KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives
Abstract
:1. Introduction
2. Biology of Rearrangements
3. Clinical Aspects
3.1. Incidence, Clinical Features, and Prognosis in Infancy and Childhood
3.2. Incidence, Clinical Features, and Prognosis in Adulthood
4. Clinical Management of KMT2A-Rearranged AML and Current Clinical Practice
4.1. Chemotherapy
4.2. Less Intensive Regimens
4.3. Hematopoietic Stem Cell Transplantation
5. Menin Inhibitors
5.1. Revumenib
5.2. Ziftomenib
5.3. Other Menin Inhibitors
6. Experimental Data of Combination Therapy
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Partner Gene | Chromosomal Location | Infant AML | Pediatric AML |
Adult AML | % Total AML |
---|---|---|---|---|---|
MLLT3 | (9p22) | 28.4% | 36.5% | 24.4% | 30.4% |
MLLT10 | (10p12.3) | 27.4% | 23.4% | 9.9% | 18.7% |
KMT2A-PTD | (11q23.3) | 0 | 1.5% | 25.6% | 10.7% |
ELL | (19p13.1) | 15.2% | 6.8% | 11.5% | 10.1% |
AFDN | (6q27) | 1.5% | 9.03% | 10.2% | 8.1% |
MLLT1 | (19p13.3) | 1% | 6.02% | 3.6% | 4.2% |
MLLT11 | (1q21.3) | 6.59% | 2.15% | 0.9% | 2.4% |
SEPTIN6 | (Xq24) | 3.55% | 2.15% | 0.45% | 1.7% |
MLLT6 | (17q12) | 0 | 1.07% | 2.72% | 1.6% |
EPS15 | (1p32.3) | 1.01% | 1.07% | 1.58% | 1.3% |
SEPTIN9 | (17q25) | 1.01% | 1.29% | 1.36% | 1.3% |
CBL | Del (11) (q23.3q23.3) | 0 | 0 | 0.22% | 0.89% |
AFF1 | (4q21) | 1.5% | 0.2% | 1.1% | 0.8% |
SEPTIN5 | (22q11.2) | 1.01% | 0.64% | 0.45% | 0.71% |
ABI1 | (10p11.2) | 1.52% | 1.07% | 0 | 0.71% |
Population | Drugs | KMT2Ar Type | Outcome | Reference # |
---|---|---|---|---|
Adult AML | -cytarabine/daunorubicin-based induction chemotherapy ± autologous stem cell transplantation -decitabine ± bortezomib | t(9;11) (p22;q23) t(6;11) (q27;q23) t(11;19) (q23;p13.1) t(11;19) (q23;p13.3) t/ins(10;11) (p13;q23) | % CR (42-77) % 3-year OS (41-5) | [10] |
-venetoclax + HMA | t(9;11) (p22;q23) t(11;19) (q23;p13.1) t(6;11) (q23;q27) t(10;11) (p11.2;q23) t(4;11) (q21.3;q23) t(11;17) (q13;q23) t(11;11) (q13;q23) t/ins(10;11) (p13;q23) | % CR 83 median OS 11.05 months | [36] | |
-allo-HSCT | t(6;11) (q27;q23) t(9;11) (p22:q23) t(11;19) (q23;p13.1) t(10;11) (p12;q23) t(1;11) (q21;q23) | % 3-year OS 59.1 | [38] | |
-intensively treated | KMT2A-PTD | % CR 64.5 median OS 24.4 months | [42] | |
Adult R/R AML | -venetoclax + HMA | t(9;11) (p22;q23) t(11;19) (q23;p13.1) t(6;11) (q23;q27) t(10;11) (p11.2;q23) t(4;11) (q21.3;q23) t(11;17) (q13;q23) t(11;11) (q13;q23) t/ins(10;11) (p13;q23) | % CR 17 median OS 6.05 months | [36] |
Adult R/R AML-ALL-MPAL | -revumenib (SNDX-5613) | t(9;11) (p22:q23) t(4;11) (q21.3;q23) t(11;19) (q23;p13.1) t(6;11) (q27;q23) t(11;17) (q13;q23) Mut. NPM1 | % CR 33 | [47] |
Pediatric AML | -intensively treated + GO | t(6;11) (q23;q27) t(10;11) (p11.2;q23) t(10;12) (p12;q23) t(4;11) (q21.3;q23) t(11;19) (q23;p13.3) | % CR 77 % 5-year OS 50 | [34] |
-allo-HSCT | t(9;11) (p22:q23) t(11;19) (q23;p13.1) t(1;11) (q21;q23) t(6;11) (q27;q23) t(10;11) (p12;q23) t(4;11) (q21.3;q23) t(5;11) (q31;q23) t(7;11) (q22;q23) t(8;11) (q24;q23) | % 3-year OS 52.1 | [39] |
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Guarnera, L.; D’Addona, M.; Bravo-Perez, C.; Visconte, V. KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives. Int. J. Mol. Sci. 2024, 25, 9023. https://doi.org/10.3390/ijms25169023
Guarnera L, D’Addona M, Bravo-Perez C, Visconte V. KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives. International Journal of Molecular Sciences. 2024; 25(16):9023. https://doi.org/10.3390/ijms25169023
Chicago/Turabian StyleGuarnera, Luca, Matteo D’Addona, Carlos Bravo-Perez, and Valeria Visconte. 2024. "KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives" International Journal of Molecular Sciences 25, no. 16: 9023. https://doi.org/10.3390/ijms25169023