Page 274 - Haematologica - Vol. 105 n. 6 - June 2020

P. Vo et al.
in patients with an advanced burden of active leukemia at the time of transplantation.1 We previously combined iodine-131-labeled anti-CD45 monoclonal antibody (131I- BC8) with a reduced-intensity conditioning regimen to decrease relapse in older patients with advanced or refrac- tory myeloid malignancies.2 While the study was not designed to examine potential efficacy, the 3-year disease- free survival was 38% for 58 patients with active relapsed/refractory leukemia, a rate superior to historical experience where the 3-year overall and disease-free sur- vival estimates of these patients were only 23% and 13%, respectively.1,3 Furthermore, 86% of the patients had acute myeloid leukemia (AML) in active relapse or MDS with more than 5% blasts in their marrow by morphology at the time of HCT. All patients achieved a complete remission as well as 100% donor chimerism in the CD3 and CD33 com- partments by day 28. The maximum-tolerated dose (MTD) was estimated to be 24 Gy delivered by 131I-BC8 to the nor- mal organ receiving the highest dose (liver), with renal insufficiency and cardiopulmonary toxicities being dose- limiting.
We used 131I as the therapeutic radionuclide in our prior clinical studies because it was readily available, there was extensive experience with its medical use, the technology for directly radiolabeling antibodies with iodine has been well established, and its gamma-ray component allowed direct determination of labeled antibody biodistribution in the patient after a tracer infusion. However, the high abun- dance gamma radiation component of 131I requires that patients be treated and sequestered in radiation isolation and poses a potential radiation exposure risk for staff and family, presenting a major limitation to the wide-spread exportability of this modality. As an alternative, ytrium-90 (90Y) has been explored as a pure β-emitter that has been available in high specific activity and purity. Moreover, the β particles from 90Y have a high energy (Emax =2.28 MeV) with greater tissue penetrating range (up to 11 mm) that may be more favorable for near-uniform deposition of radi- ation energy in tumor masses.4
In this current study, we evaluated the safety and poten- tial efficacy of 90Y-labeled anti-CD45 antibody (90Y-DOTA- BC8) followed by a standard reduced-intensity regimen with fludarabine (FLU) and 2 Gy total body irradiation (TBI) as a means of developing an improved HCT strategy for high-risk acute leukemia or MDS patients.
Methods
Patient and donor selection
Patients aged 18 years and older were eligible if they had advanced AML (beyond first remission, primary refractory, relapsed with >5% marrow blasts by morphology, or evolved from previous myeloproliferative neoplasm or MDS), MDS with >5% blasts in the marrow, or chronic myelomonocytic leukemia-2, and if they had an HLA-matched donor. Patients were excluded if they had evidence of major organ dysfunction, seropositivity for human immunodeficiency virus, allergies to mouse protein, or human antibody specific for mouse immunoglobulin (HAMA). All patients signed consent forms approved by the institutional review board of Fred Hutchinson Cancer Research Center. (NCI Clinical Trials Network registration: clinicaltrials.gov identifier: NCT01300572.)
Treatment plan
The patients received an infusion of 0.5 mg/kg ideal body
weight of anti-CD45 antibody (DOTA-BC8) trace-labeled with 5- 10 mCi of the imaging radionuclide indium-111 (111In), which pro- vides gamma photons (0.171 and 0.245 MeV) for imaging (not provided by 90Y), to evaluate the biodistribution of the anti-CD45 antibody and calculate the radiation-absorbed doses delivered to normal organs and the whole body, as described previously.2 The subsequent therapy infusion of 90Y-DOTA-BC8 was calculated to not exceed a maximum value dose to the critical normal organ. The therapy dose was administered on approximately day -12 of the preparative regimen. FLU 30 mg/kg/day was given intra- venously (i.v.) on days -4 through -2, followed by TBI (2 Gy) and subsequent infusion of unmanipulated, G-CSF-mobilized periph- eral blood stem cells on day 0. Mycophenolate mofetil and cyclosporine was given for graft-versus-host-disease (GvHD) pro- phylaxis.5
Dose-adjustment schema and statistical analysis
The primary objective of this study was to estimate the MTD of 90Y-DOTA-BC8 used in combination with FLU/2-Gy TBI. The MTD was defined as the radiation dose to the normal organ asso- ciated with a dose-limiting toxicity (DLT) rate of 25% using Bearman criteria, developed specifically for HCT patients.6 A DLT was defined as a Bearman grade III or IV regimen-related toxicity occurring up to day 100 after HCT.6 A two-stage approach described by Storer et al. was planned for dose adjustment.7 In stage I, single patient cohorts were enrolled, and each successive patient received 2 Gy more radiation to the dose-limiting normal organ than the previous patient until the first DLT was observed. Dose escalation could proceed only if the patient receiving the pre- vious dose was observed for at least 30 days after HCT; if not, the newly enrolled patient had to be treated at the same dose level as the previous patient. If a DLT was observed, stage II would be ini- tiated at the next lower dose level, treating patients in cohorts of four patients each; this cohort size was dictated by the target DLT rate of 25%.
Secondary objectives included evaluation of potential efficacy in the context of a dose-finding study. Overall survival (OS) and relapse-free survival (RFS) were estimated according to the Kaplan-Meier method, and relapse and non-relapse mortality (NRM) were summarized using cumulative incidence estimates. NRM was considered a competing risk for relapse, and relapse was treated as a competing risk for NRM.
Results
Patients’ characteristics
Sixteen patients with high-risk leukemia/MDS were enrolled to the study. One patient was withdrawn from the study due to HAMA seroconversion after receiving the 111In-DOTA-BC8 test dose. Thus, fifteen patients, median age 62 years (range 37-76 years) years, were treat- ed: ten patients had advanced AML and five had high-risk MDS. At the time of HCT, nine patients had refractory active diseases (pre-HCT marrow blast range 7-83.9%), while six had minimal residual disease documented by flow cytometry and cytogenetics (Table 1). Among the ten AML patients, three patients with de novo AML had relapsed disease and were refractory to a median of four lines of previous chemo-induction (range 3-6). Seven patients with secondary AML had received a median of three (range 1-6) induction chemotherapies prior to the HCT. Three of the 15 patients had failed previous allo- HCT. According to Southwest Oncology Group criteria,8 eight patients had high-risk/unfavorable cytogenetic
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