131I-apamistamab-Led Allogeneic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients with TP53 Mutated R/R AML
Hannah Choe, MD, Ben K. Tomlinson, MD, Boglarka Gyurkocza, MD, Rajneesh Nath, MD, Stuart Seropian, MD, Mark R. Litzow, MD, Camille N. Abboud, MD, Patrick J. Stiff, MD, Sunil Abhyankar, MD, James Foran, MD, Sameem Abedin, MD, George Chen, MD, Zaid Al-Kadhimi, MD, Partow Kebriaei, MD, Mitchell Sabloff, MSc, MD, FRCPC, Johnnie J. Orozco, MD, PhD, Katarzyna Joanna Jamieson, MD, Margarida Magalhaes- Silverman, MD, Koen Van Besien, MD, PhD, Michael W. Schuster, MD, Arjun D. Law, MD, Sebastian A. Mayer, MD, Hillard M. Lazarus, MD, Jennifer Spross, MA, Kate L Li, PhD, Elaina Haeuber, MS, Madhuri Vusirikala, MD, Akash Nahar, MD, MPH, Brenda M. Sandmaier, MD, John M. Pagel, MD, PhD, Sergio A. Giralt, MD, Avinash Desai, MD and Nebu Koshy, MD.
Background
- Patients with TP53 mutated R/R AML have a dismal prognosis with limited treatment options and are seldom offered alloHCT due to high post-transplant relapse rates.
- 131I-apamistamab(Iomab-B) is an anti-CD45 radioimmunoconjugate designed to deliver high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells to enable alloHCT in patients with active R/R AML while limiting off-target toxicity and being mutation- agnostic
- The SIERRA trial compared Iomab-B followed by alloHCT to physician's choice of conventional care, recently reporting that the study met its primary endpoint of durable complete remission lasting at least 6 months
- We compared the outcomes and safety data in patients enrolled in the SIERRA trial with a documented TP53 mutation versus wildtype
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SIERRA - A Phase 3 Randomized Trial in R/R AML
Total Accrual: N=153
Active, Relapsed | ||
or Refractory | RANDOMIZED 1:1 | |
AML | ||
Key Eligibility Criteria:
- R/R AML ≥55 years of age with active disease (BM blast count ≥5% or the presence of circulating blasts)
- Karnofsky score ≥70
- 8/8 allele-level, related or unrelated matched donor
- Previous HCT were excluded
Iomab-B
HCT
Crossover*
*Control arm subjects
with no CR offered
crossover
Conventional Care**
**Wide range of flexible options at physician's discretion
No CR
CR
No CR or
MLFS
CR or
MLFS
Endpoints: | ||
Pre-Specified Primary: | ||
dCR | dCR = CR/CRp lasting | |
≥180 days post-CR | ||
Secondary: OS and EFS | ||
Standard of Care
Physician's Choice
HCT | dCR | |
3
Personalized Single Dose Combined Induction/Conditioning
Dosimetric Dose | Therapeutic Dose | |
≤20 mCi | • Upper limit of 24 Gy to liver | |
• Median 16 Gy to marrow | ||
-19-18 | -15 | -12 |
Imaging
RIC | |||
FLU | TBI | ||
30 mg/m2/d | 200 cGy | ||
HCT | |||
-4-3-2-1 0
Tac/CSA + MMF
RIC: reduced intensity conditioning; FLU: fludarabine; TBI: total body irradiation; HCT: hematopoietic cell transplant;
Tac/CSA: tacrolimus/cyclosporine; MMF: mycophenolate mofetil
4
SIERRA Patient Distribution
153 Pts Randomized
Iomab-B
N=76
Conventional Care
N=77
- 4 pts did not receive dosimetric dose
-
6 pts did not proceed to therapeutic dose with
HCT
• TP53+: 33.3% (2 / 6)
1 pt did not
receive treatment
(TP53+)
No CR/CRp/MLFS
Achieved
CR/CRp/MLFS
66 patients received | Crossover to Iomab-B | |||||
therapeutic dose | N=44 | |||||
4 pts did not proceed to | ||||||
therapeutic dose with HCT | ||||||
TP53+: 50% (2 / 4) | ||||||
HCT
N=66
TP53+: 22.7%
(15 / 66)
HCT
N=40
TP53+: 20%
(8 / 40)
No Further Treatment
N=18
TP53+: 44.4%
(8 / 18)
Conventional HCT
N=14
TP53+: 7.1%
(1 / 14)
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Baseline Characteristics in Patients with TP53 Mutations (N = 37)
Iomab-B (N=17) | Conventional (N=10) | Crossover (N=10) | |
Age, years | 63 (56-74) | 66 (61-71) | 64 (55-74) |
Median (Range) | |||
Pts >65 yrs: 6 (35.3) | Pts >65 yrs: 7 (70.0) | Pts >65 yrs: 4 (40.0) | |
N (%) | |||
Disease Status at | Primary Induction Failure: 12 (70.6) | Primary Induction Failure: 7 (70.0) | Primary Induction Failure: 4 (40.0) |
First Early Relapse: 4 (23.5) | First Early Relapse: 2 (20.0) | ||
Randomization | First Early Relapse: 5 (50.0) | ||
Relapse/Refractory: 0 (0.0) | Relapse/Refractory: 1 (10.0) | ||
N (%) | Relapse/Refractory: 0 (0.0) | ||
2nd + Relapse: 1 (5.9) | 2nd + Relapse: 0 (0.0) | ||
2nd + Relapse: 1 (10.0) | |||
Prior Lines of | |||
Treatment | 2 (1-4) | 3 (1-4) | 4 (1-6) |
Median (Range) | |||
Prior Venetoclax | |||
Treatment | 9 (52.9.) | 6 (60.0) | 6 (60.0) |
N (%) | |||
Karnofsky | ≥90: 9 (52.9) | ≥90: 1 (10.0) | ≥90: 5 (50.0) |
Performance Status | |||
<90: 8 (47.1) | <90: 9 (90.0) | <90: 5 (50.0) | |
N (%) | |||
HCT Co-Morbidity | 0-2:9 (52.94) | 0-2:6 (60.0) | 0-2:6 (60.0) |
Index | |||
≥3: 8 (47.05) | ≥3: 4 (40.0) | ≥3: 4 (40.0) | |
N (%) | |||
1. Per NCCN Guidelines, Version 3, 2020
6
CR and dCR by TP53 Mutation Status and Treatment Received
- Overall dCR Rates at 6 months were 22% in the Iomab-B group vs. 0% in the CC group (95% CI;12.29, 34.73; p<0.0001), irrespective of TP53 mutational status.
- Median OS of TP53 positive patients on CC arm was 1.66 mos versus 5.49 mos in TP53 positive patients who received Iomab-B and alloHCT
Iomab-B + Crossover | Conventional Care | ||||||||
N | % | 95% CI | N | % | 95% CI | ||||
TP53 Positive | N = 27 | N = 10 | |||||||
CR | 15 | 55.56 | (35.33, 74.52) | 0 | 0 | - | |||
Durable CR | 4 | 14.81 | (4.19, 33.73) | 0 | 0 | - | |||
TP53 Wildtype | N = 93 | % | 95% CI | N = 23 | % | 95% CI | |||
CR | 54 | 58.06 | (47.38, 68.22) | 4 | 17.39 | (4.95, 38.78) | |||
Durable CR | 15 | 16.13 | (9.32, 25.20) | 0 | 0 | - | |||
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Survival Probability (%)
Improved Survival with 131I-apamistamab in Patients with TP53 Mutation
Iomab-B + | Conventional | ||
Crossover | Care | ||
N = 27 | N = 10 | ||
Iomab-B + | Median OS (mos) | 5.49 | 1.66 |
(95% CI) | (3.94, 8.25) | (0.99, 2.96) | |
Crossover | |||
CC | Hazard Ratio | 0.23 | |
(95% CI) | (0.10, 0.52) | ||
p value (log-rank) | 0.0002 | ||
Overall Survival (Months)
8
SIERRA Trial Patients with TP53 Mutation
Treatment-Emergent Adverse Events (Grade ≥3)
TP53 Positive Patients | TP53 Negative Patients | ||
Receiving Iomab-B + | Standard HCT | ||
Receiving Iomab-B + HCT1 | |||
HCT1 | |||
N = 14 | |||
N = 83 | |||
N = 23 | |||
Febrile | |||
Neutropenia | 11 (47.8) | 35 (42.2) | 7 (50.0) |
N (%) | |||
Mucositis2 | 4 ( 17.4) | 13 (15.7) | 3 (21.4) |
N (%) | |||
Sepsis | 4 (17.4) | 8 (9.6) | 4 (28.6) |
N (%) | |||
Cumulative | |||
Incidence | 8.7 (1.4, 24.7) | 8.6 (3.8, 16.1) | 14.3 (2.1 , 37.6) |
aGVHD (Gr III-IV) | |||
% (95% CI)
• TP53 mutations are not associated with increased transplant-related toxicity
• Safety data in TP53 positive patients transplanted with Iomab-B aligns that of the entire Iomab-B-treated population
1. Includes patients randomized to Iomab-B arm and CC patients who crossed over to Iomab-B
2. 'Mucositis' includes the Preferred Terms 'Stomatitis' and 'Mucosal Inflammation'
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Actinium Pharmaceuticals Inc. published this content on 08 December 2023 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 11 December 2023 13:51:28 UTC.