Page 277 - Haematologica - Vol. 105 n. 6 - June 2020

90Y-Anti-CD45 Antibody for Leukemia/Myelodysplasia
nancy effect is most effective in patients with a low bur- den of malignant cells.1,12,13 In a study of 274 patients who had allogeneic HCT after non-myeloablative conditioning using FLU and 2 Gy TBI for the treatment of AML, patients in first and second complete remission had better 5-year survival rates than patients with more advanced disease (37% and 34% vs. 18%, respectively). Most treat- ment failures were caused by recurrent AML.14 These data suggest that a graft-versus-leukemia effect alone may be inadequate for patients with AML/MDS in relapse or with refractory disease, whereas additional targeted antileukemic therapy may be beneficial. Our group previ- ously explored the safety and feasibility of 131I-BC8 anti- body to deliver targeted radiation to malignant cells in the marrow and spleen, and combined this approach with the non-myeloablative conditioning regimen of 2 Gy TBI and FLU in patients with advanced myeloid malignancies.2,15
Table 4. Acute graft-versus-host disease overall grading with organ staging of the 15 patients.
Grade/stage Overall (n) Gut (n) Liver (n) Skin (n)
I/1 1 9 2 1
II/2 8 0 0 2 III/3 1 0 1 4 IV/4 1 1 0 0
While results were encouraging, one major limitation of this approach was the medium energy gamma component of 131I and 8-day physical half-life that required patients to be treated in radiation isolation due to the exposure risk for staff and family. 90Y was selected as the therapeutic radionuclide for this current clinical trial because it is a pure β-emitter that is available in high specific activity and purity. Moreover, the β particles from 90Y have a high ener- gy (Emax =2.28 MeV) with greater tissue penetrating range (up to 11 mm) than β particles from 131I, characteris- tics that may be more favorable for therapy of large tumor masses.4 Finally, replacement of 131I with 90Y may be more feasible for studies at additional centers.
As a phase I dose-finding trial, the current study was not designed to determine the efficacy of the conditioning reg- imen of 90Y-DOTA-BC8 combined with FLU/TBI. However, the experience reported in this dose-escalation study suggests that the delivery of supplemental doses of 90Y–DOTA-BC8 could improve 2-year OS and RFS of very high-risk AML/MDS patients to 46% and 46%, respec- tively, compared with patients who received HCT with the use of the FLU/TBI conditioning regimen alone.1,3,14 Although the estimated probability of relapse at one year remains high at 41%, these results are encouraging, con- sidering that all of the patients in our study had either active AML/MDS or measurable residual disease (MRD) prior to the beginning of the conditioning regimen. Patients with detectable disease have historically dismal
Table 5. Outcomes of the 15 patients who received a therapeutic dose of 90Y-DOTA-BC8.
Pt Age/ n. Gender
1 51/M
2 69/M 3 74/M
4 76/M
5 52/F 6 65/M 7 48/F 8 60/M 9 56/F 10 37/F
11 71/M
12 72/M 13 65/F
14 62/F 15 37/F
Diagnosis at HCT
Relapsed secondary AML
Refractory secondary AML MDS-RAEB
MDS-RAEB
Refractory secondary AML Refractory secondary AML Relapsed secondary AML Refractory secondary AML Relapse/refractory AML Relapse/refractory AML
MDS-RAEB
Secondary AML Untreated CMML
MDS-RAEB Relapse/refractory AML
Disease status at transplant
Active disease
MRD (+) MRD (+)
Active disease
MRD (+) MRD (+) MRD (+) Active disease Active disease Active disease
Active disease
MRD (+) Active disease
Active disease Active disease
Pre-HCT BM/PB blast (%)
83.9/0
0/0‡ 1.4/0
13.6/0
3.5/0 0.22/1.1 0.17/0 17.6/3.6 31.6/0 70.0/0
7.0/0
2.5/1.5 0.89/0
11.4/0.38 43.0/4.0
Cytogenetic CR† risk* Achievement
Donor Grade
Current status, days after HCT
Persistent disease; died day 23
Alive and in CR: 2137 d
Died day 218 due to renal failure (in CR)
Died day 80 due to steroid
refractory aGvHD (in CR) Died day 694 due to relapse Alive and in CR: 1234 d Died day 395 due to relapse Alive and in CR: 767 d
Alive and in CR: 727 d
Persistent disease; died
day 109
Alive, on azacytidine, achieved CR with MRD (-): 583 d
Died day 318 due to relapse
Alive: relapsed on day
351. Currently on azacytidine and now CR with MRD (-)
Alive and in CR: 394 d
Alive and in CR with MRD (+):
316 d
status acute post HCT GvHD
high No
high Yes Int. Yes
Int. Yes
Int. Yes Int. Yes high Yes, with high Yes Int. Yes Int. No
high Yes, with
high Yes Int. Yes
high Yes high Yes, with
MRD
MRD
MRD
URD 0
URD§ 2 URD 0
URD‖ 4 URD 2
URD 2 URD 2 URD 0 URD 2 URD 3
RD 0
URD 2 RD 2
RD 1 URD 2
BM: bone marrow; CMML: chronic myelomonocytic leukemia; CR: complete remission; F: female; Int.: intermediate; M: male; MDS-RAEB: myelodysplastic syndrome-refractory anemia with excess blast; MRD: measurable residual disease; PB: peripheral blood; RD: HLA-matched related donor; URD: unrelated donor. *According to Southwest Oncology Group criteria.8 †Protocol-defined CR as bone marrow with blasts <5% by morphology with blood count recovery.‡MRD by cytogenetics.§Patient had a DQ allele mismatch unrelated donor.‖Patient had an HLA-A antigen mismatch unrelated donor.
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