Combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast‐phase myeloproliferative neoplasms

Devillier, Raynier; Raffoux, Emmanuel; Rey, Jérôme; Lengliné, Étienne; Ronchetti, Anne-Marie; Sébert, Marie; Boissel, Nicolas; Robin, Marie; Vey, Norbert; Kiladjian, Jean‐Jacques; Dombret, Hervé; Cluzeau, Thomas

doi:10.1111/bjh.13516

Cited by 16 publications

(9 citation statements)

References 10 publications

(15 reference statements)

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“…RUX monotherapy was effective at improving survival in a murine model transplanted with TP53 knockout/ JAK2 V617F positive leukaemic cells but was insufficient to induce remissions and was inferior to combination therapy with a histone deacetylase inhibitor (HDACi) or a Heat shock protein 90 inhibitor [74]. Clinical data is sparse but small numbers of patients have shown improved responses in combination with intensive chemotherapy induction and alongside HDACi [75–77]. In MF, patients with an excess of blasts between 5 and 9% in bone marrow or peripheral blood demonstrated an improved response to RUX which was not seen for those with an accelerated phase defined by 10–19% blasts [78].…”

Section: Main Textmentioning

confidence: 99%

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

et al. 2018

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The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.

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Section: Main Textmentioning

confidence: 99%

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

et al. 2018

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“…To solve this vexing drug resistance problem, combination therapy has been the solution over the last two decades, owing to their synergistic effects seen in some trials [4][5][6]. Although drug resistance is a common phenomenon in chemotherapy, the puzzling mechanism involving complicated signaling pathways is not entirely clear.…”

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confidence: 99%

Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells

Zhang¹,

Bao²,

Mu³

et al. 2016

neo

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Cisplatin is regularly used in the treatment of lung cancer. However, its efficacy is limited because of drug resistance. In this study, we found that Akt expression and activity was increased in lung cancer cells with acquired cisplatin resistance (A549/DDP cells and H460/DDP cells) when compared to their parental cells. Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt kinase activity by its natural inhibitor, Wortmannin, could sensitize DDP-resistant cells to DDP and reverse DDP resistance. Combination treatment of Wortmannin with cisplatin is capable of increasing the mortality rate of both A549/DDP cells and H460/DDP cells. The present study also demonstrated that hyperactivation of PI3K/Aktpathway is closely associated with cisplatin resistance by regulating the Bax-mitochondria-mediated apoptosis pathway in human lung cancer. Inhibition of PI3K/Aktactivity in A549/DDP cells and H460/DDP cells could reverse cisplatin resistance by enhancing the effect of cisplatin on Bax oligomerization and release of Cytochrome C, allowing activation of the caspase-mediated apoptosis pathway. In conclusion, cisplatin resistance of lung cancer can be reversed via the inhibition of the PI3K/Akt signaling pathway. Therefore, both PI3K and Akt may be potential targets for overcoming cisplatin resistance in lung cancer.

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“…In the phase 2 trial that followed, recruiting 25 patients, the main results were similar with an overall response rate and a median OS of 44% and 9.5 months, respectively (trial identifier NCT02076191) [42]. A French study has investigated the combination of ruxolitinib and intensive induction therapy ("3 + 7") in a pilot study on six cases [43], obtaining two CR and two PR. The intent of the investigators relied on the idea that ruxolitinib might increase the depth of response, and thus serve as a better bridge to HSCT compared to chemotherapy alone.…”

Section: Jak1/2 Inhibitorsmentioning

confidence: 82%

Acute Myeloid Leukemia Evolving from Myeloproliferative Neoplasms: Many Sides of a Challenging Disease

Mannelli¹

2021

JCM

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The evolution to blast phase is a frequently unpredictable and almost invariably fatal event in the course of myeloproliferative neoplasms. The molecular mechanisms underlying blast transformation have not been elucidated and the specific genetic and epigenetic events governing leukemogenesis remain unclear. The result of the long-lasting dynamics, passing through progressive genetic steps, is the emergence of one or more clones often characterized by complex genetics, either at conventional karyotyping or at modern high-throughput sequencing analyses, with all clinical and prognostic correlates. The current therapeutic approaches are largely inadequate and incapable of modifying the inherent unfavorable outcome. In this perspective, the application of targeted strategies should aim to prevent the occurrence of leukemic evolution. At transformation, the crucial target of treatment should be the allocation to allogeneic transplant for eligible patients. With this in mind, novel combination treatments may provide useful bridging strategies, beyond potentially improving outcomes for patients who are not candidates for intensive approaches.

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Combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast‐phase myeloproliferative neoplasms

Cited by 16 publications

References 10 publications

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells

Acute Myeloid Leukemia Evolving from Myeloproliferative Neoplasms: Many Sides of a Challenging Disease

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