Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor–naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.

Background Usefulness of iron chelation therapy in myelodysplastic patients is still under debate but many authors suggest its possible role in improving survival of low-risk myelodysplastic patients. Several reports have described an unexpected effect of iron chelators, such as an improvement in hemoglobin levels, in patients affected by myelodysplastic syndromes. Furthermore, the novel chelator deferasirox induces a similar improvement more rapidly. Nuclear factor-κB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes. Design and Methods We evaluated deferasirox activity on nuclear factor-κB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 μM deferasirox for 18h. Results Nuclear factor-κB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate. Conclusions Nuclear factor-κB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. This could explain the hemoglobin improvement after in vivo treatment, such that our hypothesis needs to be validated in further prospective studies.

The Wilms’ tumor gene WT1 is a reliable marker for minimal residual disease assessment in acute leukemia patients. The study was designed to demonstrate the potential use of WT1 to establish quality of remission in acute leukemia patients for early identification of patients at high risk of relapse. A prospective study based on a quantitative Real–Time PCR (TaqMan) assay in 562 peripheral blood samples collected from 82 acute leukemia patients at diagnosis and during follow-up was established. The evaluation of WT1 in peripheral blood samples after induction chemotherapy can distinguish the continuous complete remission patients from those who obtain only an “apparent” complete remission and who could relapse within a few months. WT1 helps identify patients at high risk of relapse soon after induction chemotherapy allowing post-induction therapy in high risk patients to be intensified.

The transcription nuclear factor κB (NF-κB) can intervene in oncogenesis through to its capacity to regulate the expression of a large number of genes that regulate apoptosis, cell proliferation and differentiation as well as inflammation, angiogenesis and tumor migration. Impaired NF-κB activity has been demonstrated not only in solid cancers but also in various types of hematologic malignancies including acute myeloid leukemia, chronic myelogenous leukemia and in a subset of myelodysplastic syndromes. The underlying mechanisms, illustrated in the text and although quite diverse in different diseases, provide the rationale for new therapeutic strategies combining different NF-κB or proteasome inhibitors. It has, therefore, been proposed that inhibition of NF-κB could be an adjuvant therapy for cancer and many phase I/II clinical studies are ongoing with different inhibitors. This review highlights the in vitro and in vivo results of NF-κB inhibition in myeloid malignancies.

Purpose: Most patients with chronic-phase chronic myeloid leukemia (CML) who receive imatinib achieve a complete cytogenetic remission (CCgR) and low levels of BCR-ABL transcripts. CCgR is durable in the majority of patients but relapse occurs in a subset. Experimental Design: To determine the potential of quantitative reverse transcription-PCR of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 97 CML patients with an imatinib-induced CCgR. Patients with late chronic phase CML after IFN-α failure were treated with imatinib (400 mg daily). Results: During the imatinib median follow-up time of 36 months (range, 12-54 months), disease monitoring occurred by cytogenetics and quantitative PCR. Twenty percent of patients experienced cytogenetic relapse at a median of 18 months after CCgR and a median of 24 months after starting imatinib. None of the possible prognostic factors studied in univariate and multivariate analyses seemed to predict for loss of cytogenetic response but the reduction of BCR-ABL transcript levels at the time of CCgR is an important prognostic factor. Conclusions: In our study, we showed not only that achieving a major molecular remission at 12 months is predictive of a durable cytogenetic remission but also that patients who achieved a major molecular remission (expressed both as the BCR-ABL/β2 microglobulin ratio % <0.0005 and as a 3-log reduction from median baseline value) already at the time of first achieving a CCgR have significantly longer cytogenetic remission durations than those without this magnitude of molecular response (P < 0.05).