Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated ...histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results of patients with acute leukaemia (leukaemia cohort).
In this dose-escalation, phase 1 study we recruited patients from seven university hospital centres (in France five, UK one, and Canada one). Adults with acute leukaemia who had failed or had a contraindication to standard therapies were eligible to participate. OTX015 was given orally at increasing doses from 10 mg/day to 160 mg/day (14 of 21 days), using a conventional 3 + 3 design. In this open-label trial, OTX015 was initially administered once a day, with allowance for exploration of other schedules. The primary endpoint was dose-limiting toxicity (DLT), assessed during the first treatment cycle (21 days). The study is ongoing and is registered with ClinicalTrials.gov, NCT01713582.
Between Jan 18, 2013, and Sept 9, 2014, 41 patients, 36 with acute myeloid leukaemia, a median age of 70 years (IQR 60-75) and two lines of previous therapy, were recruited and treated across six dose levels of OTX015. No DLT was recorded until 160 mg/day, when one patient had grade 3 diarrhoea and another had grade 3 fatigue. However, concomitant grade 1-2 non-DLT toxic effects (ie, gastrointestinal, fatigue, or cutaneous) from 120 mg doses hampered patient compliance and 80 mg once a day was judged the recommended dose with a 14 days on, 7 days off schedule. Common toxic effects for all OTX015 doses were fatigue (including grade 3 in three patients) and bilirubin concentration increases (including grade 3-4 in two patients). OTX015 plasma exposure increased proportionally up to 120 mg/day with trough concentrations in the in-vitro active range from 80 mg/day (274 nmol/L). Three patients (receiving 40 mg/day, 80 mg/day, and 160 mg/day) achieved complete remission or complete remission with incomplete recovery of platelets lasting 2-5 months, and two additional patients had partial blast clearance. No predictive biomarkers for response have been identified so far.
The once-daily recommended dose for oral, single agent oral OTX015 use in patients with acute leukaemia for further phase 2 studies is 80 mg on a 14 days on, 7 days off schedule.
Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp.
B7-H1 (PD-L1) is a B7-related protein that inhibits T-cell responses. B7-H1 participates in the immunoescape of cancer cells and is also involved in the long-term persistence of leukemic cells in a ...mouse model of leukemia. B7-H1 can be constitutively expressed by cancer cells, but is also induced by various stimuli. Therefore, we examined the constitutive and inducible expression of B7-H1 and the consequences of this expression in human acute myeloid leukemia (AML). We analyzed B7-H1 expression in a cohort of 79 patients with AML. In addition, we studied blast cells after incubation with interferon-gamma or toll-like receptors (TLR) ligands. Finally, we evaluated functionality of cytotoxic T-cell activity against blast cells. Expression of B7-H1 upon diagnosis was high in 18% of patients. Expression of TLR2, 4 and 9 was detected in one-third of AML samples. Expression of TLR2 and TLR4 ligands or IFN-γ induced by B7-H1 was found to protect AML cells from CTL-mediated lysis. Spontaneous B7-H1 expression was also found to be enhanced upon relapse in some patients. MEK inhibitors, including UO126 and AZD6244, reduced B7-H1 expression and restored CTL-mediated lysis of blast cells. In AML, B7-H1 expression by blasts represents a possible immune escape mechanism. The inducibility of B7-H1 expression by IFN-γ or TLR ligands suggests that various stimuli, either produced during the immune response against leukemia cells or released by infectious microorganisms, could protect leukemic cells from T cells. The efficacy of MEK inhibitors against B7-H1-mediated inhibition of CTLs suggests a possible cancer immunotherapy strategy using targeted drugs.
We retrospectively examined the results of a new chemo-free approach combining blinatumomab with ponatinib (blina/pona) in 26 relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic ...leukemia (ALL) patients. All but one achieved complete morphologic remission, and 23 achieved a complete molecular response. With a median follow-up of 34.4 months, the median overall (OS) and event-free (EFS) survivals were 20 and 15.3 months, respectively. After blina/pona, 8 patients underwent an allotransplant (allo), while among the 18 non-transplanted cases, 15 received ponatinib in maintenance. Fifteen relapse/progressions occurred with a significant difference between allo and non allo cases (12.5% vs 82.3%, p = 0.003). However, OS and EFS were similar between both groups. Finally, blina/pona was well tolerated with eight reversible neurologic events and three cytokine release syndromes. Prospective studies are needed to properly assess the safety, tolerability and efficacy of the combination therapy.
CD9 is a cell surface protein and belongs to the tetraspanin family. Its role in carcinomagenesis has been widely studied in solid tumors but remains controversial, depending on the cancer type. ...Although CD9 seems to be associated with unfavorable outcome and disease progression in acute lymphoblastic leukemia (ALL), this marker has not yet been studied in acute myeloid leukemia (AML). First, we explored its prognostic role and its association with biological factors in a cohort of 112 AML patients treated with intensive chemotherapy. CD9 was expressed in 40% of AML and was associated with a favorable outcome (event‐free survival and relapse‐free survival) in univariate (P = 0.009 and P = 0.048, respectively) and multivariate (P = 0.004 and P = 0.039, respectively) analyses. Interestingly, CD9 expression was different between the more immature physiologic and AML cells (CD34+CD38−) as it was also expressed in AML on putative leukemic stem cells (LSCs) but not on hematopoietic stem cells (HSCs). Hence, CD9 could be a very relevant marker for minimal residual disease (MRD) monitoring in AML based on LSC targeting.
CD9 is an interesting marker to discriminate hematopoietic stem cells from leukemic stem cells
Introduction
There is a dearth of evidence to document treatment of
FMS-like tyrosine kinase 3
(
FLT3
)-mutated acute myeloid leukemia (AML) in real-world settings before the introduction of FLT3 ...inhibitors. A retrospective cohort study was conducted to understand treatment practices prior to the availability of FLT3 inhibitors in patients with
FLT3
-mutated AML from two registries in France.
Methods
Patient data from January 1, 2009 to December 31, 2017 were collected from the Hauts-de-France and Midi-Pyrénées registries. Patients aged ≥ 18 years at diagnosis with
FLT3
-mutated AML were included. Demographic and disease characteristics of patients with
FLT3
-mutated AML and relapsed or refractory (R/R)
FLT3
-mutated AML were documented. Treatment regimens, overall survival (OS), and event-free survival were assessed in patients with R/R
FLT3
-mutated AML who did not participate in clinical trials.
Results
Overall, 819 and 1244 adult patients with AML from the Midi-Pyrénées and Hauts-de-France cohorts, respectively, underwent
FLT3
mutation testing; 172 (21.0%) and 263 (21.1%) patients, respectively, had a
FLT3
mutation. Primary R/R status was identified in 41.3% (
n
= 71/172) of the Midi-Pyrénées and 34.6% (
n
= 91/263) of the Hauts-de-France cohorts. Before R/R AML diagnosis, 82.0% and 97.5% of patients in the Midi-Pyrénées and Hauts-de-France cohorts, respectively, achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) following induction chemotherapy; after diagnosis of R/R AML, CR/CRi rates with salvage therapy were 33.3% and 28.1%, respectively. Median OS (interquartile range) in patients receiving salvage therapy (
n
= 49,
n
= 78) was 5.2 (2.3–11.1) and 6.1 (2.5–35.2) months, in the Midi-Pyrénées and Hauts-de-France cohorts, respectively. Across both cohorts, patients with R/R
FLT3
-mutated AML had low rates of CR/CRi with salvage therapy and a median OS of approximately 6 months.
Conclusion
Before FLT3 inhibitor availability, real-world treatment patterns and outcomes in French patients with R/R
FLT3
-mutated AML were consistent with clinical trial data, highlighting a poor prognosis and unmet need for effective treatment.
Plain Language Summary
Acute myeloid leukemia is a cancer affecting the blood and bone marrow. The presence of specific mutations in the
FMS-like tyrosine kinase 3
(
FLT3
) gene in patients with acute myeloid leukemia can negatively impact response to standard chemotherapy. Patients with these mutations may not respond to chemotherapy or have a shortened duration of response causing a return of the disease, which in turn substantially decreases their life span. In the era prior to the availability of drugs specifically designed to counteract the negative effects of
FLT3
mutations, evidence related to patient characteristics and treatment effects in individuals with acute myeloid leukemia harboring
FLT3
mutations was mainly derived from clinical studies, with little evidence based on real-world experience. To better understand real-world patient characteristics and treatment effects in patients with acute myeloid leukemia and
FLT3
mutations, we analyzed patients from two French registries, Midi-Pyrénées and Hauts-de-France, with a focus on patients who did not respond to or whose disease returned after initial chemotherapy. Patient data from between January 2009 and December 2017 included patients with
FLT3
-mutated acute myeloid leukemia from Midi-Pyrénées and Hauts-de-France who did not respond to or had recurrent disease after responding to initial chemotherapy, had low response to salvage chemotherapy, and a survival duration of 6 months or less. Our real-world observations in patients with relapsed or refractory
FLT3
-mutated acute myeloid leukemia from these two registries were consistent with results reported in clinical trials. Our results highlight the bleak forecast for these patients in the absence of effective drugs.
-mutated (
) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission CR) with ...azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.
This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R
MDS and AML patients.
Fifty-two
patients (34 MDS, 18 AML including seven with more than 30% blasts) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved
next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset (
< .01) and higher age (
= .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively.
In this very high-risk population of
MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.
Abstract FLT3 internal tandem duplication ( FLT3 -ITD) is usually considered as a bad marker for minimal residual disease (MRD) follow-up in acute myeloid leukemia (AML). Our objective was to ...evaluate the suitability of FLT3 -ITD as a target for MRD detection by real-time quantitative PCR, in comparison with two other molecular MRD markers, NPM1 mutation and WT1 overexpression, in 20 adult AML patients treated in Acute Leukemia French Association (ALFA) trials. Overall, these 3 MRD markers showed comparable kinetics in 17/20 (85%) cases. Furthermore, we found that FLT3 -ITD MRD levels after induction chemotherapy are predictive of complete remission duration.
Abstract The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan to kynurenine, blocking T-cell activation and inducing immunosuppression. In patients with acute myeloid leukemia (AML), the ...serum kynurenine/tryptophan ratio (Kyn/Trp) was raised, suggesting a higher IDO activity than in healthy people. Patients with higher Kyn/Trp ratios showed lower survival. IDO activity was also detected in AML cells after exposure to IFN-γ in vitro , suggesting that the higher Kyn/Trp ratio in serum of AML patients might have resulted from stimulated leukemic blast cells. Thus, in AML, the activity of IDO can be easily monitored, providing a tool for future clinical testing of IDO-blocking drugs.
Abstract Tryptophan catabolism, which is mediated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), produces kynurenine. Kynurenine itself is converted by ...downstream enzymes into secondary catabolites. We evaluated the serum levels of primary and secondary tryptophan catabolites in a cohort of patients with myelodysplastic syndromes (MDS). The MDS patients showed significantly higher levels tryptophan catabolites which correlated with cytopenia. The tryptophan catabolites inhibited progenitor expansion during the in vitro culture of hematopoietic cells. Thus, MDS patients are characterized by high tryptophan catabolism resulting in elevated primary and secondary metabolites, which both have inhibitory effects on hematopoiesis.
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