 253 charts identified 8 cases meeting diagnostic criteria for VOD and are potentially missed cases. Diagnosed cases had a mean age of 48 years [18-72] equally distributed between genders. All were early onset prior to day 21 [1-20]; six moderate, six severe, and four very severe cases. Transplant indications included AML [n=5], ALL [n=3], MDS [n=2], secondary AML [n=2], primary myelofibrosis [n=2], and myeloproliferative neoplasms [n=2]. AML ELN risk included four adverse and one intermediate risk patient. Donor sources were MRD [n=6] and MUD [n=10]. The remission status at SCT were CR [n=11], no response [n=4], and never treated [n=1]. Only 19% of the VOD cohort had a KPS > 90%. The majority received a MA regimen [n=12] and the remainder received a RI regimen. Bu treatment was used in 75% of VOD cases compared to 62% in the entire cohort. Reduced left ventricular function, pulmonary hypertension, previous cholecystectomy, splenectomy, pre-existing liver disease were not predictors for VOD. Univariable regression analysis identified higher baseline absolute neutrophil counts (ANC) of 4.2 x 109 compared to 2.6 x 109 [p=0.035] and lower platelet count of 104 x109 compared to 140 x 109 [p=0.034] in VOD and nonVOD cases as independent risks for developing VOD. There were no COVID-19 cases in VOD patients.
Average inpatient stay was 56 days [24-178] and eight patients were in ICU for an average of 6 days [0-42] for all diagnosed VOD cases. Five of the sixteen diagnosed VOD patients died within 100 days [9-59], four from VOD. Five remain alive and six died after day 100 [125 - 419]. Treatments included diuretics [n=15], steroids [n=3], and defibrotide [n=9]. Of the nine patients treated with defibrotide graded as moderate [n=2], severe [n=4], and very severe [n=3], seven died with 3 deaths before day 100.
Conclusions: The incidence of VOD cases was less common than in most series and carried a high fatality rate. VOD cases were overrepresented in patients with KPS < 90%, adverse ELN risk, MA preparative regimen, MUD donor source and Bu treatment. No VOD cases received a haplo transplant. Higher ANC and lower platelet counts at the start of the preparative regimen were independent risk factors for VOD. Hospital and ICU stays were longer in VOD patients who were more likely to die within the first 100 days. VOD may be under-diagnosed and this underscores the need for ongoing education and resources to allow for early intervention.
Pond:Profound Medical and Traferox: Consultancy; Merck: Consultancy; Astra-Zeneca: Consultancy; Roche: Current equity holder in publicly-traded company; Takeda: Honoraria. Trus:Jazz Pharmaceuticals: Research Funding.
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