Defibrotide Prophylaxis of Sinusoidal Obstruction Syndrome in Adults Treated With Inotuzumab Ozogamicin Prior to Hematopoietic Stem Cell Transplantation

Abstract

Sinusoidal Obstruction Syndrome (SOS) is a life threatening HSCT complication and it can rapidly evolve in Multiple Organ Dysfunction Syndrome, with a mortality exceeding 80%. Early treatment with defibrotide is the leading factor for efficacy. Its prophylactic use is recommended in the pediatric setting, but its value isn’t validated for adults, although factors for individual risk assessment are debated. We here present a real-world experience of Defibrotide prophylaxis in adults at very high risk of SOS. We treated with prophylactic Defibrotide and Ursodeoxycholic Acid seven patients receiving allogeneic HSCT for high risk B-ALL, previously treated with single agent Inotuzomab-Ozogamicin. They all had other high risk factors for SOS such as previous hepatotoxicity, previous allo-HSCT, double alkylating conditioning. All patients received Treosulfan-Fludarabine conditioning, Thiotepa was added in 4 patients and 4GyTBI in 2 patients. GvHD prophylaxis included post-transplant cyclophosphamide, rapamycin and mycophenolate. Donor source was PBSC. Five patients received family MMRD transplant, 1 patient a MRD transplant and 1 patient a MUD transplant. Non-severe gastrointestinal bleeding occurred in two patients requiring defibrotide temporarily discontinuation. SOS occurred in 3/7 cases within 21 days after HSCT and no late-onset SOS were diagnosed. SOS caused death in all cases. All three patients were characterized by a common pattern of very high risk factors by prior HSCT, they all received a myeloablative conditioning with Treosulfan-Thiotepa and a MMRD transplant. Defibrotide prophylaxis apparently failed to protect against the development of SOS in those patients treated with a double alkylator-based conditioning regimen, while a possible efficacy for the other high-risk patients is debatable.

Impact of inotuzumab ozogamicin on outcome in relapsed or refractory acute B-cell lymphoblastic leukemia patients prior to allogeneic hematopoietic stem cell transplantation and risk of sinusoidal obstruction syndrome/venous occlusive disease

“…18 If prophylactic treatment with defibrotide, as recommended in the pediatric setting, 32 might have reduced the rate of VOD, remains elusive. 31,33 The CR/CRi rate in our cohort was higher than that reported from the INO-VATE trial (84% as compared to 73.8%) 34 and other real-world data. 35 However, in our cohort, the MRD-negative rate was lower as compared to that of the INO-VATE trial.…”

“… 18 If prophylactic treatment with defibrotide, as recommended in the pediatric setting, 32 might have reduced the rate of VOD, remains elusive. 31 , 33 …”

“…Our real-life data confirm the detrimental effect of double alkylator conditioning for patients undergoing allo-HCT previously treated with INO, a feature that we now recognize as one of the most important risk factors for the development of SOS/VOD in this treatment setting. 20,31 In addition, we also identified allo-HCT during first-line therapy and in trend allo-HCT ≤60 days after INO as risk factors for SOS/VOD. In contrast to previous data more than two INO cycles before allo-HCT was not significant.…”

Case Report: Favorable outcome of allogeneic hematopoietic stem cell transplantation in SARSCoV2 positive recipient, risk-benefit balance between infection and leukemia

“…Figure 1 The pre-engraftment phase was characterized by uncomplicated febrile neutropenia without documented infections. Despite trying to minimize the risk factors for veno-occlusive disease (VOD) in the context of IO exposure and a TBI-based myeloablative-preparing regimen, administering ursodeoxycholic acid prophylaxis and using CsA rather than sirolimus as GVHD prophylaxis (19), VOD occurred at day +13 (thinning of hepatic veins, thickening of gallbladder, ascites, bilirubin peak 2.3 mg/dL, Fibroscan peak 75kPa), requiring defibrotide treatment to obtain a slow but complete resolution of this complication.…”

Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions

“…avoiding in patients were severe underlying hepatic dysfunction, avoiding dual alkylator conditioning regimens in transplanted patients, limiting INO to a cumulative dose of 2.7 to 3.6 mg/m 2 in patients proceeding to allogeneic HSCT, use of high dose steroids at the first sign of liver dysfunction, and distancing the last dose of INO from time of HSCT [ 21 ]. Ursodiol prophylaxis 300 mg three times daily should be considered for all patients receiving INO, although there is no clear role for defibrotide as prophylaxis, even for high-risk patients [ 22 ].…”