CHRONIC IMMUNE

THROMBOCYTOPENIA
TREATMENT IN THE
SETTING OF
PANCYTOPENIA
Cat herine E ichler, PharmD
Nov emb er 10, 2022
Int ernal Med icine
Park view H eal th
 a patient case regarding immune thrombocytopenia
Evaluate and acute chemo-induced neutropenia

Objectives Understand the pathophysiology of immune thrombocytopenia

Analyze available literature for safe immune thrombocytopenia

and apply treatment with fostamatinib to a patient case
PATIENT CASE
Patient CD
◦ 74-year-old male
◦ CC: generalized weakness
◦ PMH: stage IV lung cancer currently on chemotherapy, COPD, asthma, GERD, AFib on apixaban, OSA on CPAP,
diverticulosis, lymphedema, immune thrombocytopenia (hx since 2018)
◦ HPI:
◦ Follows with Fort Wayne Oncology (Lutheran)
◦ Chemotherapy q23 days
◦ Last chemotherapy 5 days before presentation - Paraplatin (carboplatin), Alimta (pemetrexed), Avastin (bevacizumab)
◦ Neulasta (pegfilgrastim) given as part of chemotherapy regimen
◦ Admitted in July and Sept with similar presentation: pancytopenia, fever, uncomplicated cellulitis – throbbing and increased
swelling of LE after chemo
Prior to Admission Medications
Albuterol HFA 2 puffs q4h PRN for wheezing or shortness of breath
Albuterol nebulizer solution 2.5mg by nebulization q6h PRN
Eliquis 5mg 1 tab PO BID
Atorvastatin 40mg 1 tab PO daily
CBD extract Take PO daily PRN
Advair 250-50 mcg/dose 1 puff into the lungs BID
Folic acid 1mg 1 tab PO daily
Furosemide 20mg 1 tab PO BID
Gabapentin 600mg 1 tab PO TID
Norco 10-325mg 1 tab PO q4h PRN
Lactulose 10g/15ml solution 10mg PO daily
Meclizine 100mg 1 tab PO BID
Omega-3 fatty acids 500mg 1 cap PO daily
Tavalisse (fostamatinib) 100mg 1 tab PO BID
 HPI Timeline
Aug: admitted for fever,
acute on chronic anemia and
pancytopenia
Aug: Paraplatin (carboplatin),
Alimta (pemetrexed), Avastin
Feb: Avastin (bevacizumab) for (bevacizumab) for NSCLC
NSCLC Aug: first documentation of
May: metastatic lung cancer Feb: Nplate (romiplostim) for Tavalisse (fostamatinib)
(NSCLC) diagnosis ITP therapy

2016 2018: 2019 2020 2022

July: Avastin (bevacizumab) Aug: Avastin (bevacizumab) for

and Alimta (pemetrexed) for NSCLC
NSCLC maintenance
ITP first documented:
prednisone 60mg, started
Nplate (romiplostim)
Vitals/Labs at presentation
Temp (˚F, C) Heart rate (bpm) Blood pressure (mmHg) Respiratory rate (rpm)
98.7 (37.1) 99 126/83 16

Na (mmol/L) K (mmol/L) Mg (mg/dL) Ionized Ca (mg/dL) SCr (mg/dL)

141 3.3 1.1 4.0 1.11

WBC (th/uL) RBC (mi/L ) Hgb (g/dL) Platelets (th/uL) ANC (th/mL)
3.3 1.74 6.0 111 2.32
Lab Trends
180 10
160 9

ANC AND WBC (TH/UL)

140 8
PLATELETS (TH/UL)

120 7
6
100
5
80
4
60 3
40 2
20 1
0 0
Day Day Day Day Day Day Day Day
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 8 Day 9
10 11 12 13 14 15 16 17
Platelets (th/uL) 111 86 54 31 17 10 8 12 23 41 73 94 111 135 140 154
ANC (th/uL) 2.32 1.79 0.64 0.51 1.14 2.11 2.71 3.32 2.95 1.79 1.64 1.55 2.16 2.3 2.78
WBC (th/uL) 3.3 2.4 1 1.1 1.6 2.9 3.9 4.5 5.2 5.2 3.9 4 3.5 4.5 4.6 5.9
TIME
Hospital Course
◦ Day 2: Dr. Gonzalez (patient's oncologist at Lutheran) updated. He stated to continue
patient’s Tavalisse (fostamatinib) regardless of labs. He said we may add Neupogen
(filgrastim) 480mcg TID to aid in regenerating cell count.
◦ Zosyn 3375mg q8h started, discontinued on day 4
◦ Temperature 100.6˚F
◦ Day 5: daptomycin and meropenem 500mg q6h
◦ Transferred to PRMC
◦ Day 7: Platelets: 8 - 1 unit of platelets ordered with improvement of platelets to 11
◦ Hgb: 6.9 – 1 unit PRBC transfusion done with improvement in Hgb to 8.4-7.5
◦ Per oncology note: “Known ITP now with likely contribution to thrombocytopenia from sepsis
and antibiotics”
BACKGROUND
Immune thrombocytopenia (ITP)
• An autoantibody-mediated bleeding disorder due to destruction
of platelets and impaired production of platelets
• Platelets <100x109
• Incidence: 6.1 per 100,000 persons
• Primary: caused by pathogenic anti-platelet autoantibodies, T cell-
mediated platelet destruction, and impaired megakaryocyte
• 80% of adult ITP patients
• Secondary: caused by chronic infections (H. pylori, HIV) or
autoimmune diseases (systemic lupus, rheumatoid arthritis)
• 20% of adult ITP patients

Miltiadous O, Hou M, Bussel JB. Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment. Blood. 2020 Feb 13;135(7):472-490. doi: 10.1182/blood.2019003599.
Zufferey A, Kapur R, Semple JW. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). J Clin Med. 2017 Feb 9;6(2):16. doi: 10.3390/jcm6020016.
Weycker D, Hanau A, Hatfield M, et al. Primary immune thrombocytopenia in US clinical practice: incidence and healthcare burden in first 12 months following diagnosis. J Med Econ. 2020 Feb;23(2):184-192. doi: 10.1080/13696998.2019.1669329.
ITP
Pathophysiology
◦ Anti-platelet autoantibodies
◦ T cell-mediated platelet destruction
◦ Impaired megakaryocyte function
 Symptoms
◦ Asymptomatic
◦ Low platelet count  increased risk of
bleeding
◦ Symptoms of bleeding:
◦ Nose bleed, blood in urine or stool, hematoma,
heavy menstrual bleeding
◦ Petechiae, purpura

National Heart, Lung and Blood Institute. Immune Thrombocytopenia (ITP). Updated March 24, 2022. Accessed November 6, 2022. https://www.nhlbi.nih.gov/health/immune-thrombocytopenia
Clinical Phases
Acute/newly diagnosed
• First 3 months post-diagnosis

Persistent
• Symptoms lasting 3-12 months

Chronic
• Symptoms lasting >12 months

Refractory
• No response to standard treatment

Severe
• Active intervention needed for bleeding symptoms

Miltiadous O, Hou M, Bussel JB. Identifying and treating refractory ITP: difficulty in diagnosis and role of combination treatment. Blood. 2020 Feb 13;135(7):472-490. doi: 10.1182/blood.2019003599.
Zufferey A, Kapur R, Semple JW. Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). J Clin Med. 2017 Feb 9;6(2):16. doi: 10.3390/jcm6020016.
 Treatment
• Corticosteroids and/or intravenous immunoglobulin (IVIG)
First-line:

• Rituximab, Thrombopoietin receptor agonists or TPO-RAs [Nplate

Second- (romiplostim) and Promacta (eltrombopag)], splenectomy
line:

• Fostamatinib, immune suppressants (azathioprine, cyclophosphamide,

Third-line:
cyclosporine, mycophenolate)

Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966.
Tavalisse
(fostamatinib)
◦ Mechanism of action: spleen tyrosine kinase (Syk) inhibitor
◦ Syk linked to B cell receptor and autoantibody
production
◦ Syk inhibition  reduction in platelet destruction
◦ Indications:
◦ Adult, chronic, immune thrombocytopenia (ITP) with
insufficient response to previous treatment
◦ Dosing:
◦ Initiation: 100mg by mouth twice daily
◦ If platelet count not > 50 x 109/L after a month, increase
to 150mg by mouth twice daily
◦ Dose adjustments for adverse effects
◦ Adverse effects:
◦ Hypertension
◦ Diarrhea
◦ Hepatotoxicity
◦ Neutropenia

Tavalisse. [PRESCRIBING INFORMATION]. Rigel Pharmaceuticals, Inc. 2018.

Pharmacokinetics

Onset of Time to
Half-life: 15
action: 15 peak: 1.5
hours
days hours
Dose Adjustment

• If absolute neutrophil count decreases (ANC less

than 1.0 × 10 /L) and remains low after 72 hours,
Neutropenia temporarily interrupt fostamatinib until resolved
(ANC greater than 1.5 × 10 /L). Resume
fostamatinib at the next lower daily dose.

Tavalisse. [PRESCRIBING INFORMATION]. Rigel Pharmaceuticals, Inc. 2018.

LITERATURE
REVIEW
 Fostamatinib for the treatment of adult persistent and chronic immune
thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials
Objective • Reports the two identical studies comparing fostamatinib to placebo in subjects with
persistent and chronic ITP who has failed prior treatments
Study • Two identical studies: FIT1 and FIT2
Design • Parallel, multicenter, randomized, double-blind, placebo-controlled, phase 3
• Randomized 2:1 for fostamatinib 100mg BID to placebo
• One concomitant ITP medication allowed if at a stable dose 14 days before baseline
Outcome • Primary: stable response by week 24 (defined as platelets ≥ 50,000/µL on at least 4 of
the 6 clinic visits
• Secondary: if baseline platelet <15,000/µL, achievement of platelet counts ≥30 000/µ
and at least 20 000/µL above baseline at weeks 12 and 24
Results • Stable responses in 18% of those on fostamatinib vs. 2% of those on placebo (P=.0003)
• Median platelet count over the 24 weeks was 95,000/ µL for the stable responders and
49,000/µL for overall responders
• 46% of patients continued a concomitant ITP medication
• Neutropenia occurred in 6% of fostamatinib group and 0% of placebo
• Diarrhea and hypertension were the most common reason for a dose adjustment
Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018 Jul;93(7):921-930. doi:
10.1002/ajh.25125.
 Long-term fostamatinib treatment of adults with immune thrombocytopenia during
the phase 3 clinical trial program
Objective • To evaluate the long-term safety and efficacy of fostamatinib
Study • Randomized, multi-center, international, placebo-controlled, open-label extension (OLE)
Design • Included patients must have been enrolled in one of the other two placebo-controlled
studies
• Had to have completed 28 weeks of treatment
• Treatment: fostamatinib at 100 mg BID, could increase the dose after 4 weeks or later to
150 mg BID - concomitant ITP medication at a stable dose and rescue medications were
allowed
Outcome • Primary: stable response
• Defined as: a platelet count ≥50,000/μL at ≥4 of 6 biweekly visits during weeks 14 to 24
Results • N = 123 subjects enrolled
• 17% of fostamatinib patients achieved a stable response versus placebo
• Adverse effects were reported in 86% of patient, 41% were moderate and 21% were mild
• Three cases of therapy discontinuation due to neutropenia

Mayer J, Zayed H, Tong S, Duliege AM. Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program. Am J Hematol. 2019 May;94(5):546-553. doi: 10.1002/ajh.25444.
PATIENT CASE -
REVISITED
 HPI Timeline
Aug: admitted for fever,
acute on chronic anemia and
pancytopenia
Aug: Paraplatin (carboplatin),
Alimta (pemetrexed), Avastin
Feb: Avastin (bevacizumab) for (bevacizumab) for NSCLC
NSCLC Aug: first documentation of
May: metastatic lung cancer Feb: Nplate (romiplostim) for Tavalisse (fostamatinib)
(NSCLC) diagnosis ITP therapy

2016 2018: 2019 2020 2022

July: Avastin (bevacizumab) Aug: Avastin (bevacizumab) for

and Alimta (pemetrexed) for NSCLC
NSCLC maintenance
ITP first documented:
prednisone 60mg, started
Nplate (romiplostim)
Timeline Revisited
◦ Day 4: Eliquis held
◦ Day 8: 1 unit of platelets ordered, improvement of platelets to 12
◦ Per oncology, consider giving IVIG if platelets < 10,000
◦ Not given
◦ Day 9:
◦ Mild improvement in Hgb and platelets, not requiring transfusion
◦ Antibiotics completed, afebrile
◦ Day 10: Neutropenia and thrombocytopenia has improved. Hgb stable.
◦ Day 12:
◦ Patient received 3 units of PRBC total
◦ Continued improvement of neutropenia and thrombocytopenia
◦ Day 15: Eliquis restarted
◦ Platelets 135, ANC 2.16, WBC 4.5
◦ Day 17: Discharged
Conclusion – Pharmacist’s Role
If a patient on fostamatinib presents to the hospital
with neutropenia, it is important to assess the factors
that could be contributing

If fostamatinib is the responsible factor, a hold

then dose reduction is necessary

Bleeding risk versus clot risk should be considered when

creating anticoagulation plan

Treatments are non-formulary – help facilitate filling

process
References
◦ Miltiadous O, Hou M, Bussel JB. Identifying and treating refractory ITP: difficulty in diagnosis and role of
combination treatment. Blood. 2020 Feb 13;135(7):472-490. doi: 10.1182/blood.2019003599.
◦ Zufferey A, Kapur R, Semple JW.
Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). J Clin Med. 2017 Feb
9;6(2):16. doi: 10.3390/jcm6020016
◦ Weycker D, Hanau A, Hatfield M, et al. Primary immune thrombocytopenia in US clinical practice: incidence and
healthcare burden in first 12 months following diagnosis. J Med Econ. 2020 Feb;23(2):184-192. doi:
10.1080/13696998.2019.1669329
◦ National Heart, Lung and Blood Institute. Immune Thrombocytopenia (ITP). Updated March 24, 2022. Accessed
November 6, 2022. https://www.nhlbi.nih.gov/health/immune-thrombocytopenia
◦ Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune
thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966.
◦ Tavalisse. [PRESCRIBING INFORMATION]. Rigel Pharmaceuticals, Inc. 2018.
 IMMUNE
THROMBOCYTOPENIA
TREATMENT IN THE
SETTING OF
PANCYTOPENIA
Cat herine E ichler, PharmD
Nov emb er 10, 2022
Int ernal Med icine
Park view H eal th