8 research outputs found
BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells
SummaryMost forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed âROS-lowâ). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation
âPreleukemic or smolderingâ chronic myelogenous leukemia (CML):BCR-ABL1 positive: A brief case report
Chronic myelogenous leukemia (CML), in the Chronic Phase (CP), is often suspected as a result of a complete blood count (CBC), which shows increased granulocytes, mostly mature including a peak in myelocytes, increased basophils, and rarely blasts and/or promyelocytes. Morphologic dysplasia is not present. CML is confirmed by detecting the characteristic Philadelphia chromosome (Ph)[t(9;22)(q34;q11.2)] by routine cytogenetics or fluorescent in situ hybridization (FISH) or molecular studies (RT-PCR) for the bcr-abl fusion gene.
The most common feature of CML is an elevated WBC count, usually above 25Ă103/”L, and frequently above 100Ă103/”L. We report a case of confirmed Ph+CML with a normal CBC detected because of the presence of rare myelocytes and 2% basophils [Fig. 1]. Previous leukocyte counts for the preceding eight years were normal with the exception of one done four months prior to his presentation that showed an abnormal differential with 1% basophils, 2% metamyelocytes and 2% myelocytes
Discovery of Potent Parthenolide-Based Antileukemic Agents Enabled by Late-Stage P450-Mediated CîžH Functionalization
The sesquiterpene lactone parthenolide
has recently attracted considerable
attention owing to its promising antitumor properties, in particular
in the context of stem-cell cancers including leukemia. Yet, the lack
of viable synthetic routes for re-elaborating this complex natural
product has represented a fundamental obstacle toward further optimization
of its pharmacological properties. Here, we demonstrate how this challenge
could be addressed via selective, late-stage <i>sp</i><sup>3</sup> CâH bond functionalization mediated by P450 catalysts
with tailored site-selectivity. Taking advantage of our recently introduced
tools for high-throughput P450 fingerprinting and fingerprint-driven
P450 reactivity prediction, we evolved P450 variants useful for carrying
out the highly regioselective hydroxylation of two aliphatic sites
(C9 and C14) in parthenolide carbocyclic backbone. By chemoenzymatic
synthesis, a panel of novel C9- and C14-modified parthenolide analogs
were generated in order to gain initial structureâactivity
insights on these previously inaccessible sites of the molecule. Notably,
some of these compounds were found to possess significantly improved
antileukemic potency against primary acute myeloid leukemia cells,
while exhibiting low toxicity against normal mature and progenitor
hematopoietic cells. By identifying two âhot spotsâ
for improving the anticancer properties of parthenolide, this study
highlights the potential of P450-mediated CâH functionalization
as an enabling, new strategy for the late-stage manipulation of bioactive
natural product scaffolds
P367: LONG-TERM OUTCOMES OF ADULTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH BREXUCABTAGENE AUTOLEUCEL IN ZUMA-3 BY AGE, PRIOR THERAPIES, AND SUBSEQUENT TRANSPLANT
BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells
KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study
International audienceBACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1âĂâ10(6) CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company