DNMT3A mutation + IDH mutation

(1) The rare but recurrent cytogenetic aberration i(7)(p10) is mainly found in AML, where associations with mutations in IDH2, DNMT3A and BCOR were observed. By contrast, other AML-defining mutations ( NPM1, FLT3-ITD, CEPBA) were largely absent, further no defining fusions/rearrangements or a complex karyotype were detected. (2) The vast majority of patients were female and younger than patients with IDH2 mutation without i(7)(p10).

Early relapse, observed in 19% of patients, mostly in the first 3 months after allo-SCT, was the most important factor that impacted treatment feasibility. This underlines that the timing of SOR start should be as early as possible after allo-SCT.

Contrary to the immunophenotype, the genetic profile in AML is significantly associated with a high/low number of leukocytes. The highest leukocyte counts were followed by a combination of epigenetic and driver mutations (DNMT3A/TET2/IDH1/2 plus NPM1/ FLT3/CEBPA) in both intermediate and unfavorable risk groups. We have also shown that patients' driver mutations (NPM1/FLT3/ CEBPA) are characterized by an immunologically more mature immunophenotype (CD34-) of the tumor clone.

This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. DNA methylation did not show significant shift. This safe and active initial therapy regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL.

These samples also show remarkable sensitivity to panobinostat, an HDAC inhibitor, which suppresses mTORC1 signaling and OXPHOS...Cluster 3-like AML cell-lines also show remarkable sensitivity to the JAK inhibitor, ruxolitinib...We validated these clusters using the TCGA AML (n=173) and a second BeatAML cohort (n=182).We further confirmed the existence and therapeutic value of these clusters by projecting them onto single-cell RNA-seq data obtained from a patient before and after VEN+azacitidine treatment...While Cluster 1 like cells were characterized by activation of metabolic pathways, the more proliferative Cluster 2 like cells dominated the tumor after relapse. Our study systematically identified and characterized mechanistic heterogeneity in venetoclax resistant AMLs and can aid therapeutic decision making and development of effective combination therapies with venetoclax.

Post-transplantation SOR reduces the risk of relapse in FLT3+ AML. In our experience SOR was well tolerated even if 4 patients stopped the treatment because of toxicity. Early relapse, observed in 19% of patients, mostly in the first 3 months after allo-SCT, was the most important factor that impacted treatment feasibility.

Patients & Eighty-six patients with relapsed/refractory AITL or nodal follicular helper T-cell lymphoma were randomized between CC-486 (n=42) and investigator's choice (gemcitabine, n=24, bendamustine n=16, romidepsin n=4) between November 2018 and February 2021. The trial did not meet its primary endpoint, most likely due to an optimistic hypothesis of PFS improvement, resulting in a study including 86 patients which could be underpowered to detect a clinically meaningful difference. 5-azacytidine had a favourable safety profile compared to standard of care and was associated with prolonged overall survival, suggesting that this drug might have a role in the treatment of TFH PTCL and could be investigated in combination with other agents.

The treatment regimens consisted of Venetoclax in combination with either chemotherapy (Venetoclax 600mg/d with low dose Cytarabine 20mg/m2 D1-10 and/or Actinomycin D 12.5mcg/kg D1-3), or hypomethylating (HMA) agents (Venetoclax 400mg/d with Decitabine 20mg/m2 D1-5/D1-10 or Azacitidine 75mg/m2 D1-7)...Patients with targetable mutations (FLT3, N(K)RAS, BCR-ABL1) received concomitant FLT3-inhibitors, Trametinib or BCR-ABL1-inhibitors... Venetoclax based regimens produce high remission rates in both ND and R/R AML or MDS-EB2 in the real-life setting. Poor performance status, TP53 and PTPN11 mutations negatively impact OS, whereas DNMT3A, IDH2 mutations and bridging to alloSCT are associated with improved OS.