MYELOPROLIFERATIVE SYNDROMES: MYELOPROLIFERATIVE NEOPLASMS - CLINICAL FEATURES AND THERAPEUTICS
Long-Term Follow up and Optimized Dosing Regimen of INCB018424 in Patients with Myelofibrosis: Durable Clinical, Functional and Symptomatic Responses with Improved Hematological Safety.
Srdan Verstovsek, MD, PhD1,
Hagop Kantarjian, MD2,
Ruben A. Mesa, MD3,
Jorge Cortes-Franco, MD*,4,
Animesh D. Pardanani, MBBS, PhD5,
Deborah A. Thomas, MD2,
Zeev Estrov, MD6,
Edward C Bradley, MD*,7,
Susan Erickson-Viitanen, PhD*,8,
Kris Vaddi, Ph.D.*,7,
Richard Levy, MD*,9 and
Ayalew Tefferi, MD5
1 Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA, 2 Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 3 Mayo Clinic, Scottsdale, AZ, USA, 4 Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, 5 Hematology, Mayo Clinic, Rochester, MN, USA, 6 Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 7 Incyte Corporation, Wilmington, DE, USA, 8 Incyte Co., Wilmington, DE, 9 Incyte, Wilmington, DE, USA
Background: Myelofibrosis (MF) is the most serious of chronic myeloproliferativeneoplasms (MPNs) for which there is no approved therapy. ExaggeratedJAK2 signaling, either by gain-of-function mutations (eg, JAK2V617F)or high circulating levels of JAK1/2 activating cytokines (eg,interleukin [IL]-6), is believed to play a key role in MPN pathogenesis.INCB018424 (424), a selective oral inhibitor of JAK1/2, hasdemonstrated clinical benefits including reduction of splenomegalyand improvement of symptoms in a Phase I/II trial in MF patients.Thrombocytopenia was identified as the dose limiting toxicityoccurring in 30% of patients at 25mg BID.
Methods: Patients with primary, post-PV or post-ET MF were enrolled inthe study. Following the characterization of multiple dosingregimens, an individually optimized dose regimen strategy wasdeveloped, based on available efficacy and safety data. In asubset of patients, spleen volume change was measured by MRIat 1, 3 and 6 months of treatment in order to establish an objectivemeasure of spleen response. The impact of 424 on MF associatedsymptoms was assessed using a validated instrument, MFSAF (Mesaet al., Leukemia Research 2009). As a surrogate marker of functionalbenefit, exercise capacity was assessed with a standardized6-minute walk test (6MWT) at baseline, 1, 3 and 6 months oftherapy.
Results: 155 patients were enrolled in the study, with median durationof treatment of 1+ years and the duration of drug exposure of>150 patient years (76 patients received >1 year of therapy).Clinical responses have been maintained over the entire durationof treatment and most patients remain on therapy (115 of 155patients; 74%). Progression to AML occurred in 3 patients, whichis below the expected frequency based on published data (Barosiet al., Blood 2007). SAEs related to 424 occurred in 12 patients,and are generally related to bone marrow suppression or returnof or exacerbation of signs and symptoms of MF when therapyis discontinued. Further optimization of the dosing regimenutilized baseline platelet count to determine the starting dose(10 or 15mg BID) and allowed dose titration after 1 and 2 monthsof therapy; most patients were optimized to 15 or 20mg BID.This approach significantly reduced the incidence of thrombocytopenia(<5%, N=35), while providing equivalent efficacy to higherdose regimens. With an optimized dosing regimen, spleen volumereduction was evident as early as 1 month, and durable over6 months, of therapy (33 % median decrease after 6 months, N=23).Eleven of 23 (48%) of patients achieved 35% reduction (equivalentto IWG clinical improvement criteria of 50% reduction by palpation)from baseline in spleen volume at month 6. MF patients haveimpaired exercise capacity at baseline (decreased 6MWT performanceby 60-90 meters vs. age-matched controls). Treatment with 424resulted in improved 6MWT performance, with median increasefrom baseline of 33, 58 and 70 meters after 1,3 or 6 monthsof therapy, respectively. Rapid and durable reduction of a totalsymptom score based on key symptoms (fatigue, abdominal discomfort/pain,bone/muscle pain, night sweats and pruritus) was noted (51 %and 58% of patients achieving 50% reduction in the total scorefollowing 1 and 6 months of treatment, respectively). Improvementin symptoms coincided with a rapid and sustained reduction inpro-inflammatory cytokines, including IL-1b, IL-1ra, IL-6 andTNFa, without tachyphylaxis to therapy. Finally, spleen responsewas associated with greater improvements in total symptom score,exercise capacity, and reduced fatigue (see Table).
Total symptom score (mean change vs baseline)
6MWT (Change vs baseline, meters)c
Fatigue (mean change vs baseline)
a Defined as 15-34% reduction in spleenvolume by MRI or 25-49% reduction in palpated spleen length
b Defined as 35% reduction in spleen volume by MRI or 50%reduction in palpated spleen length
c + denotes increase and– denotes decrease in walking distance
Conclusion: An optimized dosing regimen of INCB018424 resulted in sustainedclinical, symptomatic and functional benefits in MF patientswith an improved hematological safety profile compared to a25 mg BID regimen. Safety and efficacy of 424 in MF patientsis further supported by the follow-up data of >1 yr of 424therapy.