5  JAK inhibitors in Myelofibrosis

• Type I JAKi (Ruxolitinib, Fedratinib, pacritinib, momelotinib) stabilize the active kinase conformation
• Type II JAKi binds JAK2 in the inactive conformation (“DFG-out” state), where the inhibitor occupies the ATP binding site and an induced hydrophobic pocket. The inactive conformation was stabilized consistent with decreased phosphorylation of the activation loop.
• Conventional (type 1) adenosine triphosphate–competitive JAK inhibitors bind to and stabilize the active conformation of JAKs, whereas type 2 inhibitors bind to and stabilize the inactive conformation, preventing the kinase from cycling to the active conformation.

require(DiagrammeR)

Loading required package: DiagrammeR

# Create the myelofibrosis treatment algorithm diagram
mf_diagram <- grViz("
digraph myelofibrosis {
  # Graph settings
  graph [rankdir = TB, fontname = 'Arial', splines = true, nodesep = 0.8, ranksep = 0.5, bgcolor = white]
  node [shape = box, style = filled, fontname = 'Arial', fontsize = 14, margin = '0.2,0.1', height = 0.5, width = 2.0]
  edge [fontname = 'Arial', fontsize = 12, arrowsize = 0.8, color = black]
  
  # Node definitions with colors
  MF [label = 'Myelofibrosis', shape = oval, fillcolor = '#8FA0C0', style = filled]
  SP [label = 'Splenomegaly and\nconstitutional symptoms', shape = oval, fillcolor = '#9F7EB5', style = filled]
  
  # First-line options
  RUX1 [label = 'Ruxolitinib', fillcolor = '#5DADE2', style = filled]
  MOML_TOP [label = 'Momelotinib', fillcolor = '#E84393', style = filled]
  PAC_TOP [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Second-line options
  FED [label = 'Fedratinib', fillcolor = '#9B59B6', style = filled]
  RUX2 [label = 'Ruxolitinib\n20 mg BID', fillcolor = '#5DADE2', style = filled]
  RUX3 [label = 'Ruxolitinib\n15 mg BID', fillcolor = '#5DADE2', style = filled]
  RUX4 [label = 'Ruxolitinib\n5 mg BID', fillcolor = '#5DADE2', style = filled]
  PAC1 [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Treatment after fedratinib
  MP [label = 'Momelotinib or\nPacritinib', fillcolor = '#F39C12', style = filled]
  MOM2 [label = 'Momelotinib', fillcolor = '#E84393', style = filled]
  PAC3 [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Follow-up Ruxolitinib options
  RUX5 [label = 'Ruxolitinib', fillcolor = '#5DADE2', style = filled]
  PAC4 [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Connections
  MF -> SP
  
  SP -> MOML_TOP [label = '+ anemia (TD)\n1L']
  SP -> PAC_TOP [label = 'plts <50×10⁹/L\n1L']
  SP -> RUX1 [label = 'no\ncytopenias\n1L']
  
  # Special case direct from MF to treatments
  MF -> MOML_TOP [label = '+ anemia +\nplts ≥25×10⁹/L']
  
  # Ruxolitinib dose based on platelet count
  RUX1 -> RUX2 [label = 'plts>200×10⁹/L\n1L']
  RUX1 -> RUX3 [label = 'plts 100-200×10⁹/L\n1L']
  RUX1 -> RUX4 [label = 'plts 50 to <100×10⁹/L\n1L']
  RUX1 -> PAC1 [label = 'plts <50×10⁹/L\n1L']
  
  # Second-line treatment
  RUX1 -> FED [label = 'worsening spleno-\nmegaly/symptoms,\nno cytopenias\n2L']
  
  # After fedratinib
  FED -> MP [label = 'cytopenias']
  MP -> MOM2 [label = 'anemia (TD)\n≥ 2L']
  MP -> PAC3 [label = 'anemia and/or\nlow platelets\n≥ 2L']
  
  # Second-line after Momelotinib
  MOML_TOP -> RUX5 [label = 'platelets\n≥50×10⁹/L\n2L']
  MOML_TOP -> PAC4 [label = 'platelets\n<50×10⁹/L\n2L']
  
  # Title at the top
  TITLE [label = 'Selection of JAK Inhibitors in Patients with Myelofibrosis', shape = plaintext, fontsize = 20, fontcolor = '#B71C1C', labelloc = 't']
  
  # Invisible edge from title to top node to control placement
  TITLE -> MF [style = invis]
  
  # Node arrangement
  {rank = same; MOML_TOP; RUX1; PAC_TOP}
  {rank = same; RUX2; RUX3; RUX4; PAC1}
  {rank = same; MOM2; PAC3}
  {rank = same; RUX5; PAC4}
}
")

# Display the diagram
mf_diagram

library(DiagrammeR)
library(DiagrammeRsvg)
library(rsvg)

Linking to librsvg 2.61.0

library(png)

# Create the myelofibrosis treatment algorithm diagram
mf_diagram <- grViz("
digraph myelofibrosis {
  # Graph settings
  graph [rankdir = TB, fontname = 'Arial', splines = true, nodesep = 0.8, ranksep = 0.6, bgcolor = white, dpi = 300]
  node [shape = box, style = filled, fontname = 'Arial', fontsize = 14, margin = '0.2,0.1', height = 0.5, width = 2.0]
  edge [fontname = 'Arial', fontsize = 12, arrowsize = 0.8, color = black]
  
  # Node definitions with colors
  MF [label = 'Myelofibrosis', shape = oval, fillcolor = '#8FA0C0', style = filled]
  SP [label = 'Splenomegaly and\\nconstitutional symptoms', shape = oval, fillcolor = '#9F7EB5', style = filled]
  
  # First-line options
  RUX1 [label = 'Ruxolitinib', fillcolor = '#5DADE2', style = filled]
  MOML_TOP [label = 'Momelotinib', fillcolor = '#E84393', style = filled]
  PAC_TOP [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Second-line options
  FED [label = 'Fedratinib', fillcolor = '#9B59B6', style = filled]
  RUX2 [label = 'Ruxolitinib\\n20 mg BID', fillcolor = '#5DADE2', style = filled]
  RUX3 [label = 'Ruxolitinib\\n15 mg BID', fillcolor = '#5DADE2', style = filled]
  RUX4 [label = 'Ruxolitinib\\n5 mg BID', fillcolor = '#5DADE2', style = filled]
  PAC1 [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Treatment after fedratinib
  MP [label = 'Momelotinib or\\nPacritinib', fillcolor = '#F39C12', style = filled]
  MOM2 [label = 'Momelotinib', fillcolor = '#E84393', style = filled]
  PAC3 [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Follow-up Ruxolitinib options
  RUX5 [label = 'Ruxolitinib', fillcolor = '#5DADE2', style = filled]
  PAC4 [label = 'Pacritinib', fillcolor = '#62D165', style = filled]
  
  # Connections
  MF -> SP
  
  SP -> MOML_TOP [label = '+ anemia (TD)\\n1L']
  SP -> PAC_TOP [label = 'plts <50×10⁹/L\\n1L']
  SP -> RUX1 [label = 'no\\ncytopenias\\n1L']
  
  # Special case direct from MF to treatments
  MF -> MOML_TOP [label = '+ anemia +\\nplts ≥25×10⁹/L']
  
  # Ruxolitinib dose based on platelet count
  RUX1 -> RUX2 [label = 'plts>200×10⁹/L\\n1L']
  RUX1 -> RUX3 [label = 'plts 100-200×10⁹/L\\n1L']
  RUX1 -> RUX4 [label = 'plts 50 to <100×10⁹/L\\n1L']
  RUX1 -> PAC1 [label = 'plts <50×10⁹/L\\n1L']
  
  # Second-line treatment
  RUX1 -> FED [label = 'worsening spleno-\\nmegaly/symptoms,\\nno cytopenias\\n2L']
  
  # After fedratinib
  FED -> MP [label = 'cytopenias']
  MP -> MOM2 [label = 'anemia (TD)\\n≥ 2L']
  MP -> PAC3 [label = 'anemia and/or\\nlow platelets\\n≥ 2L']
  
  # Second-line after Momelotinib
  MOML_TOP -> RUX5 [label = 'platelets\\n≥50×10⁹/L\\n2L']
  MOML_TOP -> PAC4 [label = 'platelets\\n<50×10⁹/L\\n2L']
  
  # Title at the top
  TITLE [label = 'Selection of JAK Inhibitors in Patients with Myelofibrosis', shape = plaintext, fontsize = 20, fontcolor = '#B71C1C', labelloc = 't']
  
  # Invisible edge from title to top node to control placement
  TITLE -> MF [style = invis]
  
  # Node arrangement
  {rank = same; MOML_TOP; RUX1; PAC_TOP}
  {rank = same; RUX2; RUX3; RUX4; PAC1}
  {rank = same; MOM2; PAC3}
  {rank = same; RUX5; PAC4}
}
")

# Convert to SVG then to PNG
svg_content <- DiagrammeRsvg::export_svg(mf_diagram)
svg_file <- tempfile(fileext = ".svg")
writeLines(svg_content, svg_file)

# Create PNG with high resolution
png_file <- tempfile(fileext = ".png")
rsvg_png(svg_file, png_file, width = 2400, height = 1800)

# Display diagram
mf_diagram

5.1 Ruxolotinib

5.1.1 Overall survival with Ruxolitinib

5.2 Fedratinib

5.3 Pacritinib

5.4 Momelotinib

5.4.1 Momelotinib plus luspatercept

Odyssey Trial (Phase II):

• An open-label, multicenter study evaluating momelotinib (200 mg daily) plus luspatercept (1 mg/kg every 3 weeks, titratable to 1.75 mg/kg) in transfusion-dependent MF patients (≥4 RBC units or hemoglobin <8 g/dL in 8 weeks prior).
• It includes JAK inhibitor-naïve (cohort 1) and -experienced (cohort 2) patients with intermediate-1, -2, or high-risk MF.
• Primary Endpoint: TI rate by week 24 (no RBC transfusions for ≥12 weeks).
• Secondary Endpoints: Safety, tolerability, pharmacokinetics, and alternative TI definitions.
• Exploratory Endpoints: Symptom improvement, quality of life, spleen size reduction, and biomarkers (iron metabolism, inflammatory cytokines).
• Status: Ongoing, with no published results as of the latest updates.

5.4.2 Thrombocytopenia adjustment for momelotinib

• Momelotinib (Ojjaara) prescribing information makes the following recommendations for thrombocytopenia:
• Baseline PLT >100k

• PLT 20-50K: reduce daily dose by 50 mg

• PLT <20k: interrupt until PLT reach 50k, then reduce by 50 mg Baseline PLT <50

• PLT < 20k: interrupt until PLT reach 50K (or baseline if baseline < 50K) then restart with 50 mg dose reduction

• In pooled analysis of Simplify-1, Simplify-2 and Momentum, grade 3+ thrombocytopenia occurred in 16.4% (25% all grade)

5.5 Type 2 JAKi

5.5.1 INCB160058

• Pseudokinase (JH2)-bidning inhibitor

5.5.2 AJ1-10502

5.5.3 Jaktinib

5.5.4 Flonoltinib Maleate

• ASH 2024 Chen et al. (2024)
• JAK2/FLT3i

Chen, Lijuan, Yongsheng Wang, Jie Wang, Linyu Yang, and Ting Niu. 2024. “First-in-Human Phase i/IIa Safety and Efficacy of Flonoltinib Maleate, a New Generation of JAK2/FLT3 Inhibitor in Myelofibrosis.” Blood 144 (Supplement 1): 486–86. https://doi.org/10.1182/blood-2024-210674.