Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS) is a rare complication characterized by hepatomegaly, right-upper quadrant pain, jaundice, and ascites, occurring after high-dose chemotherapy, hematopoietic stem cell transplantation (HSCT) and, less commonly, other conditions. We review pathogenesis, clinical appearance and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD occurring post-HSCT. The injury of the sinusoidal endothelial cells with loss of wall integrity and sinusoidal obstruction is the basis of development of postsinusoidal portal hypertension responsible for clinical syndrome. Risk factors associated with the onset of VOD and diagnostic tools have been recently updated both in the pediatric and adult settings and here are reported. Treatment includes supportive care, intensive management, and specific drug therapy with defibrotide. Because of its severity, particularly in VOD with associated multiorgan disease, prophylaxis approaches are under investigation. During the last years, decreased mortality associated to VOD/SOS has been reported being it attributable to a better intensive and multidisciplinary approach.

A B S T R A C T Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complication affecting patients undergoing hematopoietic stem cell transplantation (HSCT). The survival rate is higher when specific therapy is initiated early; thus, improving early, noninvasive diagnosis of VOD/SOS is an important need. In an adult population undergoing HSCT, we aimed to assess the role of liver stiffness measurement (LSM), evaluated by transient elastography (TE), for diagnosing VOD/SOS. Between April 2016 and March 2018, 78 consecutive adult patients with indications for allogeneic HSCT were prospectively included. LSM was performed before HSCT and at days +9/10, +15/17, and +22/24 post-HSCT. New European Society for Blood and Marrow Transplantation criteria were used to establish VOD/SOS diagnosis. Four patients developed VOD/SOS (5.1%) during the study period, with a median time of +17 days post-HSCT. A sudden increase in LSM compared with previously assessed values and pre-HSCT values, was seen in all patients who developed VOD/SOS. LSM increases occurred from 2 to 12 days before clinical SOS/VOD appearance. The VOD/SOS diagnostic performance of increased LSM over pre-HSCT assessment showed an area under the receiver operating characteristic curve of 0.997 (sensitivity 75%; specificity 98.7%). LSM gradually decreased following successful VOD/SOS-specific treatment. Interestingly, LSM values did not increase significantly in patients experiencing hepatobiliary complications (according to the Common Terminology Criteria) other than VOD/SOS. LSM by TE can be considered a promising method to perform an early, preclinical diagnosis and follow-up of VOD/SOS.

Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.

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We conducted a retrospective, nationwide analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with a TKI based therapy. Patients and results: A total of 441 patients were included in the study. The median age at HSCT was 44 (range: 18-70). All 441 patients (100%) received TKI before HSCT (performed between 2005-2016). Of these patients, 404 (92%) were in cytologic complete remission (CR) while 37 (8%) had an active disease at the time of HSCT. Molecularly Measurable Residual Disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of cases. The prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (TBI-based in 50%) and included ATG in 51% of cases. With a median follow-up after HSCT of 39.4 months (range: 1-145), the probability of Overall Survival (OS) at 1, 2 and 5 years was 69.6%, 61.1%, and 50.3%, respectively, with a median OS of 62 months. Progression Free Survival (PFS) at 1, 2 and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients with CR and MRD-negativity at the time of transplant compared to patients with CR but MRD-positive (50% OS not reached vs. 36 months, P=0,015; 50% PFS not reached vs. 26 months, P=0.003). The cumulative incidence of relapse (CIR) at 5 years was significantly lower in patients with CR and MRD-negativity (19.5% vs. 35.4%, P=0.001). The non relapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95%CI: 15.5-22.9), 20.7% (95%CI: 17-24.7), and 24.1% (95%CI: 20-28.5), respectively. The subgroup of patients with MRD-negative both at HSCT and at 3rd month after HSCT had a better outcome (5 year OS 70%). Conversely, the 37 patients who underwent HSCT with active Ph+ALL had a median OS and PFS of 7 and 5 months, respectively. Conclusions: The median OS of all patients with Ph+ALL, treated with TKI based therapy and allografted in recent years at the GITMO Centers, is 62 months. The outcome of Ph+ALL patients undergoing HSCT after TKI therapy has improved (with a 2 yrs NRM of 20,7%), particularly for younger patients and those achieving a molecular remission before transplant (50% OS and PFS not reached). HSCT remains a standard of care consolidation treatment for Ph+ALL and only prospective randomized trials can suggest a survival benefit of non transplant based treatment strategies.