A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms

Rita Assi, Hagop M. Kantarjian, Guillermo Garcia-Manero, Jorge E. Cortes, Naveen Pemmaraju, Xuemei Wang, Graciela Nogueras-Gonzalez, Elias Jabbour, Prithviraj Bose, Tapan Kadia, Courtney D. Dinardo, Keyur Patel, Carlos Bueso-Ramos, Lingsha Zhou, Sherry Pierce, Romany Gergis, Carla Tuttle, Gautam Borthakur, Zeev Estrov, Rajyalakshmi LuthraJuliana Hidalgo-Lopez, Srdan Verstovsek, Naval Daver

Research output: Contribution to journalArticle

Abstract

Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28-day cycles for the first 3 cycles. Azacytidine 25 mg/m2 (Day 1-5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m2 (Days 1-5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty-five patients were treated (MDS/MPN-U, n =14; CMML, n =17; aCML, n =4), with a median follow-up of 15.2 months (range, 1.0–41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2-mutated (P =.02) and had splenomegaly (P =.03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN-U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P =.034). The combination of ruxolitinib and azacytidine was well-tolerated with an ICP MDS/MPN-response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN-U.

Original languageEnglish (US)
Pages (from-to)277-285
Number of pages9
JournalAmerican Journal of Hematology
Volume93
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

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Azacitidine
Myelodysplastic Syndromes
Neoplasms
Splenomegaly
INCB018424
Survival
Platelet Count
Anemia

ASJC Scopus subject areas

  • Hematology

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A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. / Assi, Rita; Kantarjian, Hagop M.; Garcia-Manero, Guillermo; Cortes, Jorge E.; Pemmaraju, Naveen; Wang, Xuemei; Nogueras-Gonzalez, Graciela; Jabbour, Elias; Bose, Prithviraj; Kadia, Tapan; Dinardo, Courtney D.; Patel, Keyur; Bueso-Ramos, Carlos; Zhou, Lingsha; Pierce, Sherry; Gergis, Romany; Tuttle, Carla; Borthakur, Gautam; Estrov, Zeev; Luthra, Rajyalakshmi; Hidalgo-Lopez, Juliana; Verstovsek, Srdan; Daver, Naval.

In: American Journal of Hematology, Vol. 93, No. 2, 01.02.2018, p. 277-285.

Research output: Contribution to journalArticle

Assi, R, Kantarjian, HM, Garcia-Manero, G, Cortes, JE, Pemmaraju, N, Wang, X, Nogueras-Gonzalez, G, Jabbour, E, Bose, P, Kadia, T, Dinardo, CD, Patel, K, Bueso-Ramos, C, Zhou, L, Pierce, S, Gergis, R, Tuttle, C, Borthakur, G, Estrov, Z, Luthra, R, Hidalgo-Lopez, J, Verstovsek, S & Daver, N 2018, 'A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms', American Journal of Hematology, vol. 93, no. 2, pp. 277-285. https://doi.org/10.1002/ajh.24972
Assi, Rita ; Kantarjian, Hagop M. ; Garcia-Manero, Guillermo ; Cortes, Jorge E. ; Pemmaraju, Naveen ; Wang, Xuemei ; Nogueras-Gonzalez, Graciela ; Jabbour, Elias ; Bose, Prithviraj ; Kadia, Tapan ; Dinardo, Courtney D. ; Patel, Keyur ; Bueso-Ramos, Carlos ; Zhou, Lingsha ; Pierce, Sherry ; Gergis, Romany ; Tuttle, Carla ; Borthakur, Gautam ; Estrov, Zeev ; Luthra, Rajyalakshmi ; Hidalgo-Lopez, Juliana ; Verstovsek, Srdan ; Daver, Naval. / A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. In: American Journal of Hematology. 2018 ; Vol. 93, No. 2. pp. 277-285.
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AU - Assi, Rita

AU - Kantarjian, Hagop M.

AU - Garcia-Manero, Guillermo

AU - Cortes, Jorge E.

AU - Pemmaraju, Naveen

AU - Wang, Xuemei

AU - Nogueras-Gonzalez, Graciela

AU - Jabbour, Elias

AU - Bose, Prithviraj

AU - Kadia, Tapan

AU - Dinardo, Courtney D.

AU - Patel, Keyur

AU - Bueso-Ramos, Carlos

AU - Zhou, Lingsha

AU - Pierce, Sherry

AU - Gergis, Romany

AU - Tuttle, Carla

AU - Borthakur, Gautam

AU - Estrov, Zeev

AU - Luthra, Rajyalakshmi

AU - Hidalgo-Lopez, Juliana

AU - Verstovsek, Srdan

AU - Daver, Naval

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N2 - Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28-day cycles for the first 3 cycles. Azacytidine 25 mg/m2 (Day 1-5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m2 (Days 1-5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty-five patients were treated (MDS/MPN-U, n =14; CMML, n =17; aCML, n =4), with a median follow-up of 15.2 months (range, 1.0–41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2-mutated (P =.02) and had splenomegaly (P =.03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN-U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P =.034). The combination of ruxolitinib and azacytidine was well-tolerated with an ICP MDS/MPN-response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN-U.

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