Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML)

Abstract

Acute myeloid leukemia (AML) with 11q23/MLL rearrangement (MLL-r AML) is allocated to the intermediate- or high-risk cytogenetic prognostic category depending on the MLL fusion partner. A more favorable outcome has been reported in patients receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT), but this has not been confirmed in large series. We analyzed the outcome of alloHSCT among adult patients reported to the Acute Leukemia Working Party between 2000 and 2010. We identified 159 patients with 11q23/MLL rearranged AML allografted in first complete remission (CR1, n=138) or CR2, mostly corresponding to t(9;11), t(11;19), t(6;11) and t(10;11) translocations. Two-year overall survival (OS), leukemia-free survival (LFS), relapse incidence and non-relapse mortality were 56±4%, 51±4%, 31±3% and 17±4%, respectively. The outcome differed according to 11q23/MLL rearrangement, being more favorable in patients with t(9;11) and t(11;19) compared with t(10;11) and t(6;11) (2-year OS: 64±6% and 73±10% vs 40±13% and 24±11%, respectively; P<0.0001). Multivariate analysis for OS identified t(6;11), t(10;11), age>40 years and CR2 as unfavorable features, whereas t(6;11), t(10;11), CR2 and the use of reduced-intensity conditioning regimen affected poorly the LFS. This study confirms the potential role of alloHSCT for adult patients with 11q23/MLL rearranged AML in CR1.

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

“…Mixed-lineage leukemia (MLL) including acute myeloid (AML) and acute lymphoblastic leukemia (ALL) are very aggressive blood cancers with unique clinical and biological characteristics, and are often lethal due to the development of resistance and high relapse rates with established therapies including hematopoietic stem cell transplantation (Pigneux et al, 2015; Tomizawa et al, 2007). MLL leukemia are characterized and driven by the recurrent translocations of an allele of the MLL gene ( MLL , KMT2A ) with a variety of other chromosomes (Mohan et al, 2010b).…”

Non‐acute promyelocytic leukemia variant, acute myeloid leukemia with translocation (11;17)

“…9,14,15 Allo-HSCT offers a favorable outcome for these cases when received in early phase. 8 Although t(11;17) is usually seen with APLv where it occurs between the RARA gene at 17q21.2 and different partners including: ZBTB16 and NUMA1, 2,16 in this case, it occurred at different break points which are t(11;17)(q23;q25), harboring the KMT2A and SEPT9 genes, respectively. The diagnosis of APLv was excluded by the negative results of FISH for PML/RARA, as this probe can detect an aberrant RARA gene, hence a variant RARA translocation.…”

“…[4][5][6] KMT2A gene rearrangements include a wide range of mutations, such as translocations, inversions, insertions, and partial tandem duplications that result in the production of chimeric oncoproteins. 7,8 These oncoproteins cause a gain of function of the KMT2A gene that upregulates the expression of the HOX (homeotic gene complex), which has a major role in the regulation of early hematopoiesis. 9,10 These rearrangements occur in heterogeneous groups of lymphoid, myeloid, and mixed-lineage leukemias.…”

The who, how and why: Allogeneic transplant for acute myeloid leukemia in patients older than 60 years

“…In the largest report of 11q23 AML patients, a significant difference in 2-year OS was found depending on translocation with t(9;11) and t(11;19) faring better at 64% and 73%, respectively than t(6;11) and t(10;11) at 40% and 24%, respectively (p<0.0001). In multivariate analysis, these trends in translocations were again demonstrated as were poorer outcomes for patients receiving RIC, older than 40, and undergoing transplant in CR2 rather than CR1 18 . This study included patients up to 67 years of age, but outcomes in elderly patients with mutations involving 11q23 have not been studied independently.…”