MLL rearrangement

P2, N=27, Recruiting, University of Illinois at Chicago | Trial completion date: Nov 2024 --> Dec 2026 | Trial primary completion date: Nov 2024 --> Dec 2026

Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of BRAF mutations in AML. We further posit whether patients with BRAF V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms.

P1/2, N=413, Recruiting, Syndax Pharmaceuticals | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2027

Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

P3, N=5949, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

Conclusions : Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.

P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

Chidamide combined with (+)-JQ-1 can inhibit the proliferation of MLL-r AML cells, inhibit the initiation of protective self-repair of these leukemia cells by inhibiting the DNA damage response pathway, and ultimately increase the apoptosis of these cells, but non- MLL-r AML cells have no similar results.

This effect of 37 is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound 37 has prolonged anti-leukemic action and exhibits promising in vivo efficacy, making it a valuable probe for further menin-MLL interaction studies.

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2024 --> Jun 2025

EP300/CREBBP inhibitor selectively exerted potent anti-leukemia activity through blocking the MLL-r-BET complex binding to H3K27Ac modification on critical genes loci, distinct from global histone acetylation. Collectively, our study identified EP300/CREBBP as a critical epigenetic driver of MLL-r leukemia and validated their therapeutic potential through targeting inhibition, offering a promising avenue for improving clinical outcomes in this aggressive leukemia.

P2, N=10, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Dec 2024 --> Jun 2024

P2, N=54, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

We characterize the KMT2A fusions present in myeloid malignant samples. We also describe the abundance of KMT2A PTDs in both healthy donor and myeloid samples, with myeloid cases showing significantly higher PTD read counts. KMT2A PTD read count >2000 is present only in malignant samples but not in healthy donors.

P2, N=46, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

Compared to each drug, co-treatment with FHD-286 and BETi, MI, decitabine or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as promising therapy of AML with MLL1r or mtNPM1.

Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics...The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range.

Our study first identify vulnerability to ferroptosis by regulating MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway. Combined treatment with HMAs and FINs provides a potential therapeutic choice for AML patients, especially for R/R-AML.

The findings underscore the significance of LAMP5-AS1 in MLL leukemia progression through the regulation of the autophagy pathway. Additionally, this study unveils the novel lncRNA-DOT1L-LAMP5 axis as promising therapeutic targets for degrading MLL fusion proteins.

It is very important to analyze the maintenance role of PHF6 in AML, which is different from its tumor-suppressing function in T-cell acute lymphoblastic leukemia (T-ALL). Our study showed that inhibiting PHF6 expression may be a potential therapeutic strategy targeting AML patients.

Our results suggest that JOA may be considered a promising anti-leukemia compound to develop to surmount the differentiation block in AL patients.

P2, N=31, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2023 --> Dec 2025

P=N/A, N=11, Completed, Universitair Ziekenhuis Brussel | Unknown status --> Completed | Phase classification: P1/2 --> PN/A | N=20 --> 11

They were all maintemanced with chidamide, except one with chidamide plus sorafenib. Maintenance therapy with chidamide might decrease the relapse in fusion gene-positive AML patients with MRD-positive or ELN-high risk, who could not take allo-HSCT, and prolong their survival, with a well toleration.

We performed cell viability experiments on leukemia cell lines (MV4; 11, MOLM13, RS4; 11, THP1, SEM, KOPN8, NOMO1, HL60, ML2) with single, two and three drug combinations using a menin inhibitor (VTP50469), a DOT1L inhibitor (EPZ5676), and a CDK9 inhibitor (AZD4573). Based on our preclinical in vitro findings, the co-inhibition of menin-DOT1L or menin-CDK9 is a promising approach for the treatment of MLL-r leukemia. The varying responses of different MLL-r leukemia cell lines to drug combination treatment indicate that not all cases of MLL-r leukemia will respond uniformly to treatment combinations. Taken together, our data provide a strategy to determine optimal treatment combinations for personalized treatment of MLL-r leukemia.

P2, N=10, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Nov 2022 --> Dec 2024

Haplo-HSCT is not inferior to HLA-matched transplant. The children with MLL rearrangement had an acceptable 5-year OS, while complications and relapse should be monitored.

We also demonstrated that CAD204520 treatment of MLLr cells significantly reduces NOTCH1 and its target genes as well as NOTCH1 receptor expression. This was not observed with a comparable cytarabine treatment, indicating the specificity of the small molecule...In conclusion, our findings uncover the oncogenic relevance of the NOTCH1 pathway in MLLr leukemia. Its inhibition leads to specific anti-leukemic effects and paves the way for further evaluation in clinical settings.

P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2023 --> Oct 2025 | Trial primary completion date: Oct 2023 --> Oct 2024

Overall, our findings indicate that Latino children are significantly less likely to have favorable cytogenetic subtypes, TCF3::PBX1 and iAMP21 and prognostically neutral cytogenetics. Further evaluation of cytogenetic subtypes and race/ethnicity may elucidate their contribution to outcome disparities.

Background: Bisantrene (Bis), is a topoisomerase-II inhibitor with anthracycline-like activity, lower cardiotoxicity, and activity in patients (pts) with relapsed (rel)/primary refractory (PR) acute myeloid leukemia (AML) (Am J Hematol, 2021). In this Phase II study in a very advanced group of relapsed refractory AML pts resistant to multiple previous lines of chemotherapy including transplantation and with a median of 50% blasts at study initiation, Bis/Clo/Flu combination therapy was found to be safe and well tolerated without cardiac toxicity or tumor lysis syndrome. The maximum length of Bis/Clo/Flu administration was 4 days due to rapidly reversible liver toxicity, and transaminitis. As expected in this highly pretreated population, the infection rates were high.

In this study, we present the in vivo effectiveness of DS-1594b in combination with venetoclax in a PDX model of NPM1-mutated AML. Moreover, the combination treatment exhibits differentiation-inducing effects, which contribute to its therapeutic effectiveness, and was safe. Overall, our findings strongly indicate that the combination of DS-1594b and venetoclax exhibits promising anti-leukemic activity in vivo and holds potential as a therapeutic strategy for AML patients with mtNPM1 mutations.

Finally, high expression of BRCA1 and BRCA2 genes in the host cells, at remission, is strongly correlated with a higher risk of relapse. Although this study has been performed with an adequate number of children with B-ALL, it is mandatory to perform a prospective project with a larger population.

1) Extensive genetic profiling indicated a substantial clonal evolution in the progression from CP to BP CML including loss of ASXL1 mutations, expansion of RUNX1 mutated clones, multiple CNA, and the frequent acquisition of a BCR rearrangement in BP with a transcriptomic phenotype resembling B-ALL. 2) A subset of CML cases in CP already showed a transcriptomic phenotype resembling acute leukemia indicating a rapid progression to BP. 3) The presence of a RUNX1 mutated subclone or a clonal BCR rearrangement seem to represent a warning signal in CML CP.

Targeting MLLT1/3 is an attractive approach and has the potential for single agent activity across a broad range of molecular defined acute leukemias, with a differential profile to menin inhibitors.

We utilized genetic and pharmacological (mycophenolate mofetil, MMF, a purine biosynthesis inhibitor of IMPDH) approaches to target the enhanced purine metabolism and found inhibition of the purine synthesis pathway promotes myeloid differentiation of both murine and human LSCs...Moreover, we found that the myeloid differentiation induced by MMF or CX-5461 is associated with reduced chromatin occupancy of the MLL-AF9 complex, especially Menin, and downregulated expression of MLL-AF9 target genes, such as Meis1, Hoxa9, and Myc, suggesting a regulatory role of nucleolar rRNA transcription on MLL-AF9 oncogenic gene expression program...Altogether, our findings reveal that purine metabolism maintains nucleolar rRNA transcription homeostasis to modulate MLL fusion complex-induced leukemogenic transcriptional activity in LSCs. The enhanced purine metabolism emerges as a crucial dependency for LSCs, providing potential targets for novel therapeutic strategies in treating MLL-rearranged leukemia.

Study confirmed that MLL-rearranged ALL cells are highly sensitive to the broad-spectrum HDAC inhibitor panobinostat. Furthermore, when exploring therapeutic options for targeting MLLr-AML, we found that combining the BCL-2 inhibitor Venetoclax (VEN) with an MLL-Menin specific inhibitor (MEN1i) specifically downregulated the expression of HDAC9 and had a favorable synergistic killing effect on MLLr-AML in both in vitro and in vivo models, further suggesting an important role of HDAC9 in the treatment of MLLr-AML. To sum up, through this study, we can shed light on the role of specific HDAC molecules in MLLr-AML and provide a new potential target for the degradation of MLL fusion protein to eradicate MLLr-AML.

He started therapy with azacitidine and venetoclax and achieved morphologic remission, measurable residual disease positive (<0.01%). Deletion of chromosome 11q is a rare chromosomal lesion in myeloid malignancies. As the mixed lineage leukemia (MLL) gene is located at the long arm of chromosome 11, it is commonly associated with poor prognosis, especially in therapy-related settings. Although no MLL rearrangement was detected in our case, the multiple relapses and persistent disease despite chemotherapy might be potentially due to having additional EWSR1::FLI1 fusion.

The rapid demise of these two patients with BRAF V600E-mutant AML highlights their poor prognosis. Few cases of BRAF V600E-mutant AML have been described in the literature, all of which reported poor survival. Intriguingly, most cases exhibited monocytic morphology and concurrent KMT2A rearrangements, as was observed in case 2.