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A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea.

Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, Rumi E, Gattoni E, Pieri L, Guglielmelli P, Elena C, He S, Contel N, Mookerjee B, Sandor V, Cazzola M, Kantarjian HM, Barbui T, Vannucchi AM - Cancer (2014)

Bottom Line: Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation.Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial.

Methods: Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to <45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms.

Results: Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit <45% without phlebotomy was achieved in 97% of patients by week 24.Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.

Conclusions: Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

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Related in: MedlinePlus

Response to ruxolitinib is shown as measured by modified 2009 European LeukemiaNet criteria. (a) Kaplan-Meier plot of the cumulative probability over time of achieving either a complete response (CR) or a partial response (PR) as the observed first response is shown. (b) Kaplan-Meier plot of the cumulative probability over time of achieving a best response of a CR or PR is shown. Note that the cumulative probability of CR and PR does not add up to 1 because patients with a CR as their best response were censored at the time of CR for analysis of PR. (c) Kaplan-Meier plot of time to first hematocrit ≥ 45% is shown.
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fig01: Response to ruxolitinib is shown as measured by modified 2009 European LeukemiaNet criteria. (a) Kaplan-Meier plot of the cumulative probability over time of achieving either a complete response (CR) or a partial response (PR) as the observed first response is shown. (b) Kaplan-Meier plot of the cumulative probability over time of achieving a best response of a CR or PR is shown. Note that the cumulative probability of CR and PR does not add up to 1 because patients with a CR as their best response were censored at the time of CR for analysis of PR. (c) Kaplan-Meier plot of time to first hematocrit ≥ 45% is shown.

Mentions: Response, as defined by modified 2009 ELN criteria, was achieved in 97% of patients by week 24 (Fig. 1a). Twenty patients (59%) achieved a CR as their best response and 13 patients (38%) achieved a PR as their best response. The majority of CRs occurred within the first year (Fig. 1b). Response was durable; among responding patients, the probability of maintaining a hematocrit < 45% without phlebotomy for 48 weeks and 144 weeks, respectively, was 85% and 61% (Fig. 1c). Of the 11 patients who lost their response by experiencing a hematocrit ≥ 45% at any time after their initial response, 8 patients had a subsequent hematocrit < 45% without an intervening phlebotomy, 2 patients discontinued therapy (AE of renal neoplasm, consent withdrawn), and 1 patient remains on therapy, but without an available follow-up hematocrit measurement before data cutoff.


A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea.

Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rosen PJ, Rumi E, Gattoni E, Pieri L, Guglielmelli P, Elena C, He S, Contel N, Mookerjee B, Sandor V, Cazzola M, Kantarjian HM, Barbui T, Vannucchi AM - Cancer (2014)

Response to ruxolitinib is shown as measured by modified 2009 European LeukemiaNet criteria. (a) Kaplan-Meier plot of the cumulative probability over time of achieving either a complete response (CR) or a partial response (PR) as the observed first response is shown. (b) Kaplan-Meier plot of the cumulative probability over time of achieving a best response of a CR or PR is shown. Note that the cumulative probability of CR and PR does not add up to 1 because patients with a CR as their best response were censored at the time of CR for analysis of PR. (c) Kaplan-Meier plot of time to first hematocrit ≥ 45% is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231215&req=5

fig01: Response to ruxolitinib is shown as measured by modified 2009 European LeukemiaNet criteria. (a) Kaplan-Meier plot of the cumulative probability over time of achieving either a complete response (CR) or a partial response (PR) as the observed first response is shown. (b) Kaplan-Meier plot of the cumulative probability over time of achieving a best response of a CR or PR is shown. Note that the cumulative probability of CR and PR does not add up to 1 because patients with a CR as their best response were censored at the time of CR for analysis of PR. (c) Kaplan-Meier plot of time to first hematocrit ≥ 45% is shown.
Mentions: Response, as defined by modified 2009 ELN criteria, was achieved in 97% of patients by week 24 (Fig. 1a). Twenty patients (59%) achieved a CR as their best response and 13 patients (38%) achieved a PR as their best response. The majority of CRs occurred within the first year (Fig. 1b). Response was durable; among responding patients, the probability of maintaining a hematocrit < 45% without phlebotomy for 48 weeks and 144 weeks, respectively, was 85% and 61% (Fig. 1c). Of the 11 patients who lost their response by experiencing a hematocrit ≥ 45% at any time after their initial response, 8 patients had a subsequent hematocrit < 45% without an intervening phlebotomy, 2 patients discontinued therapy (AE of renal neoplasm, consent withdrawn), and 1 patient remains on therapy, but without an available follow-up hematocrit measurement before data cutoff.

Bottom Line: Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation.Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial.

Methods: Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to <45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms.

Results: Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit <45% without phlebotomy was achieved in 97% of patients by week 24.Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.

Conclusions: Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

Show MeSH
Related in: MedlinePlus