Azacytidine in combination with tyrosine kinase inhibitors induced durable responses in patients with advanced phase chronic myelogenous leukemia

Ruggiu, Mathilde; Oberkampf, Florence; Gourichon, David; Cony‐Makhoul, Pascale; Beckeriche, Florence; Cano, Isabelle; Taksin, Anne‐Laure; Benbrahim, Omar; Ghez, Stéphanie; Farhat, H.; Rigaudeau, Sophie; Gunzburg, Noémie de; Lara, Diane; Terré, Christine; Raggueneau, Victoria; García, Isabel; Spentchian, Marc; Botton, Stéphane de; Rousselot, Philippe

doi:10.1080/10428194.2017.1397666

Cited by 19 publications

(8 citation statements)

References 29 publications

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“…Results of imatinib combination were disappointing (107, 108), partly because the majority of these patients had already failed imatinib (111). Combination of azacytidine and dasatinib, nilotinib or ponatinib determined better hematologic, cytogenetic and molecular responses, and OS of 2 years or more were observed (109, 110).…”

Section: Tki and Chemotherapy For The Treatment Of Advanced Phasementioning

confidence: 99%

Management of Chronic Myeloid Leukemia in Advanced Phase

et al. 2019

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Management of chronic myeloid leukemia (CML) in advanced phases remains a challenge also in the era of tyrosine kinase inhibitors (TKIs) treatment. Cytogenetic clonal evolution and development of resistant mutations represent crucial events that limit the benefit of subsequent therapies in these patients. CML is diagnosed in accelerated (AP) or blast phase (BP) in <5% of patients, and the availability of effective treatments for chronic phase (CP) has dramatically reduced progressions on therapy. Due to smaller number of patients, few randomized studies are available in this setting and evidences are limited. Nevertheless, three main scenarios may be drawn: (a) patients diagnosed in AP are at higher risk of failure as compared to CP patients, but if they achieve optimal responses with frontline TKI treatment their outcome may be similarly favorable; (b) patients diagnosed in BP may be treated with TKI alone or with TKI together with conventional chemotherapy regimens, and subsequent transplant decisions should rely on kinetics of response and individual transplant risk; (c) patients in CP progressing under TKI treatment represent the most challenging population and they should be treated with alternative TKI according to the mutational profile, optional chemotherapy in BP patients, and transplant should be considered in suitable cases after return to second CP. Due to lack of validated and reliable markers to predict blast crisis and the still unsatisfactory results of treatments in this setting, prevention of progression by careful selection of frontline treatment in CP and early treatment intensification in non-optimal responders remains the main goal. Personalized evaluation of response kinetics could help in identifying patients at risk for progression.

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Section: Tki and Chemotherapy For The Treatment Of Advanced Phasementioning

confidence: 99%

Management of Chronic Myeloid Leukemia in Advanced Phase

et al. 2019

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“…TKIs with hypomethylating agents have dem on strated some effi cacy and OS ben e fit. 32,33 Overall, BPCML is a rare entity, and defin ing uni fied treat ment guide lines is chal leng ing. However, patients with high blast bur den almost always need treat ment with stan dard che mo ther apy in addi tion to TKIs.…”

Section: Treatment Of Bp-cmlmentioning

confidence: 99%

Blast and accelerated phase CML: room for improvement

2021

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Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). With TKI therapy, the percentage of patients who progress to accelerated phase (AP) or blast phase (BP) CML has decreased from more than 20% to 1% to 1.5% per year. Although AP- and BP-CML occur in a minority of patients, outcomes in these patients are significantly worse compared with chronic phase CML, with decreased response rates and duration of response to TKI. Despite this, TKIs have improved outcomes in advanced phase CML, particularly in de novo AP patients, but are often inadequate for lasting remissions. The goal of initial therapy in advanced CML is a return to a chronic phase followed by consideration for bone marrow transplantation. The addition of induction chemotherapy with TKI is often necessary for achievement of a second chronic phase. Given the small population of patients with advanced CML, development of novel treatment strategies and investigational agents is challenging, although clinical trial participation is encouraged in AP and BP patients, whenever possible. We review the overall management approach to advanced CML, including TKI selection, combination therapy, consideration of transplant, and novel agents.

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“…In order to target the epigenome together with BCR-ABL, the combination of TKI and epigenetic drugs, such as decitabine or azacytidine, was recently explored. Few preliminary clinical trials showed that treatment with hypomethylating agents is able induce responses in CML patients, even in advanced stages and despite imatinib-refractoriness (73). However, responses to this combo are usually not durable, and might be considered only as a possible bridge to transplant in patients not responding to TKIs.…”

Section: Strategies To Fight Bcr-abl Independent Resistancementioning

confidence: 99%

BCR-ABL Independent Mechanisms of Resistance in Chronic Myeloid Leukemia

Loscocco¹,

Visani²,

Galimberti

et al. 2019

Front. Oncol.

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Not all chronic myeloid leukemia (CML) patients are cured with tyrosine kinase inhibitors (TKIs), and a proportion of them develop resistance. Recently, continuous BCR-ABL gene expression has been found in resistant cells with undetectable BCR-ABL protein expression, indicating that resistance may occur through kinase independent mechanisms, mainly due to the persistence of leukemia stem cells (LSCs). LSCs reside in the bone marrow niche in a quiescent state, and are characterized by a high heterogeneity in genetic, epigenetic, and transcriptional mechanisms. New approaches based on single cell genomics have offered the opportunity to identify distinct subpopulations of LSCs at diagnosis and during treatment. In the one hand, TKIs are not able to efficiently kill CML-LSCs, but they may be responsible for the modification of some LSCs characteristics, thus contributing to heterogeneity within the tumor. In the other hand, the bone marrow niche is responsible for the interactions between surrounding stromal cells and LSCs, resulting in the generation of specific signals which could favor LSCs cell cycle arrest and allow them to persist during treatment with TKIs. Additionally, LSCs may themselves alter the niche by expressing various costimulatory molecules and secreting suppressive cytokines, able to target metabolic pathways, create an anti-apoptotic environment, and alter immune system functions. Accordingly, the production of an immunosuppressant milieu may facilitate tumor escape from immune surveillance and induce chemo-resistance. In this review we will focus on BCR-ABL-independent mechanisms, analyzing especially those with a potential clinical impact in the management of CML patients.

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Azacytidine in combination with tyrosine kinase inhibitors induced durable responses in patients with advanced phase chronic myelogenous leukemia

Cited by 19 publications

References 29 publications

Management of Chronic Myeloid Leukemia in Advanced Phase

Management of Chronic Myeloid Leukemia in Advanced Phase

Blast and accelerated phase CML: room for improvement

BCR-ABL Independent Mechanisms of Resistance in Chronic Myeloid Leukemia

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