Hepatic veno-occlusive disease following sirolimus-based immune suppression

Abstract

Sirolimus-based graft vs. host disease (GVHD) prophylaxis is associated with higher incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after allogeneic hematopoietic cell transplantation (HCT). However, whether the clinical manifestations and prognosis of VOD/SOS differs when diagnosed in the setting of sirolimus-based GVHD prophylaxis is not well studied. To address this question, we examined presenting features and treatment outcome of VOD/SOS cases identified in a large retrospective cohort of consecutive HCT procedures (n = 818 total, sirolimus (SIR)/tacrolimus (TAC) n = 308, and methotrexate (MTX) or mycophenolate mofetil (MMF)/TAC n = 510). In multivariate analysis, sirolimus-based GVHD prophylaxis (p = 0.006, HR 3.33, 1.94-5.7) increased risk for VOD/SOS. A total of 58 patients were clinically diagnosed with VOD/SOS (SIR/TAC 38/308, 12.3%, vs. MTX or MMF/TAC 20/510, 3.9%). VOD/SOS diagnosed following SIR/TAC prophylaxis demonstrated later time of onset (median 39 vs. 26 days; p = 0.005), less severe hyperbilirubinemia (Bili > 2, 65% vs. 90% p = 0.04), lesser degree of weight gain (weight gain > 5%, 52% vs 80%, p = 0.04), and more frequent complete resolution of hepatic injury (79% vs. 55%, p = 0.05). Presenting features and natural history of VOD/SOS in the context of SIR/TAC GVHD prophylaxis differ and thus warrant particular clinical attention to later hepatic injury in these patients.

Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children's Oncology Group Protocol AALL1621

“…Continuous safety monitoring for a cycle 1 DLT rate of ≥ 30% and SOS rate of ≥ 15% was performed. 9 SOS was defined by the modified Seattle criteria 10 ; SOS grading reported herein uses Common Terminology Criteria for Adverse Event version 5.0. The monitoring boundary for SOS was exceeded in stage 1.…”

“…Continuous safety monitoring for a cycle 1 DLT rate of $ 30% and SOS rate of $ 15% was performed. 9 SOS was defined by the modified Seattle criteria 10…”

Sirolimus versus cyclosporine in haploidentical stem cell transplantation with posttransplant cyclophosphamide and mycophenolate mofetil as graft‐versus‐host disease prophylaxis

“…Of note, the two SOS‐related deaths were detected, both in the PTCy–CsA–MMF subgroup. The use of sirolimus has been associated with larger risk of SOS in the setting of CNI‐based GVHD prophylaxis [ 36 ], although previous experience in the context of CNI‐free regimens does not support this association [ 7 , 10 , 11 ]. The higher incidence of SOS in our study could be related to our target of sirolimus levels, which are higher than previous studies [ 7 , 11 ], following prior evidence of a lower incidence of CMV [ 8 ].…”

Hepatic sinusoidal obstruction syndrome/veno-occlusive disease after hematopoietic cell transplantation: historical and current considerations in Korea

“…The EBMT previously suggested three risk factor subgroups: factors related to HCT; factors related to the patient's susceptibility to SOS/VOD, including underlying disease; and hepatic-related factors (e.g., preexisting hepatic disease) [6,7]. Recent research has focused on several novel agents used for remission induction or GVHD prevention, which may be risk factors for SOS/ VOD [9,10,[23][24][25][26].…”

“…Sirolimus, which is used for GVHD prophylaxis, was associated with SOS/VOD development, particularly when used with a busulfan-containing regimen or concomitantly with calcineurin inhibitors and methotrexate [23,55]. Notably, patients who underwent sirolimus-based GVHD prophylaxis demonstrated later onset of SOS/VOD and less severe features (i.e., less severe hyperbilirubinemia and weight gain, as well as more frequent complete resolution of SOS/VOD) [24]. There have also been several reports of oxaliplatin-related hepatic SOS/VOD, particularly in patients with solid organ malignancies and hepatic metastasis [56][57][58].…”