Autologous Hematopoietic Stem Cell Collection and Transplantation in Acute Myeloid Leukemia Patients in Second Remission after Treatment with Fractionated Gentuzumab Ozogamycin.
Authors: Rea Delphine , Raffoux Emmanuel , Taksin Anne Laure , De Labarthe Adrienne , Boissel Nicolas , Miclea Jean Michel , Castaigne Sylvie , Dombret Herve 
Published: October 2019

Gemtuzumab ozogamicin (GO) at fractionated doses of 3 mg/m2 on days 1, 4 and 7 has recently shown efficacy with minimal liver toxicity and without veino occlusive disease (VOD) in patients with acute myeloid leukemia (AML) in first relapse. We report on autologous hematopoietic stem cell (HSC) collection and transplantation in 4 AML patients (median age 61; 54–64) in 2nd remission (CR2) after fractionated GO treatment uneligible for allogeneic HSC transplantation.

Peripheral blood (PB)-HSC were collected by leukapheresis after mobilization with amsacrine + AraC (patients 1–3) or high dose AraC (patient 4) and subsequent G-CSF at 5 microgr/kg/day. In patient 1 (AML2 normal karyotype Flt3 wt), PB-HSC collection started at day 22 post-chemotherapy (CT) with a CD34 count of 13.4/microl and 2 cytapheresis were required to yield a total of 11.8×108 nucleated cells (NC)/kg, 3.7×106 CD34/kg and 6.9×104 CFU-GM/kg. In patient 2 (AML4, normal karyotype, Flt3 ITD), PB-HSC collection started at day 20 post-CT with a CD34 count of 8.2/microl and 3 cytapheresis were required to yield a total of 14.8×108 NC/kg, 3.1×106 CD34/kg and 33.7×104 CFU-GM/kg. In patient 3 (AML2 normal karyotype, Flt3 ITD), PB-HSC collection started at day 20 post-CT with a CD34 count of 30.2/microl and 2 cytapheresis were required to yield a total of 5.3×108 NC/kg, 6×106 CD34/kg and 42.5×104 CFU-GM/kg. PB-HSC from patient 3 were purged in vitro with mafosfamide, yielding final CN, CD34 and GM-CFU doses of respectively 4.9×108/kg, 5.2×106/kg and 0×104/kg. In patient 4 (AML1 normal karyotype, Flt3 wt), bone marrow (BM)-HSC were harvested and purged with mafosfamide. Prior purging, CN, CD34 and GM-CFU doses were respectively 1.7×108/kg, 6.7×106/kg and 16.1×104/kg. After purging, CN, CD34 and GM-CFU doses were respectively 0.36×108/kg, 3.6×106/kg and 0.1×104/kg. In patient 4, PB-HSC collection for rescue started at day 16 post-CT with a CD34 count of 27.4/microl and 1 cytapheresis was sufficient to yield a total of 1.8×108 NC/kg, 3.4×106 CD34/kg and 36.7×104 CFU-GM/kg. Autologous HSCT was performed after conditionning with busulfan and cyclophosphamide. Autologous grafts consisted in unpurged PB-HSC in patient 1 and 2, purged PB-HSC in patient 3 and purged BM-HSC in patient 4. All patients received continuous heparin infusion at 100U/kg/day as VOD prophylaxis. Extra hematological adverse events comprised grade 3–4 oral mucitis, grade 2–3 nausea and vomiting (n=4), grade 2–3 diarrhea (n=3), grade 1 liver enzyme elevation (n=4) and grade 1–3 cholestasis. Three patients presented fever of unknown origin, one showed gram-negative systemic infection and one showed clostridium difficile-associated diarrhea. No VOD was observed. Neutrophil recovery above 0.5/L occurred between day 25 and day 40. Platelet recovery above 20/L occurred at day 18 and day 300 in patients 2 and 4, and never occurred in patients 1 and 2. These latter relapsed 3 months after transplantation. Patients 3 and 4 are still in CR2, 7 and 21 months after transplantation. PB and BM collection after fractionated GO treatments for AML is feasible. After autologous transplantation, no VOD is observed but platelet recovery is severely impaired.