Here we demonstrate that in a niche-like coculture system, cells from both primary and cultured acute myeloid leukemia (AML) sources take up functional mitochondria from murine or human bone marrow ...stromal cells. Using different molecular and imaging approaches, we show that AML cells can increase their mitochondrial mass up to 14%. After coculture, recipient AML cells showed a 1.5-fold increase in mitochondrial adenosine triphosphate production and were less prone to mitochondrial depolarization after chemotherapy, displaying a higher survival. This unidirectional transfer enhanced by some chemotherapeutic agents required cell–cell contacts and proceeded through an endocytic pathway. Transfer was greater in AML blasts compared with normal cord blood CD34+ cells. Finally, we demonstrate that mitochondrial transfer was observed in vivo in an NSG immunodeficient mouse xenograft model and also occurred in human leukemia initiating cells and progenitors. As mitochondrial transfer provides a clear survival advantage following chemotherapy and a higher leukemic long-term culture initiating cell potential, targeting mitochondrial transfer could represent a future therapeutic target for AML treatment.
•Bone marrow mesenchymal stromal cells transfer functional mitochondria to AML cells in vitro and in vivo through endocytic pathways.•This mitochondria transfer is enhanced by some chemotherapies and confers a survival advantage to leukemic blasts and leukemia initiating cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience ...primary or secondary treatment failure. The outcome of these patients has not yet been described.
Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program).
The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care.
Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.
IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIR-mediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have ...conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mg/kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenty-three patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapse-free survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. Registered with the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) as 2005-005298-31.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The
(
) gene is mutated in 25-30% of patients with acute myeloid leukemia (AML). Because of the poor prognosis associated with
-internal tandem duplication mutated AML, allogeneic hematopoietic ...stem-cell transplantation (SCT) was commonly performed in first complete remission. Remarkable progress has been made in frontline treatments with the incorporation of FLT3 inhibitors and the development of highly sensitive minimal/measurable residual disease assays. Similarly, recent progress in allogeneic hematopoietic SCT includes improvement of transplant techniques, the use of haploidentical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as post-transplant maintenance therapy. Nevertheless, current transplant strategies vary between centers and differ in terms of transplant indications based on the internal tandem duplication allelic ratio and concomitant nucleophos-min-1 mutation, as well as in terms of post-transplant maintenance/consolidation. This review generated by international leukemia or transplant experts, mostly from the European Society for Blood and Marrow Transplantation, attempts to develop a position statement on best approaches for allogeneic hematopoietic SCT for AML with
-internal tandem duplication including indications for and modalities of such transplants and on the potential optimization of post-transplant maintenance with FLT inhibitors.
For several decades, we have known that epigenetic regulation is disrupted in cancer. Recently, an increasing body of data suggests epigenetics might be an intersection of current cancer research ...trends: next generation sequencing, immunology, metabolomics, and cell aging. The new emphasis on epigenetics is also related to the increasing production of drugs capable of interfering with epigenetic mechanisms and able to trigger clinical responses in even advanced phase patients. In this review, we will use myeloid malignancies as proof of concept examples of how epigenetic mechanisms can trigger or promote oncogenesis. We will also show how epigenetic mechanisms are related to genetic aberrations, and how they affect other systems, like immune response. Finally, we will show how we can try to influence the fate of cancer cells with epigenetic therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with peripheral blood cytopenias, dysplastic cell morphology, and a variable ...risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine have been used for over a decade in MDS treatment and lead to a modest survival benefit. However, response rates are only around 40% and responses are mostly transient. For HMA-refractory patients the prognosis is poor and there are no therapies approved by the United States Food and Drug Administration.
Combinations of HMAs, especially along with immune checkpoint inhibitors, have shown promising signals in both the frontline and HMA-refractory setting. Several other novel agents including orally available and longer acting HMAs, the BCL-2 inhibitor venetoclax, oral agents targeting driver mutations (IDH1/2, FLT3), immunotherapies, and new options for intensive chemotherapy have been studied with variable success and will be reviewed herein. Except for the minority of patients with targetable driver mutations, HMAs – likely as part of combination therapies – will remain the backbone of frontline MDS treatment. However, the wider use of genetic testing may enable a more targeted and individualized therapy of MDS patients.
Introduction:
The results of conventional treatment for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remain poor and innovative strategies are warranted. With this aim, epigenetic ...modulation became a promising approach over the last years. Vorinostat is an epigenetic targeted drug belonging to the histone deacetylase (HDAC) inhibitors family. It is the second-generation HDAC inhibitor that has been more extensively studied in AML and MDS.
Areas covered:
In this review, we will present the rationale for its use in AML and MDS, describe the drug pharmacologic properties and review the current data available from clinical trials. The data presented here will allow the reader to overview the common mechanisms of action of this class of compounds in AML and MDS, as well as to better understand the biological specificities of vorinostat, and its current and future clinical development in the field.
Expert opinion:
Vorinostat has shown an acceptable toxicity profile with mainly gastrointestinal and constitutional side effects. Efficacy as a single agent is limited in that group of patients, but promising results are currently observed with combinations of vorinostat and either conventional chemotherapy or investigational agents, including demethylating agents.
Although core-binding factor-acute myeloid leukemia (CBF-AML) (t8;21 or inv16/t16;16) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive ...chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t8;21, 86 inv16/t16;16) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.
•GO before transplant improves outcome of CBF-AML patients in first relapse.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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