Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome

Palandri, Francesca; Breccia, Massimo; Mazzoni, Camilla; Auteri, Giuseppe; Elli, Elena Maria; Trawinska, Malgorzata; Polverelli, Nicola; Tiribelli, Mario; Benevolo, Giulia; Iurlo, Alessandra; Tieghi, Alessia; Heidel, Florian H.; Caocci, Giovanni; Beggiato, Eloise; Binotto, Gianni; Cavazzini, Francesco; Miglino, Maurizio; Bosi, Costanza; Crugnola, Monica; Bocchia, Monica; Martino, Bruno; Pugliese, Novella; Biondo, Mattia; Venturi, Marta; Scaffidi, Luigi; Isidori, Alessandro; Cattaneo, Daniele; Krampera, Mauro; Pane, Fabrizio; Cilloni, Daniela; Semenzato, Gianpietro; Lemoli, Roberto M.; Cuneo, Antonio; Abruzzese, Elisabetta; Bartoletti, Daniela; Paglia, Simona; Vianelli, Nicola; Cavo, Michèle; Bonifacio, Massimiliano; Palumbo, Giuseppe Alessandro Parasiliti

doi:10.1002/cncr.34722

Cited by 16 publications

(6 citation statements)

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“…It is an inhibitor of JAK 1 and 2 receptors. It has been employed in the management of different hematopoietic dyscrasia (like myelofibrosis and polycythemia) for many years [ 27 , 28 ]. As a topical treatment, it has been evaluated in several dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and psoriasis [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

New Perspectives in the Management of Chronic Hand Eczema: Lessons from Pathogenesis

Tancredi,

Buononato,

Caccavale

et al. 2023

IJMS

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Chronic hand eczema (CHE) is a common inflammatory skin condition that significantly impacts the quality of life. From work-related disabilities to social embarrassment, pain, and financial costs, the burden on society is substantial. Managing this condition presents challenges such as long-term treatment, poor patient compliance, therapy side effects, and economic feasibility. As a result, significant efforts have been made in this field in recent years. Specifically, the broader understanding of CHE pathogenesis has led to the development of new drugs, both topical and systemic. The aim of this narrative review is to summarize the current available data on hand eczema pathophysiology and explore the resulting developments in drugs for its treatment. A comprehensive search on PubMed and the other main scientific databases was conducted using keywords related to CHE and its pathogenesis. The most relevant pathways targeted by therapies include the JAK-STAT cascade, IL-4, and IL-13 axis, phosphodiesterase 4 enzyme, and chemo-attractant cytokines. In the near future, physicians will have a plethora of therapeutic alternatives. Consequently, they should be well-trained not only in how to use these alternatives but also how to combine these treatments to address the ongoing challenges related to efficacy, tolerability, and safety.

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Section: Resultsmentioning

confidence: 99%

New Perspectives in the Management of Chronic Hand Eczema: Lessons from Pathogenesis

Tancredi,

Buononato,

Caccavale

et al. 2023

IJMS

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“…Но, к сожалению, большинство пациентов, полу чавших руксолитиниб, с течением времени теряют достигнутый ответ: в исследовании COMFORTII по казано, что сохранение ответа в течение 5 лет возмож но менее чем в 50 % случаев [46,47]. Это обусловлива ет как необходимость разработки новых лекарственных подходов (новые лекарственные препараты, комбина ции руксолитиниба с ингибиторами других мишеней и т.…”

Section: Discussionunclassified

Molecular markers as possible efficacy predictors of targeted therapy for myelofibrosis: single-center study

Vinogradova,

Shikhbabaeva,

Kobzev

et al. 2023

Onkogematologiâ

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Background. Targeted therapy is the most promising in the treatment of myelofibrosis, but it is necessary to search for the reasons limiting its effectiveness. There are known factors negatively affecting the development of myelofibrosis, but data on their negative impact in the context of targeted therapy are scarce.Aim. Assessing the impact of cytogenetic and genetic abnormalities on the course and therapy results for primary and secondary myelofibrosis during ruxolitinib therapy.Materials and methods. The prospective study included 106 patients with myelofibrosis in the chronic phase (53 (50 %) men and 53 (50 %) women) who received ruxolitinib at the Moscow City Hematology Center, S.P. Botkin City Clinical Hospital. The median age of patients was 62 (18–84) years. The median disease duration before initiation of ruxolitinib therapy was 79 (1–432) months. Before therapy, genetic studies were performed, including next-generation sequencing. The median duration of ruxolitinib therapy was 33 (1–111) months. The influence of the cytogenetic landscape, driver mutations, allele burden of JAK2 (over time) and CALR, additional mutations on the dynamics of symptoms, spleen size, achievement of hematological response, overall survival, progression-free survival, survival without blast crisis and without progression of myelofibrosis with targeted therapy was assessed.Results. The studied genetic factors did not have a significant correlation with hemogram parameters. The hematological response in patients with JAK2 and CALR mutations compared favorably with the response in the groups with the MPL mutation and triple negative status (TNS). Higher hematological response rate was obtained in the group with initially low allele burden <50 % of JAK2 or CALR. Significant differences in 5-year overall survival were found between groups of patients with TNS and JAK2 and CALR mutations (p <0.05); with CALR allele burden <50 % and ³50 % before initiation of ruxolitinib therapy (p = 0.01); the presence or absence of positive dynamics of the JAK2 allele burden during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with different number of pathogenic mutations (1 or ³2), the presence or absence of pathogenic mutations in the ASXL1 (p = 0.002) and SETBP1 (p = 0.00001) genes. The 5-year progression-free survival was significantly different in cohorts of patients with or without positive dynamics of the JAK2 allelic load during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with a different number of pathogenic mutations (1 or ³2), the presence or absence of a pathogenic mutation of the SETBP1 gene (p = 0.003). Progression-free survival did not correlate with the type of driver mutation or its absence; however, all patients with TNS died from myelofibrosis progression. Significant differences in 5-year blast crisis-free survival were observed between groups with JAK2 and MPL mutations (p = 0.001), JAK2 and TNS (p = 0.002); difference in 5-year survival without progression of fibrosis – between groups with pathogenic and benign (p = 0.031); uncertain and benign (p = 0.001) mutations.Conclusion. The study identified genetic markers associated with decreased efficacy of ruxolitinib therapy.

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“…Particularly, cytopenic MF is characterized by molecular alterations that have been found to correlate with worse outcomes, including low JAK2 variant allele frequencies, triple negativity, and the presence of high-risk subclonal mutations. In addition, cytopenic MF represents a great therapeutic challenge, with reduced options and a lower probability of clinical benefit that is related to the difficulty of administering adequate ruxolitinib doses and to a higher propensity to develop drug-related toxicities [17][18][19]29].…”

Section: Discussionmentioning

confidence: 99%

A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis

Palandri,

Palumbo,

Bonifacio

et al. 2023

Cancers

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Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure. As the therapeutic possibilities of MF are expanding, it is critical to identify patients predisposed to early ruxolitinib monotherapy failure and worse outcomes. We investigated predictors of early ruxolitinib discontinuation and death on therapy in 889 patients included in the “RUX-MF” retrospective study. Overall, 172 patients were alive on ruxolitinib after ≥5 years (long-term ruxolitinib, LTR), 115 patients were alive but off ruxolitinib after ≥5 yrs (short-term RUX, STR), and 123 patients died while on ruxolitinib after <5 yrs (early death on ruxolitinib, EDR). The cumulative incidence of the blast phase was similar in LTR and STR patients (p = 0.08). Overall survival (OS) was significantly longer in LTR pts (p = 0.002). In multivariate analysis, PLT < 100 × 109/L, Hb < 10 g/dL, primary MF, absence of spleen response at 3 months and ruxolitinib starting dose <10 mg BID were associated with higher probability of STR. Assigning one point to each significant variable, a prognostic model for STR (STR-PM) was built, and three groups were identified: low (score 0–1), intermediate (score 2), and high risk (score ≥ 3). The STR-PM may identify patients at higher risk of failure with ruxolitinib monotherapy who should be considered for alternative frontline strategies.

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Ruxolitinib in cytopenic myelofibrosis: Response, toxicity, drug discontinuation, and outcome

Cited by 16 publications

References 50 publications

New Perspectives in the Management of Chronic Hand Eczema: Lessons from Pathogenesis

New Perspectives in the Management of Chronic Hand Eczema: Lessons from Pathogenesis

Molecular markers as possible efficacy predictors of targeted therapy for myelofibrosis: single-center study

A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis

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