Outcome of patients with high risk Myelodysplastic Syndrome (MDS) and advanced Chronic Myelomonocytic Leukemia (CMML) treated with decitabine after azacitidine failure

Harel, Stéphanie; Cherait, Amina; Berthon, Céline; Willekens, Christophe; Park, Sophie; Rigal, Marthe; Bréchignac, Sabine; Thépot, Sylvain; Quesnel, Bruno; Gardin, Claude; Adès, Lionel; Fenaux, Pierre; Braun, Thorsten

doi:10.1016/j.leukres.2015.02.004

Cited by 44 publications

(27 citation statements)

References 14 publications

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“…Several strategies have been evaluated after failure of treatment with 5-AZA, included rigosertib (Garcia-Manero et al, 2016), decitabine (Harel et al, 2015) and vorinostat (Prebet et al, 2014), with dismal outcome. Thus, understanding pro-survival pathways elicited by long-term exposure to 5-AZA is a clinical need for tailored salvage therapy.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Reveals Autophagy as Pro-Survival Pathway Elicited by Long-Term Exposure with 5-Azacitidine in High-Risk Myelodysplasia

Romano

Giallongo

Cava³

et al. 2017

Front. Pharmacol.

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Azacytidine (5-AZA) is the standard first-choice treatment for high-risk myelodysplasia (MDS) patients. However, the clinical outcome for those patients who interrupt treatment or whose disease failed to respond is very poor. In order to identify the cellular pathways that are modified by long-term exposure to 5-AZA, we evaluated key proteins associated with the autophagy pathway by reverse-phase microarray (RPPA). Comparing bone marrow mononucleated cells (BMMCs) obtained from 20 newly-diagnosed patients and after four 5-AZA cycles we found an increased autophagy signaling. We then evaluated ex-vivo the effect of the combination of 5-AZA with autophagy inhibitors chloroquine (CQ) and leupeptin. Since 5-AZA and CQ showed synergism due to an increase of basal autophagy after 5-AZA exposure, we adopted a sequential treatment treating BMMCs with 5 μM 5-AZA for 72 h followed by 10 μM CQ for 24 h and found increased apoptosis, associated to a reduction of G2M phase and increase in G0-G1 phase. Long-term exposure to 5-AZA induced the reduction of the autophagic marker SQSTM1/p62, reversible by CQ or leupeptin exposure. In conclusion, we identified autophagy as a compensatory pathway occurring in MDS-BM after long-term exposure to 5-AZA and we provided evidences that a sequential treatment of 5-AZA followed by CQ could improve 5-AZA efficacy, providing novel insight for tailored therapy in MDS patients progressing after 5-AZA therapy.

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Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Reveals Autophagy as Pro-Survival Pathway Elicited by Long-Term Exposure with 5-Azacitidine in High-Risk Myelodysplasia

Romano

Giallongo

Cava³

et al. 2017

Front. Pharmacol.

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“…on April 6, 2019. by guest www.bloodjournal.org From dismal. 113 Somatic mutations are not predictive of treatment efficacy. 106,114 Gene expression pattern, DNA methylation pattern, and platelet doubling after the first cycle could be more informative.…”

Section: Hmasmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

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“…19 However, HMA switch is associated with a modest response rate of only approximately 20% with most responses being generally short-lived. 20 Chemotherapy is generally reserved for fit patients without adverse-risk karyotype or mutations. In one study of MDS with HMA failure, low-dose chemotherapy resulted in no responses (out of 18 patients), whereas the response rate with intensive chemotherapy was 14% (3 out of 22 patients).…”

Section: Discussionmentioning

confidence: 99%

A phase II study of omacetaxine mepesuccinate for patients with higher‐risk myelodysplastic syndrome and chronic myelomonocytic leukemia after failure of hypomethylating agents

et al. 2018

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The outcome of patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agents (HMAs) failure is poor with a median overall survival (OS) of only 4–6 months. Omacetaxine mepesuccinate (OM) is safe and effective in myeloid malignancies but has not been studied in MDS with HMA failure. We conducted a phase II study of OM in patients with MDS or chronic myelomonocytic leukemia (CMML) who had previously failed or been intolerant to HMAs. Patients received OM at a dose of 1.25 mg/m2 subcutaneously every 12 hours for 3 consecutive days on a 4–7 week schedule. The primary endpoints were the overall response rate (ORR) and OS. Forty-two patients were enrolled with a median age of 76 years. The ORR was 33%. Patients with diploid cytogenetics were more likely to respond to OM than were those with cytogenetic abnormalities (58% versus 23%, respectively; P=0.03). Overall, the median OS was 7.5 months and 1-year OS rate was 25%. Patients with diploid cytogenetics had superior OS to those with cytogenetic abnormalities (median OS 14.8 versus 6.8 months, respectively; P=0.01). Two patients had ongoing response to OM of 2 years or longer (both MDS with diploid cytogenetics and RUNX1 mutation). The most common grade ≥3 adverse events were infections in 11 patients (26%), febrile neutropenia in 4 (10%), and hemorrhage in 3 (7%). Overall, OM was safe and active in patients with MDS or CMML who experienced HMA failure. These results support the further development of OM in this setting.

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Outcome of patients with high risk Myelodysplastic Syndrome (MDS) and advanced Chronic Myelomonocytic Leukemia (CMML) treated with decitabine after azacitidine failure

Cited by 44 publications

References 14 publications

Proteomic Analysis Reveals Autophagy as Pro-Survival Pathway Elicited by Long-Term Exposure with 5-Azacitidine in High-Risk Myelodysplasia

Proteomic Analysis Reveals Autophagy as Pro-Survival Pathway Elicited by Long-Term Exposure with 5-Azacitidine in High-Risk Myelodysplasia

How I treat chronic myelomonocytic leukemia

A phase II study of omacetaxine mepesuccinate for patients with higher‐risk myelodysplastic syndrome and chronic myelomonocytic leukemia after failure of hypomethylating agents

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