Prior Treatment with Chemotherapy Associated to Gemtuzumab Ozogamicin (GO) Does Not Increase the Risk of Veno-Occlusive Disease (VOD) after Allogeneic Stem Cell Transplantation (all-SCT).
Authors: Chevallier Patrice , Prebet Thomas , Turlure Pascal , Hunault Mathilde , Vigouroux Stephane , Faucher Catherine , Guillaume Thierry , Mechinaud Francoise , Ayari Sameh , Delaunay Jacques , Milpied Noel-Jean , Harousseau Jean-Luc , Ifrah Norbert , Blaise Didier , Vey Norbert , Mohty Mohamad 
Published: April 2020

Abstract
The combination of chemotherapy and GO is increasingly used for the treatment of CD33+ AML patients either at diagnosis or at time of relapse. GO is classically known to induce liver toxicity, that may significantly increase the risk of VOD, especially in patients receiving allo-SCT. A single study by Wadleigh et al (Blood, 2003) suggested an increased risk of VOD in patients who underwent myeloablative HSCT within a short interval from GO administration (&lt;3.5 m.). However, no large series have comprehensively assessed this risk thus far. Here, we analysed the outcome of a cohort of 44 HSCT patients who had received previous combination of chemotherapy + GO in the course of their disease. This retrospective study included 44 patients (males, n=21) who received allo-SCT between Dec. 2001 and June 2008 after prior exposure to GO. Median age was 50 (range:3–67). There were 41 CD33+ AML, 2 CD33+ ALL and 1 CD33+ myeloid sarcoma. Before allo-SCT, 37 patients received the MIDAM regimen (GO: 9 mg/m², n=36; or GO 4.5 mg/m², n=1 at day 4 + Ara-C 1g/m²/12 hours day 1–5 + Mitoxantrone 12 mg/m²/day day 1–3). In 3 patients receiving MIDAM, Mitoxantrone was omitted. GO 9 mg/m² + other combinations of chemotherapy were used in the remaining 4 patients. Indications for the GO-based chemotherapy were as follow: first induction, n=3; second induction, n=4; primary refractory disease, n=14; first relapse, n=19; second relapse, n= 4. Only 1 patient developed VOD after receiving GO. In this series, 5 patients received an additional course of consolidation with GO+chemotherapy. Of note, 15 patients (34%) received prior auto-SCT. Median interval between last administration of GO and allo-SCT was 4.2 (range, 0.8–26.3) months, with 19 patients allografted &lt;3.5 months from GO administration. At time of allo-SCT, 33 patients were in CR, and 11 remained refractory. The majority of patients (n=36; 82%) received a reduced intensity conditioning (RIC) regimen prior to allo-SCT, while 8 patients received a myeloablative regimen. The stem cell source was PBSC in 26, cord blood in 15, bone marrow in 2 and a CD34+ selected PBSC in 1 patient. Eleven patients received an allograft from an HLA matched related donor (MRD), 1 from an HLA mis-MRD, 16 from an HLA matched unrelated donor (MUD), and 1 from an HLA mis-MUD. All patients (but one who received defibrotide because of a prior history of VOD) received low-dose heparin as VOD prophylaxis. Engraftment was observed in 34 patients (77%) at a median of 15 (range, 8–43) days after allo-SCT. With a median FU of 15 (range, 1.1–63) m. for surviving patients, OS and DFS after allo-SCT were 45% (95%CI, 30–61%) and 38% (95%CI, 24–54%) at 3 years respectively. At time of analysis, 22 patients were still alive, while 22 patients died. The causes of death included: disease progression in 13, 1 fungal infection, 2 acute GVHD, 1 chronic GVHD, 3 multi organ failures, 1 ARDS, and one case of VOD, for an overall incidence of TRM of 20% in this high risk population. The incidence of Grade ¾ hyper-bilirubinemia was 13.5% (n=6), with this being 21% in patients with a short (&lt;3.5 m.) GO-allograft interval (n=4/19) vs. 8% in all others (P=NS). In all, the incidence of VOD was 7% (n=3), with this being 10.5% (n=2/19) in patients with a short GO-allograft interval (&lt;3.5 m.) vs. 4% (n=1/25) for all others (P=NS). Also, a myeloablative regimen was not associated with an increased risk of VOD (12.5%, n=1/8 vs RIC 5.5%, n=2/36, P=NS). Overall, these encouraging results suggest that GO-based (mostly salvage) therapy in combination with chemotherapy prior to allo-SCT is feasible and does not result in an excessive rate of toxicity, especially VOD, after allo-SCT.