PMID- 21220608
OWN - NLM
STAT- MEDLINE
DCOM- 20110506
LR  - 20220613
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 29
IP  - 7
DP  - 2011 Mar 1
TI  - Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis.
PG  - 789-96
LID - 10.1200/JCO.2010.32.8021 [doi]
AB  - PURPOSE: Myelofibrosis is a myeloid malignancy associated with anemia, 
      splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT 
      activating mutations that are sensitive to TG101348, a selective small-molecule 
      Janus kinase 2 (JAK2) inhibitor. PATIENTS AND METHODS: In a multicenter phase I 
      trial, oral TG101348 was administered once a day to patients with high- or 
      intermediate-risk primary or post-polycythemia vera/essential thrombocythemia 
      myelofibrosis. RESULTS: Fifty-nine patients were treated, including 28 in the 
      dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting 
      toxicity was a reversible and asymptomatic increase in the serum amylase level. 
      Forty-three patients (73%) continued treatment beyond six cycles; the median 
      cumulative exposure to TG101348 was 380 days. Adverse events included nausea, 
      vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 
      incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest 
      effect on serum cytokine levels, but greater than half of the patients with early 
      satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable 
      improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of 
      patients, respectively, had achieved a spleen response per International Working 
      Group criteria. The majority of patients with leukocytosis or thrombocytosis at 
      baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts 
      after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. 
      A significant decrease in JAK2 V617F allele burden was observed at 6 months in 
      mutation-positive patients (n = 51; P = .04), particularly in the subgroup with 
      allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 
      months. CONCLUSION: TG101348 is well tolerated and produces significant reduction 
      in disease burden and durable clinical benefit in patients with myelofibrosis.
FAU - Pardanani, Animesh
AU  - Pardanani A
AD  - Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Gotlib, Jason R
AU  - Gotlib JR
FAU - Jamieson, Catriona
AU  - Jamieson C
FAU - Cortes, Jorge E
AU  - Cortes JE
FAU - Talpaz, Moshe
AU  - Talpaz M
FAU - Stone, Richard M
AU  - Stone RM
FAU - Silverman, Michael H
AU  - Silverman MH
FAU - Gilliland, D Gary
AU  - Gilliland DG
FAU - Shorr, Jolene
AU  - Shorr J
FAU - Tefferi, Ayalew
AU  - Tefferi A
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20110110
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Cytokines)
RN  - 0 (Pyrrolidines)
RN  - 0 (Sulfonamides)
RN  - 6L1XP550I6 (fedratinib)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
CIN - J Clin Oncol. 2011 Mar 1;29(7):781-3. PMID: 21220594
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Cytokines/blood
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Drug-Related Side Effects and Adverse Reactions
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Janus Kinase 2/administration & dosage/adverse effects/*antagonists & inhibitors
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Polycythemia Vera/diagnosis/drug therapy
MH  - Primary Myelofibrosis/diagnosis/*drug therapy
MH  - Pyrrolidines/*administration & dosage/*adverse effects
MH  - Risk Assessment
MH  - Severity of Illness Index
MH  - Sulfonamides/*administration & dosage/*adverse effects
MH  - Thrombocythemia, Essential/diagnosis/drug therapy
MH  - Time Factors
MH  - Treatment Outcome
PMC - PMC4979099
COIS- Authors' disclosures of potential conflicts of interest and author contributions 
      are found at the end of this article.
EDAT- 2011/01/12 06:00
MHDA- 2011/05/07 06:00
PMCR- 2011/01/10
CRDT- 2011/01/12 06:00
PHST- 2011/01/12 06:00 [entrez]
PHST- 2011/01/12 06:00 [pubmed]
PHST- 2011/05/07 06:00 [medline]
PHST- 2011/01/10 00:00 [pmc-release]
AID - JCO.2010.32.8021 [pii]
AID - 28021 [pii]
AID - 10.1200/JCO.2010.32.8021 [doi]
PST - ppublish
SO  - J Clin Oncol. 2011 Mar 1;29(7):789-96. doi: 10.1200/JCO.2010.32.8021. Epub 2011 
      Jan 10.