Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives
Abstract
:1. Introduction
2. Biological Bases of Leukemia Relapse Following Allogeneic Bone Marrow Transplantation
3. The Role of MRD Monitoring
3.1. Multiparameter Flow Cytometry (MFC)
3.2. Real-Time Quantitative PCR (RT-qPCR)
3.3. Digital PCR
3.4. Next-Generation DNA Sequencing (NGS)
3.5. Chimerism Analyses
4. Treatment of AML Relapsed after HSCT
4.1. Donor Leukocyte Infusions (DLIs)
4.2. Hypomethylating Agents in Treatment of AML Relapse: Mechanism of Action
4.3. HMAs in the Treatment of Overt Relapse: Clinical Results from Retrospective Trials
4.4. HMAs in the Treatment of Overt Relapse: Clinical Results from Prospective Trials
4.5. Second Allogeneic Hematopoietic Transplantation
- (1)
- Switch from a first MRD or UD to a second HSCT from the same donor (same donor group)
- (2)
- Switch from a first matched-related or unrelated donor to a second different matched-related or unrelated donor (second different matched donor)
- (3)
- Switch from a first matched-related or unrelated donor to a second haploidentical donor (second haplo-group).
5. Prophylaxis of Relapse of AML after HSCT
- (1)
- Maintenance: a continuative therapy starting early post-HSCT (within the first three months from HSCT during which a valid GVL effect did not yet develop) until drug intolerance or progression of the disease.
- (2)
- Consolidation: a limited number of therapy cycles to consolidate the response achieved by the previous intervention.
- (3)
- Pre-emptive therapy: a therapy which is administered when the hematological malignancy is still subclinical and it is detectable only by flow-cytometric or molecular methods, by anticipating the overt relapse.
5.1. Prophylaxis of AML Relapse after HSCT: DLIs
5.2. The Hypomethylating Agents in Prophylaxis after HSCT
5.3. FLT3-Inhibitors in Maintenance
6. Pre-Emptive Therapy
7. Immunologic Therapies
7.1. Novel Cellular-Based Interventions
- (1)
- Expression only by the tumor and by the leukemia stem cells (LSC) that are responsible for relapse.
- (2)
- Absent expression by the normal hematopoietic tissue and by the extra-medullary healthy tissues.
7.2. Immunotherapeutic Strategies
7.3. Immune Checkpoint Inhibitors
7.4. Antibody-Based Therapy
7.5. Vaccines
8. Novel Targeted Agents in Development
8.1. Small-Molecule Inhibitors
8.2. Histone-Deacetylase Inhibitors
8.3. IDH-Inhibitors
9. Extramedullary Relapse of AML
10. Concluding Remarks
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Authors | Number of Patients | Study Design | Schedule of Administration | Response | p-Value | Outcome | p-Value |
---|---|---|---|---|---|---|---|
Craddock et al., 2016 [78] | 181 (116 AML, 65 MDS) | Retrospective | AZA 75 mg/m2 for 5–7 days | CR: 8% > 2 risk factors; CR: 34% no risk factors | p < 0.0019 | 2-year OS: 3% > 2 risk factors; 37% no risk factors | p < 0.00001 |
Motabi I et al., 2016 [79] | 100 (CHT: 73 vs HMAs: 27) | Retrospective | AZA 75 mg/m2 for 5 days + DLI (55% and 33% of pts, respectively) | CR/CRi 51% vs. 19% | p < 0.004 | Median PFS:4.9 vs. 3.8 months In favour of CHT | p < 0.02 |
Schroeder et al., 2018 [80] | 36 (29 AML, 7 MDS) | Retrospective | DAC 20 mg/m2 for 5 days (67%) or 10 days (33%) | ORR: 25% CR: 17% PR: 8% | na | 2-year OS: 11% (±6%) | na |
Schroeder et al., 2013 [84] | 30 (28 AMl, 2 MDS) | Prospective, Open Label, Single-Arm, Phase II | AZA 100 mg/m2 for 5 days + DLI | ORR: 30% CR: 23% PR: 7% | na | Median OS 117 mo (not reached for pts in CR, 83 days for pts without CR) | p < 0.001 in favour of patients achieving CR |
Ghobadi A. et al., 2016 [79] | 8 AML | Prospective, Open Label, 3 + 3 dose escalation, Phase I | AZA 45 mg/m2 (37%) and 75 mg/m2 (63%) at days 4-6-8-10 after DLI | ORR: 75% CR/CRi: 50% Cytogenetic remission: 25% | na | Median DFS: 2.9 mo Median OS: 12.5 mo | na |
Craddock C. et al., 2019 [86] | 29 (24 AML, 5 MDS) | Prospective, Open Label, Dose finding, Phase I | AZA 75 mg/m2 for 7 days + Lenalidomide (4 dose-levels: 5-10-15-25 mg) | ORR: 47% CR/CRi: 40% PR: 6% | na | Median OS: 10 mo for not-responders, 27 mo for responders | p = 0.004 in favour of responders |
Woo J. et al., 2017 [87] | 39 (26 AML, 13 MDS) | Prospective Open-label, Single-Arm, Phase II | AZA 75 mg/m2 for 7 days | ORR: 30.7% CR: 8% PR: 23% | na | 2-year OS: 25% 71 % in responders) | na |
Zhao P. et al., 2021 [90] | 26 AML | Prospective Open-label, Single-Arm, Phase II | AZA 75 mg/m2 for 5 days + Venetoclax followed by DLI | ORR: 61.5% CR: 26.9% PR: 34.6% | na | Median EFS: 120 days Median OS: 284.5 days | na |
Authors | Register/ Institute | N Pts | Period | Donor Type (MRD, MMRD, UD, MMUD, HAPLO) | Outcome (OS, LFS) | Risk Factors (p-Value) |
---|---|---|---|---|---|---|
Christopeit M. et al., 2013 [91] | EBMT | 179 (132 AML, 46 ALL, 1 unclassifiable leukemia) | 1998–2009 | Previous MRD: Same MRD: 51% Different MRD: 11% UD: 38% Previous UD: Same UD (42%) Different UD (58%) | 2-year LFS: 21% 2-year OS: 25% | OS advantage: -Previous CR longer than 6 mts (p < 0.001) -CR at 2nd HSCT (p = 0.006) -1st HSCT from MRD than UD (p = 0.042) |
Orti G. et al., 2016 [92] | GETH | 116 (88 AML, 25 MDS, 3 MPN) | 1979–2011 | MRD: 83% UD: 11% MMRD: 4% Syngenic: 2% | 5-year DFS: 30% 5-year CIR: 37.8% 5-year OS: 32% | Shorter OS: -active disease (p < 0.001.) -time between 1st and 2nd HSCT <430 days (p < 0.001). -2nd HSCT from a donor different from MRD. (p = 0.03) |
Shimoni A. et al., 2019 [96] | EBMT | 556 AML | 2006–2016 | 3 groups: 1- From 1st MRD or UD to 2nd same donor group 2- From 1st MRD or UD to 2nd different MRD or UD 3- From 1st MRD or UD to 2nd HAPLO | 2-year LFS: 23.5% vs. 23.7% vs. 21.6% (p = 0.3) 2-year CIR: 51% vs. 49% vs. 44% (p = 0.9) 2-year OS: 36.4% vs. 28.7% vs. 23.3% (p = 0.21) | Shorter LFS and OS: -relapse <6 mo after 1st HSCT (p = 0.01) -advanced age (p = 0.07). -2nd HAPLO donor (p = 0.07). Better LFS and OS: -CR at 2nd HSCT (p = 0.002) |
Kharfan-Dabaja M. et al. [97] 2021 | EBMT | 455 AML | 2006–2019 | 2nd HSCT from UD (320 pts) vs. Haplo (135 pts) | 2-year LFS: 25% vs. 29% (p = 0.73) 2-year OS: 31% vs. 29% (p = 0.57) | OS advantage: -Relapse > 1 year after 1st HSCT (p < 0.0001) -CR at 2nd HSCT (p = 0.02) |
Rank A. et al., 2021 [98] | EBMT | 45 (34 AML, 11 ALL) | 2001–2018 | 3rd HSCT: 25 pts different donor from 2nd HSCT; 30% of pts had at least 2 donors | 1-year PFS: 11% 1-year OS: 20% | OS/PFS advantage: -Change donor at least one time (p = 0.009/p = 0.007) -KS > 80% (p = 0.083/p = 0.046) -3rd HSCT from UD (p = 0.014/p = 0.012) -3rd HSCT after 2010 (p = 0.011/p = 0.012) |
Kharfan-Dabaja M. et al. [99] 2018 | EBMT | 418 AML | 1992–2015 | Retrospective comparison 2nd HSCT vs. DLIs2 groups: 2nd HSCT (MRD 56%, UD 43%) vs. DLIs (MRD 54%, UD 46%) | 2-year OS in pts relapsing <6 mo: 11% vs. 9% (p = 0.86) 2-year OS in pts relapsing >6 mo: 36% vs. 37% (p = 0.53) 2-year OS in pts in CR at intervention: 35% vs. 51% (p = 0.22) 2-year OS in pts not in CR at intervention: 20% vs. 19% (p = 0.59) | OS advantage: -Relapse > 6 months after 1st HSCT (p < 0.001) -CR at 2nd HSCT (p = 0.001) -prior cGVHD (p = 0.02) |
Yalniz et al., 2021 [94] | MDACC | 91 AML | 2000–2019 | MRD: 41% UD: 37% HAPLO: 21% Cord Blood: 1% | 2-year PFS: 27% 2-year OS: 36% | Shorter OS: -cGVHD after 1st HSCT (p = 0.001) -HCT-CI ≥2 at 2nd HSCT (p < 0.003). -Relapse < 6 months after 1st HSCT (p < 0.02) -2nd HSCT before 2011 (p = 0.02) Shorter PFS: -cGVHD after 1st HSCT (p = 0.001) -HCT-CI ≥2 at 2nd HSCT (p = 0.01) |
Duncan CN et al., 2015 [93] | CIBMTR | 146 Children (64 AML, 66 ALL, 12 MDS, 4 JMMS) 179 Adults (111 AML, 54 ALL, 14 MDS) | 1980–2009 | Children: MRD: 53% UD: 41% Other Related: 5% Adults: MRD: 55% UD: 40% Other Related: 4% | 2-year OS: Children: 83% Adults: 75% 6-year OS: Children: 64% Adults: 51% 10-year OS: Children: 55% Adults: 39% | Shorter OS: -Disease not in CR before 2nd HSCT (<0.01) |
Authors | Number of Patients | Study Design | Schedule of Administration | Relapse | Outcome |
---|---|---|---|---|---|
De Lima et al., 2010 [113] | 45 (37 AML, 8 MDS) | Open Label, dose escalation, Phase I | Optimal: AZA 32 mg/m2 dd 1–5 25-day cycle | 20 mts follow-up CIR: 53% | 1-year EFS: 55% 1-year OS: 77% |
Pusic I et al., 2015 [114] | 22 evaluable (17 AML, 5 MDS) | Open Label, dose escalation, Phase I | Optimal: DAC 10 mg/m2 dd 1–5 6-wks cycle | 2-year CIR: 28% | 2-year DFS: 48% 2-year OS: 56% |
Craddock C. et al., 2016 [78] | 37 AML | Open Label, Single-Arm, Phase II | AZA 36 mg/m2 days 1–5 | Median time to relapse: 8 months | 2-year RFS: 49% 2-year OS: 49% |
De Lima et al., 2018 [116] | 30 (26 AML, 4 MDS) | Open Label, 3+3 dose escalation, Phase I/II | Oral AZA. 4 dose-levels: 200 mg for 7 days 300 mg for 7 days 150 mg for 14 days 200 mg for 14 days | 1-year CIR: 43% 7-days group; 13% 14-days group | Median OS: not reached. Estimated 1-year OS: 81% for 7-day group, 86% for 14-day group |
Guillaume T. et al., 2019 [117] | 30 (20 AML, 10 MDS) | Open Label, Single-Arm (compared with historical cohort not receiving AZA or DLIs), Phase II | AZA 32 mg/m2 days 1–5 + DLI | 2-year CIR: 27%. (41% in historical cohort, p = 0.2) | 2-year DFS: 65.5% 2-year OS: 65.5% |
Oran B. et al., 2020 [118] | 187 (140 AML, 47 MDS) | Randomized 1:1, Open Label, Double Arm, Phase III | AZA 32 mg/m2 days 1–5 vs. observation only | 1-year CIR: 41% vs. 39%p = ns | RFS: 2.07 y vs. 1.28 y (p = ns) OS: 2.52 y vs. 2.56 y (p = ns) |
Lei Gao et al., 2020 [120] | 204 AML | Randomized 1:1, Open Label, Double Arm, Phase III | rhG-CSF 100 µg/m2 days 0–5 + DAC 5 mg/m2 days 1–5 vs. observation only | 2-year CIR: 38% vs. 15% (p < 0.01) | 2-year LFS: 81.9% vs. 60.7% 2-year OS: 85.8% vs. 69.7% |
Authors | Target | CAR Construct | n. pts | Best Response |
---|---|---|---|---|
Ritchie, 2013 [154] | CD33 | CD28-CD3 | 4 | 1 CR 1 PR |
Wang, 2015 [155] | CD 33 | 4-1BB | 1 | 1 PR |
Tang, 2018 [156] | CD 33 | CD28-4-1BB | 3 | 1 CR |
Yao, 2019 [157] | CD 123 | 4-1BB | 1 | 1 CRi |
Cummins, 2019 [158] | CD 123 | CD28-CD3 | 1 CR | |
Zhang, 2021 [152] | CCL-1 | NR | 3 | 3 CR |
Baumeister, 2013 [159] | NKG2D-L | CD3 | 7 | 7 No resp |
Sallman, 2020 [160] | NKG2D-L | CD3 | 22 | 1 MLFR 1 PR 6 SD 14 no resp |
Danylesko, 2020 [161] | CD19 | CD28 | 1 | 1 CR |
Liu F, 2021 [EHA 2020] [162] | CLL-1–CD33 | NR | 9 | 7 CR |
Tambaro, 2021 [163] | CD33 | 4-1BB | 10 | No resp |
Budde LE, 2019 (EHA CAR-T 2019) [164] | CD123 | 4-1BB mRNA vector | 5 | 5 No resp |
Deeren, 2021 [ASH 2020] [165] | NKG2D-L | CD3 | 2 | 1 SD 1 no resp |
Total | 75 | 17 CR/CRi/CRh |
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Leotta, S.; Condorelli, A.; Sciortino, R.; Milone, G.A.; Bellofiore, C.; Garibaldi, B.; Schininà, G.; Spadaro, A.; Cupri, A.; Milone, G. Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives. J. Clin. Med. 2022, 11, 253. https://doi.org/10.3390/jcm11010253
Leotta S, Condorelli A, Sciortino R, Milone GA, Bellofiore C, Garibaldi B, Schininà G, Spadaro A, Cupri A, Milone G. Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives. Journal of Clinical Medicine. 2022; 11(1):253. https://doi.org/10.3390/jcm11010253
Chicago/Turabian StyleLeotta, Salvatore, Annalisa Condorelli, Roberta Sciortino, Giulio Antonio Milone, Claudia Bellofiore, Bruno Garibaldi, Giovanni Schininà, Andrea Spadaro, Alessandra Cupri, and Giuseppe Milone. 2022. "Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives" Journal of Clinical Medicine 11, no. 1: 253. https://doi.org/10.3390/jcm11010253
APA StyleLeotta, S., Condorelli, A., Sciortino, R., Milone, G. A., Bellofiore, C., Garibaldi, B., Schininà, G., Spadaro, A., Cupri, A., & Milone, G. (2022). Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives. Journal of Clinical Medicine, 11(1), 253. https://doi.org/10.3390/jcm11010253