Page 276 - Haematologica - Vol. 105 n. 6 - June 2020

P. Vo et al.
Table 2. 90Y activity administered and total radiation absorbed doses* to dose-limiting organ (liver), marrow, and spleen.
Dose level (targeted dose,† Gy)
1 (6)
2 (8)
3 (10) 4 (12) 5 (14) 6 (16) 6 (16) 7 (18) 8 (20) 9 (22) 10 (24) 10 (24) 11 (26) 12 (28) 13 (30)
Patient number
1
2 3 4 5 6 7 8 9 10 11 12 13 14 15
Therapy dose delivered, mCi (MBq)
22.80 (843.60)
27.06 (1001.22) 30.30 (1121.10) 45.50 (1683.50) 38.40 (1420.80) 53.70 (1986.90) 65.10 (2408.70) 128.30 (4747.10) 70.80 (2619.60) 141.20 (5224.40) 112.40 (4158.80) 151.20 (5594.40) 81.50 (3015.50) 104.00 (3848.00) 104.70 (3873.90)
Dose to liver, cGy
570
838.86 951.42 978.25
Dose to marrow, cGy
247.38
534.43 601.45 51.87
Dose to spleen, cGy
2508
2814.24 3120.9 3676.4 7219.2 0‡ 6379.8 6568.96 7929.6 14402.4 9891.2 8542.8 0‡ 12376 13506.3
1413.12 1019.52 1594.89 622.92 1660.05 823.51 1783.37 1321.49 1932.84 730.65 2230.96 3897.12 2326.68 1354.42 2358.72 1670.76 2583.55 1662.6 2797.6 1632.8 2858.31 961.14
*Among patients who received a therapeutic dose of 90Y-DOTA-BC8. †Targeted radiation dose to normal organ receiving highest dose (liver). ‡Patients with splenectomy.
Toxicities and graft-versus-host disease
Despite premedication, grade 1-2 antibody-related infu-
sion reactions (e.g. fever and chills) were observed in 6 of 15 patients; however, the reactions resolved by the end of each infusion. Notably, no grade 4 Common Toxicity Criteria Adverse Event (CTCAE) was observed. Ten (67%) patients experienced grade 3 non-hematologic events (Table 3). Hepatic veno-occlusive disease was not observed, despite delivering an average of 17.9 Gy to the liver. Ten patients (67%) developed grade II-IV acute GvHD (grade II: n=8; III: n=1; IV: n=1) (Table 4). Five patients (33%) developed chronic GvHD, most commonly involving skin and mouth.
Overall and relapse-free survival, non-relapse mortality, and relapse
Treatment led to complete remission in 13 patients (87%) based on a day-28 BM evaluation, whereas two patients had persistent disease documented by peripheral blood flow cytometry assessment on day 6 and day 20 after HCT (Table 5). Of note, the two patients with persist- ent disease had 83.9% and 70% marrow blasts before transplant, respectively. One of these two patients had also failed a previous allogeneic HCT. Among the 15 patients who received a therapy dose infusion of 90Y-DOTA-BC8, eight patients are still alive with a median follow up of 1.8 (range 0.9-5.9) years. Estimated OS at one and two years were 66% (confidence interval, CI: 36-84) and 46% (CI: 17-71), respectively, with RFS estimated to be 46% (CI: 20- 68) at each of these time points. The 1-year estimate of relapse was 41% (16-65%). Figure 2 summarizes the prob- abilities of OS, RFS, and relapse among all 15 patients. Six patients relapsed, five of whom subsequently died due to progression of disease. The median time to relapse among these six patients was 59 days (range 6-351 days). One patient died from grade IV steroid-refractory GvHD in remission at day 71, which resulted in a 6.6% day-100 NRM. One patient died also in remission from acute renal failure seven months after HCT while receiving foscarnet for cytomegalovirus reactivation.
Table 3. Grades 3 and 4 non-hematologic adverse events of the 15 patients who received a therapeutic dose of 90Y-DOTA-BC8.
NCI CTCAE term
Febrile neutropenia
Infection
Blood bilirubin increased
Hyperglycemia
Rash
Skeletal muscular pain
Hypoxia
Atrial fibrillation
Nausea/vomiting
Diarrhea
Hematoma
Mucositis
Hematoma
Edema
Grade 3
7
2
2
1
4
4
1
1
3
2
1
1
1
1
Grade 4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
Discussion
Although allogeneic HCT is an important and frequent- ly used treatment for advanced AML and high-risk MDS, many patients have recurrent disease.9,10 In a randomized study of patients with AML in first complete remission, the relapse rate was 12% after 15.75 Gy TBI, compared with 35% after 12 Gy TBI.11 Although this study showed improved leukemia control with escalated doses of TBI, the higher doses of TBI were associated with increased NRM, resulting in no improvement in survival. The find- ing also confirmed that the high-dose TBI preparative reg- imens were at the limit of normal organ tolerance.
The results reported from studies that used reduced- intensity conditioning suggest that a graft-versus-malig-
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haematologica | 2020; 105(6)