Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial

Mesa, Ruben A.; Vannucchi, Alessandro M.; Mead, Adam J.; Egyed, Miklós; Szőke, Anita; Suvorov, Aleksandr; Jakucs, János; Perkins, Andrew C.; Prasad, Ritam; Mayer, Jiřı́; Demeter, Judit; Ganly, Peter; Singer, Jack W.; Hong, Zhou; Dean, James P.; Boekhorst, Peter A. te; Nangalia, Jyoti; Kiladjian, Jean‐Jacques; Harrison, Claire

doi:10.1016/s2352-3026(17)30027-3

Cited by 239 publications

(180 citation statements)

References 30 publications

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“…90 Pacritinib, a JAK2/FLT3 inhibitor, also deserves to be tested in proliferative CMML. 132,133 Because activation of the Hedgehog signaling pathway could contribute to the development of leukemic stem cells, CMML patients can be included in a phase 1 study of a smoothened antagonist. 134 Finally, high expression of interleukin-3 receptor (CD123) in leukemic stem cells led exploration of the efficacy of SL-401, a diphtheria toxininterleukin-3 fusion protein, 135 in patients with hematological malignancies including CMML.…”

Section: Currently Explored Therapeutic Strategies In Cmml Patientsmentioning

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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Section: Currently Explored Therapeutic Strategies In Cmml Patientsmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

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“…13 A second study of 64 patients treated in a real-life comparison confirmed that responses to salvage treatments are rare. 14 Understanding that the outcome after ruxolitinib is important for identifying patients who may benefit from specific interventions, such as allogeneic stem cell transplantation, 15 second-generation JAK inhibitors, [16][17][18] drugs with alternative mechanisms of action, 19,20 or investigational agents in combination with ruxolitinib. 21 Here, we report the outcome of 218 patients after ruxolitinib.…”

Section: Introductionmentioning

confidence: 99%

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Palandri

Breccia

Bonifacio

et al. 2019

Cancer

115

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Background After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome. Methods A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis. Results At 3 years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate‐2–risk/high‐risk category (Dynamic International Prognostic Score System), a platelet count <100 ×109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5 months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib‐related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib‐unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2 months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9 months for those who discontinued in blast phase; P < .001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib‐related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome. Conclusions The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies.

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“…Pacritinib, previously shown to be active in the PERSIST‐1 and PERSIST‐2 studies, is undergoing further development with refinement of optimal dosage . Indeed, the recently published phase 3 study results, in which pacritinib 200 mg twice daily was found to be significantly better than best available therapy, including ruxolitinib, for reducing splenomegaly and clinical symptoms in patients with MF and thrombocytopenia, for both previously untreated and those who had received prior ruxolitinib.…”

Section: Investigational Therapies For Classical Mpns In 2018mentioning

confidence: 99%

Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms

Mughal

Lion

Abdel‐Wahab

et al. 2018

Hematological Oncology

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Following the 47th American Society of Hematology Meeting in 2005, the late John Goldman and Tariq Mughal commenced a conference, the 1st Post-ASH Workshop, which brought together clinicians and scientists, to accelerate the adoption of new therapies for patients with myeloproliferative neoplasms (MPNs). The concept began with recognition of the CML success story following imatinib therapy, the discovery of JAK2 , and the demonstration that BCR-ABL1-negative MPNs are driven by abnormal JAK2 activation. This review is based on the presentations and deliberations at the XIIth Post-ASH Workshop on BCR-ABL1 positive and negative MPNs that took place on December 12 to 13, 2017, in Atlanta, Georgia, immediately following the 59th American Society of Hematology Meeting. We have selected some of the translational research and clinical topics, rather than an account of the proceedings. We discuss the role of immunotherapy in MPNs and the impact of the mutational landscape on TKI treatment in CML. We also consider how we might reduce TKI cardiovascular side effects, the potential role of nutrition as adjunctive nonpharmacologic intervention to reduce chronic inflammation in MPNs, and novel investigational therapies for MPNs.

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Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial

Abstract: CTI BioPharma Corp.

Cited by 239 publications

References 30 publications

How I treat chronic myelomonocytic leukemia

How I treat chronic myelomonocytic leukemia

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Precision immunotherapy, mutational landscape, and emerging tools to optimize clinical outcomes in patients with classical myeloproliferative neoplasms

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