Incidence of sinusoidal obstruction syndrome following Mylotarg (gemtuzumab ozogamicin): a prospective observational study of 482 patients in routine clinical practice

Abstract

The purpose of this prospective observational study was to determine the incidence of hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab ozogamicin (GO) therapy in routine clinical practice. Patients receiving GO for acute myeloid leukemia (AML) were eligible. Assessments were requested to be performed weekly for 6 weeks after the start of GO therapy or 4 weeks after the last dose (whichever was later), and after 6 months. The primary outcome variable was the incidence of SOS as judged by a panel of independent experts. A total of 512 patients were enrolled at 54 US centers and 482 were evaluable. The incidence of SOS in this study population was 9.1 % (44/482; 95 % confidence interval 6.9-12.0 %). Of the 44 patients classified as having SOS, 8 were mild, 17 moderate, and 19 severe; 33 died within 6 months (20 of disease progression and 13 of SOS and multiorgan failure). Most (68 %) patients in the study died within 6 months; most of these deaths (73 %) were due to progression of AML. Serious adverse events occurred in 85 % of patients, most (81 %) due to AML, febrile neutropenia, pyrexia, and sepsis. GO administered in routine clinical practice carries an overall 9.1 % risk of SOS and a 2.7 % risk of death from SOS and multiorgan failure. No risk factors were identified for the development of SOS.

Sinusoidal Obstruction Syndrome (Hepatic Veno-Occlusive Disease)

“…The incidence of SOS in this population of GOtreated patients is reported as 9.1%. 89 Although the 6-month mortality rate in this population of SOS-affected patients was high (68%), three quarters of the deaths were due to progression of the AML. Overall risk of death from SOS and multiorgan failure was 2.7%.…”

How I treat refractory and early relapsed acute myeloid leukemia

“…For patients who receive GO with the goal of allogeneic HSCT especially sinusoidal obstructive syndrome (SOS) of the liver is a concern. 98 No clear risk factors for the occurrence of SOS during SCT could be identified, but the rate of death related to SOS was found to be small. 98 …”

“…98 No clear risk factors for the occurrence of SOS during SCT could be identified, but the rate of death related to SOS was found to be small. 98 …”

Fcγ-receptor–mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments

“…[70][71][72] The internalization of Mylotarg by CD33 1 cells is relatively slow (takes many hours), and this could allow enough time for circulating Mylotarg-opsonized cells to transfer their deadly cargo to LSECs via trogocytosis when they circulate through the liver. FcgRIIb on LSECs can clear circulating immune complexes, 46,47,49 and acceptor cell-associated FcgRIIb can promote trogocytosis and remove RTX (human IgG1)-CD20 complexes from opsonized B cells.…”

“…Because only ;10% of patients treated with Mylotarg experience severe hepatic injury, it would be important to determine if subtle differences in FcgR activity on their LSECs, or other factors related to immune complex processing, or the unusual properties of human IgG4 antibodies in the circulation, 74 could identify those individuals most susceptible to adverse reactions. Also, because Mylotarg was removed from the market, 72 it may not be possible to unambiguously determine how it induces liver pathology. At the least, we strongly suggest that future ADC should be examined in appropriate in vitro model systems to determine if they are susceptible to potentially pathologic trogocytosis.…”