Talha Badar: A brief overview on MLL gene re-arranged AL in this thread
Talha Badar, Hematologist/Oncologist at Mayo Clinic, shared a thread on X/Twitter:
“Weekend review: MLL- rearrange acute leukaemia (AL). Recently there has been a lot of interest in the management of MLL-rearranged acute leukemia, courtesy development of novel Menin inhibitors. A brief overview on MLL gene re-arranged AL in this thread.
Rearrangements of the histone lysine[K]-MethylTransferase 2A gene (KMT2A) gene on chromosome 11q23, formerly known as mixed-lineage leukemia (MLL) gene, are found in10% of cases of AL. Common translocated genes are AFF1 (t [4,11]), MLLT3(t[9,11] [p2,p23]), and MLLT1 (t[11,19] [q23;p13.3]) Other less common are AF10 [t [10,11]], ELL [t [11, 19] (q23,p13.1)], and AF6 [t(6,11).
Risk stratification as per ELN 2022:
t(9;11) (p21.3;q23.3)/MLLT3::KMT2A intermediate risk t(v;11q23.3)/KMT2A-rearranged adverse risk.
Common clinical presentation:
Hyperleukocytosis Hepatosplenomegaly and lymphadenopathy commonly seen. High incidence of CNS involvement Relative high incidence of Leukemia Cutis Associated with therapy related leukemia (topoisomerase II inhibitor with short latency).
Drug resistance: In ALL, associated with resistance to steroids/peg asparaginase. Sensitive to cytarabine and another nucleoside analogue.
Common somatic co-mutation (> 5%): RAS pathway (NRAS or KRAS), found in 22% to 45%. Others in order of occurrence are FLT3, PTPN11, TP53, CEBPA, DNMT3A.
Novel therapeutic targets for MLL gene leukemia: Menin inhibitors, EZH inhibitors, HDAC inhibitors, DOT1L etc. Most advanced among them are Menin inhibitors.: At least 5 different menin inhibitors are being developed, including SNDX-5613 (Revumenib), KO-539 (Zeftomenib), JNJ-75276617, BMF-219, DS-1594a.
Allogeneic stem cell transplantation: Favorable outcome with allo-HCT have been reported in several retrospective/registry analysis.
CAR T-cell therapy for MLL gene rearranged acute leukemia: In small sub-group of patients responses in MLL-r-ALL were encouraging. Challenges:
- Loss of CD19 antigen, commonly seen with t(4;11) sub-type (post Blinatumomab)
- Lineage switch at relapse have been observed (especially postallo-HCT).
Several targets apart from CD19 have been evaluated including CD22, CD19/CD133.”
Link to Powerpoint Presentation.
Source: Talha Badar/X
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