MLL-PTD

"Not for use in diagnostic procedures. )"

Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. Conclusions To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R.

Isabl GxT Heme represents a myeloid cancer profiling solution that reports all clinically relevant biomarkers in AML and MDS inclusive of TP53 allelic state, MLL PTD, disease defining and risk stratifying biomarkers across mutation types. Isabl GxT Heme had comparable sensitivity to the reference test and additionally detected myeloid-relevant driver events in 27% of patients. This work demonstrates the validity and added benefit of Isabl GxT Heme in characterizing myeloid cancers.

Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups.

Compared with OST-01 alone or V, combination of OST-01 and the BCL-2 inhibitor, venetoclax (VEN) demonstrated a synergistic activity on AML cell lines and primary blasts (max synergy score: 28.16), and prolonged survival of MllPTD/WT/Flt3ITD/ITD AML mice (VEN/OST vs OST and VEN, median: 156 vs 123 and 95 days, p=0.0003 and p<0.0001; secondary transplant median: 105 vs 58 and 31 days, p<0.0001 and p<0.0001, respectively) and CM AML mice (VEN/OST vs OST and VEN, median: 85 vs 70 and 58 days, p=0.0005 and p<0.0001; secondary transplant median: 95 vs 62.5 and 48 days, p=0.0003 and p<0.0001, respectively). To date, no preclinical toxicity has been observed. We concluded that OST-01 is a non-toxic, potentially new therapy for AML; translation from the bench to the bedside is underway.

We used two complementary mouse models: a conditional RUNX1 knockout mouse, i,e, Mx-Cre; Runx1flox/flox, and a tetracycline-inducible FPD/AML patient derived RUNX1 S291fsX300 mutation knock-in crossed to a MLL-PTD knock-in mouse, i.e. MLL-PTD; RUNX1 S291fsX300..."Correction" of the RUNX1S291fsX300 mutation by doxycycline withdraw reversed the FPD phenotype as well as the cellular distribution changes in HSCs, GMPs and MEPs...RUNX1 plays a universal role in the systemic developmental program of various HSPC subpopulations but appears to engage in unique lineage specific factors to deliver subpopulation-specific functions such as mega-K cell fate-priming of HSCs, inflammatory program in GMPs, and bone marrow location signals in MEPs. Ongoing analyses of the FPD/AML mouse genomic data in this context are expected to reveal contributions of patient RUNX1 mutations to the disease development.

Although the loss of Cd36 affects the hematopoietic stem cell and erythropoiesis, limited detrimental overall impact was observed on normal Hematopoietic and leukemic microenvironments. Altogether, considering the limited impact on normal hematopoiesis, therapeutic approaches to target CD36 in cancer are unlikely to result in toxicity to normal blood cells.

The prognosis of the patients with t(8; 14) / TCRA/D::MYC-translocated T-ALL/LBL was very poor, we should pay enough attention to it. while CD7 CAR-T allows patients to achieve short-term CR. Allo-HSCT after CAR-T therapy should be considered for long survival.

The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.

Patients with MLL-r positive ALL have moderate remission rates, but are prone to relapse with low overall survival. The outcome of MLL-r positive ALL was closely related to the partner genes, and clinical attention should be paid to screening for MLL partner genes and combining them with other prognostic factors for accurate risk stratification.

Cd36 KO mice exhibited similar leukemia engraftment in the BM (88.92% vs 86.38%, P = 0.0497), spleen (76.48% vs 68.10%, P = 0.1627), liver (16.12% vs 6.70%, P = 0.2521), and blood (16.33% vs 0.96%, P = 0.2504) compared with the WT group. Altogether, our preliminary data suggest that Cd36-KO has limited impact on normal hematopoietic cells.

Conclusion A large proportion (50.1%, 2257/4437) of MDS patients analyzed have molecular findings that allow for further clinical risk stratification. These findings show the benefit of targeting a broad panel of genes using NGS for MDS prognosis and patient risk stratification.

According to our cohort of MDS patients, the proportion of cases who might benefit from the re-stratification according to the IPSS-M, in terms of potential differences in clinical management, is lower than initially expected. In spite of that, information derived from the NGS molecular should be the basis for different treatment approaches in the future. FIGURE LEGENDS: Figure 1.

In a preclinical xenograft and orthotopic model of AML, HM43239 exhibited greater antitumor potency than FLT3 inhibitor gilteritinib, SYK inhibitor entospletinib, BCL-2 inhibitor venetoclax, and demethylation agent azacitidine. As of July 14, 2022, HM43239 has delivered CRc at 80 mg, 120mg and 160 mg, and was well tolerated at these dose levels over multiple cycles with no DLTs or drug-related SAEs. Pharmacokinetic data illustrate increasing drug exposures through 120 mg and observed objective responses through 160 mg in both FLT3-WT and FLT3-mutated R/R AML patients even after gilteritinib and midostaurin treatment. An update of this study, including a planned single agent and venetoclax combination expansion, will be presented at the meeting.

Pts were randomized 1:1 to sabatolimab+HMA (azacitidine [AZA] or decitabine) or placebo+HMA in MDS1, and to sabatolimab+AZA or placebo+AZA in MDS2. Pts in MDS1 had poorer prognosis features (baseline blasts, cytogenetics and higher IPSS-R) compared with MDS2 study. This preliminary analysis is among the first in large, well-controlled trials to assess IPSS-M and shows higher-risk categories compared with IPSS-R. Until molecular testing is routine globally, pt selection for clinical trials is still dependent on IPSS-R.

Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

In conclusion, we showed here that a subpopulation of murine and human AML blasts expresses high levels of PD-1 which mediated disease initiation and growth through activation of the MAPK/ERK signaling pathways. PD-1 blocking antibody reversed these activities and might contribute to the clinical efficacy of anti-PD-1 therapy in AML.

In conclusion, FLT3-ITD is associated with different mutational and transcriptomic profiles compared with FLT3-ITD. The presence of concomitant poor-risk mutations exert negative prognostic impacts in patients with FLT3-ITD, who markedly benefit from allo-HSCT in CR1.

Acute megakaryocytic leukemia has unique and complex phenotypic and genetics characteristics.

New selective and strong inhibitors, including the recently approved gilteritinib, are rapidly changing the treatment paradigm, being able to induce remission in a significant proportion of pts with limited toxicities...In case of refractoriness to induction or relapse, patients were treated with fludarabine and high-dose cytarabine-based chemotherapy plus sorafenib, at the dose of 400 mg BID for 14 days continuously after the end of CHT...Toxicities were not negligible, but in line with those expected after intensive CHT in this population. The potential benefit of combining FLT3 inhibitors with intensive chemotherapy should be further explored in this setting for fit patients, and this strategy is currently under investigation in clinical trials testing new FLT3 inhibitors.

P2, N=50, Completed, Carlos Graux, MD, PhD | Active, not recruiting --> Completed | Trial completion date: Aug 2020 --> Nov 2019