Written By: Joshua Nubla, PharmD, NCODA
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Description: This PQI will discuss the initiation and management of patients receiving avapritinib.

 

Background: Avapritinib is a tyrosine kinase inhibitor indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. Avapritinib was approved in January 2020 and is the first therapy approved for patients with GIST with a PDGFRA exon 18 mutation. The NAVIGATOR trial included patients with a confirmed diagnosis of GIST and received 300 mg or 400 mg orally once daily until disease progression or unacceptable toxicity. Patients starting at 400 mg were later reduced to 300 mg due to toxicity. The primary endpoint was overall response rate (ORR), and 43 patients who had exon 18 PDGFRA mutations were included in the ORR analysis. For GIST patients with PDGFRA exon 18 mutations, ORR was 84% with complete response in 7% of patients and partial response in 77% of patients. Patients with PDGFRA D842V mutations had an ORR of 89% (CR 8% and PR 82%; n=38). There were 22 patients with a PDGFRA exon 18 mutation with a duration of response  6 months (61%) and 20 patients with a PDGFRA D842V mutation with a duration of response  6 months (59%). Dose reduction due to an adverse reaction occurred in 49% of patients who received avapritinib with a median time to dose reduction of 9 weeks.  The most common adverse reactions (≥ 20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness.1

PQI Process:

  • Confirm diagnosis and verify genetic testing for PDGFRA exon 18 and PDGFRA D842V mutations

Upon receiving a prescription for avapritinib:

  • Verify dose – Usual dose 300 mg orally once daily on empty stomach (1 hour before/2 hours after)
    • No dose adjustment needed with mild/moderate renal or mild/moderate hepatic impairment
    • Dose modifications:
First dose reduction200 mg once daily
Second dose reduction100 mg once daily
Third dose reductionPermanently discontinue in patients unable to tolerate 100 mg daily
  • Assess patient for antiemetic regimen; consider regular option for patient use as needed
  • Check for drug interactions
    • Avoid avapritinib administration with strong or moderate CYP3A inhibitors.
    • If combination with moderate CYP3A4 is unavoidable, reduce dose of avapritinib to 100 mg once daily
    • Avoid avapritinib administration with strong or moderate CYP3A inducers
  • Dose modifications for specific adverse reactions:
    • Intracranial Hemorrhage
      • Grade 1 or 2:
        • First Occurrence: Hold until resolution and resume at reduced dose
        • Subsequent Occurrence: Discontinue
      • Grade 3 or 4: Permanently discontinue
  • Central Nervous System Effects:
    • Grade 1:
      • Continue at same dose or hold until improvement to baseline or resolution
      • Resume at same dose or reduced dose
    • Grade 2 or 3:
      • Hold until improvement to baseline, grade 1, or resolution
      • Resume at same or reduced dose
    • Grade 4: Discontinue
  • Other adverse reactions at Grade 3 or 4:
    • Hold until improvement to less than or equal to Grade 2
    • Resume at same or reduced dose, as clinically appropriate

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) Sheet
  • Counsel patient that medication should be taken on empty stomach
  • Educate patient that a missed dose needs to be taken within 8 hours of the regular dosing time
  • Counsel patient on potential drug interactions with avapritinib
  • Monitor patient for central nervous side effects such as dizziness, trouble sleeping, changes in mood or behavior as well as any neurological signs and symptoms related with intracranial hemorrhage
    • Educate the patient and their caregiver network to be alert for cognitive changes such as memory loss, forgetfulness and confusion
  • Monitor patient for laboratory changes associated with common adverse reactions such as decreased hemoglobin and increased bilirubin

Supplemental Information:

  • Patient Support Program: YourBlueprint (https://www.yourblueprint.com/hcp/)
    • Dedicated Case Manager available at 1-888-258-7768 (1-888-BLUPRNT)
    • Monday-Friday 8AM-8PM ET
  • Co-Pay Assistance Program
    • Eligible, commercially insured patients may reduce their out-of-pocket costs ($0 per month)

References:

  1. AYVAKIT® (avapritinib) [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation.
  2. Heinrich MC, Jones RL, von Mehren M et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946.

Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

 

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Written by: Alyson Leonard, PharmD, BCPS, BCOP Cone Health
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Cabazitaxel is indicated for treatment of patients with metastatic castration-resistant prostate (mCRPC) cancer previously treated with a docetaxel-containing treatment regimen in combination with prednisone.1 The purpose of this PQI is to provide guidance for initiating cabazitaxel.

Background: Cabazitaxel was FDA approved in 2010 based on information from the phase 3 trial TROPIC that compared cabazitaxel plus prednisone to mitoxantrone in patients with mCRPC previously treated with a docetaxel-based treatment.2 The recommended dose of cabazitaxel is now 20mg/m2 every 3 weeks, the higher dose of 25mg/m2 can be used at provider discretion for select patients.1,3

The CARD trial evaluated the use of cabazitaxel with prednisone/prednisolone and G-CSF for patients with mCRPC previously treated with docetaxel and an androgen- signaling -targeted inhibitor (abiraterone or enzalutamide) who had progressed within 12 months. The study compared cabazitaxel to initiation of another androgen- signaling -targeted inhibitor not previously used. The median radiographic progression-free survival was 8 months with cabazitaxel + prednisone/prednisolone + G-CSF and 3.7 months with abiraterone + prednisone/prednisolone or enzalutamide (HR 0.54, p<0.0001). When comparing median overall survival, cabazitaxel had a longer overall survival compared to androgen-signaling-targeted inhibitor, 13.6 months vs 11 months. Overall, cabazitaxel was associated with a 36% risk of death reduction.  Secondary objectives of improvement in PFS, pain response, and time to symptomatic skeletal events favored cabazitaxel.1,4

PQI Process:

  • Review the medical record
    • Review past treatments for documentation of previous docetaxel administration
      • If docetaxel was not previously given, evaluate the reason for non-use. Per guidelines, patients who are not candidates for docetaxel can still be considered for cabazitaxel. (ex. pre-existing mild neuropathy prevented docetaxel use)5
    • Review labs for a recent CBC. Cabazitaxel is contraindicated in patients with neutrophil counts currently ≤1,500 cells/mm3.1
  • Review treatment plan: 1
    • Verify pre-medication orders:
      • Antihistamine: diphenhydramine 25 mg or equivalent antihistamine
      • Corticosteroid: dexamethasone 8 mg or equivalent steroid
      • H2antagonist: famotidine 20 mg or equivalent H2 antagonist
    • Verify cabazitaxel dosing: 20 mg/m2administered every three weeks as a one-hour intravenous infusion
      • Dose adjustments needed for hepatic impairment; no adjustment necessary for renal impairment
    • If provider is starting dosing as 25 mg/m2, strongly consider G-CSF and CINV prophylaxis, incidence of grade 3-4 nausea at this dose was 2% and grade 3-4 vomiting was 2%1
    • Verify a prescription for prednisone has been entered
  • Verify a prescription or order for antiemetic: prophylaxis recommended as needed (PO or IV)
  • Evaluate the need for primary prophylaxis with G-CSF
    • Recommended for patient with high-risk clinical features such as previous episodes of febrile neutropenia, older patients, extensive prior radiation, poor performance or nutritional status, or other serious comorbidities
  • Monitoring1
    • CBC: baseline, weekly during cycle one, then before each treatment cycle
  • Preparation1
    • Cabazitaxel requires two dilutions for preparation
    • Mix cabazitaxel vial with the entire contents of the included 5.7 mL diluent vial
    • Withdraw the patient specific dose of cabazitaxel
    • Inject dose into a 250 mL PVC-free container of 0.9% sodium chloride (NS) or 5% dextrose (D5W)
      • If dose is >65 mg use a larger volume solution so the concentration is ≤0.26 mg/mL
    • Mix the final infusion solution by gently inverting the bag
  • Administration1
    • IV over hour with a 0.22-mcm nominal pore size inline filter

Patient Centered Activities:

  • Patient Education
    • Review the risk of infusion reactions, with cabazitaxel they are most likely to occur during first or second infusion. Signs of a reaction may include rash/itching, feeling dizzy, chest or throat tightness, breathing problems, face swelling
    • Instruct patient to report any adverse events, such as fever, diarrhea, nausea/vomiting, numbness/tingling of the hands or feet, or fatigue
    • Ensure patient has access to supportive medications
      • Anti-nausea (ex. 5-HT3 receptor antagonist, metoclopramide, or prochlorperazine)
      • Anti-diarrheal (ex. loperamide)
    • Provide written information to patient on medication

Supplemental Information:

*Medicare Part B patients with no supplemental insurance coverage may be eligible

  • CareASSIST Copay Program
    • Available to commercial insurance patient to help decrease out of pocket cost

References:

  1. Jevtana® (cabazitaxel) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC.
  2. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  3. Eisenberger M, Hardy-Bessard AC, Kim CS, et al. Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer-PROSELICA. J Clin Oncol. 2017;35(28):3198-3206.
  4. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019;381(26):2506-2518.
  5. National Comprehensive Cancer Network. Prostate Cancer. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.

Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

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Written by Neal Dave, PharmD, Texas Oncology
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Description: This PQI will review appropriate patient identification and management of Polycythemia Vera (PV) with the use of ruxolitinib therapy.

Background: Common treatments for PV are aspirin, phlebotomy, hydroxyurea, interferon (not commonly used), or a JAK2 inhibitor, ruxolitinib. Hydroxyurea (HU) is considered the gold standard treatment to start with for high risk patients.3 Patients that are taking hydroxyurea and still have high blood counts or cannot tolerate it may benefit with treatment with ruxolitinib (see supplemental information section regarding treatment rationale).

PQI Process:

  • Review CBC with refill every to ensure HCT is < 45%
  • Assess patients for adverse events and document in EMR
  • Use the MPN-SAF total symptom score scale4
  • See Risk Stratification table in supplemental information section as needed
  • If HCT > 45 or symptoms are worse:
    • Low risk patients not taking HU:
      • Consider recommending HU (1-2 g/ day in 1-3 divided doses)
    • High risk patients:
      • If patient has been on HU for longer than 12 weeks and is still requires phlebotomies then recommend possibly switching to second line therapy
      • Ask prescriber if they want to consider ruxolitinib 10 mg by mouth two times

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) sheet
  • Provide education:
    • Laboratory monitoring will be required with refills
    • Possibility of dose adjustments
    • Importance of staying hydrated
    • Infection prevention: call clinic for any fever > 100.4 degrees F
    • Monitoring skin for patients on ruxolitinib:
      • Important to notice all skin lesions (examine skin at baseline)
  • Make note of any new lesions that arise while on therapy
  • Stress importance of adherence
  • Schedule follow up calls
  • Maintain adherence to treatment of secondary health conditions (high blood pressure, diabetes, high cholesterol, history of blood clots)

References:

  1. National Comprehensive Cancer Network (NCCN) Guidelines for Myeloproliferative Neoplasms. nccn.org/patients/guidelines/mpn/38/.
  2. Marchioli et al, N Engl J Med 2013; 368:22-33, January 3, 2013.
  3. Griesshammer M, Gisslinger H, Mesa R. Current and future treatment options for polycythemia vera. Ann Hematol. 2015;94(6):901-910.
  4. Scherber et al Blood, 14 July 2011 v118, n2.

Supplemental Information:

Risk Stratification:

Low Risk PCV patient characteristics:Age < 60 and no previous history of blood clots
High Risk PCV patient characteristics:Age > 60 or previous history of a blood clot

Treatment Goals Rationale:
One of the treatment goals for PCV is to reduce the cardiovascular risk of patients. Typically, clinicians try to maintain a HCT < 45% and often a target < 42% for women.1 A study published in the NEJM showed that patients with a HCT in the 45-50% range had a 4 times greater risk of cardiovascular events than patients with a HCT less than 45%.2

Proper follow up and review of CBCs are required when patients are started on hydroxyurea. Dose adjustments and possibly additional phlebotomies should be considered for these patients. Identifying the proper time to switch to another therapy is important to help manage the disease Anywhere between 20-60% of patients remain on hydroxyurea even though they are not having a proper response.3

Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

 

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Written by: Jeff Engle, PharmD, MS
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Description: This PQI will discuss effective management of adverse effects of sorafenib in the treatment of hepatocellular carcinoma and discuss data supporting the sequencing of patients to second-line therapy with regorafenib for increased survival benefit.

Background: Hepatocellular carcinoma (HCC) is associated with a high mortality rate and historically the treatment options have been limited. Prior to 2018, sorafenib was the only Food and Drug Administration approved targeted therapy for the initial treatment of unresectable HCC in patients diagnosed with late stage or metastatic disease.7 Second-line treatment options, though growing in number, have limited and at times conflicting survival data; and all factors of options should be considered.14, 18 A retrospective study of the RESORCE trial ascertained median time from start of sorafenib to death in patients receiving sequential therapy to regorafenib.  Exploratory analysis revealed time from sorafenib initiation to death as 26 months for regorafenib patients vs. 19.2 months for placebo patients.16

PQI Process: Upon receipt of a prescription for sorafenib:

  • Obtain CBC with differential, metabolic panel including magnesium and phosphorus, liver function tests, lipase and amylase prior to starting therapy and then monthly until labs have stabilized
  • Consider obtaining thyroid stimulating hormone level at baseline, every 4 weeks for 4 months, and then every 2-3 months thereafter
  • Monitor blood pressure at baseline and weekly during the first 6 weeks of sorafenib, and then monitor blood pressure, utilizing clinic appointments and treatment any developing hypertension as needed
  • Treatment associated hypertension and dermatologic toxicity are managed with dose interruptions and reductions.8 Grade 1 dermatologic toxicity may not require dosage adjustments (see table 3 for dose reductions due to toxicity)
  • Consider proactively discussing 2nd line treatment options following progression or intolerance

If regorafenib is considered for 2nd line tyrosine kinase inhibitor transitioning

  • Ensure recovery from sorafenib mediated adverse effects and that patient did not permanently discontinue sorafenib due to toxicity or inability to tolerate doses
    • RESORCE trial required that patients be able to tolerate at least 400 mg a day of sorafenib for 20 days of the last 28 days prior to withdrawal to be eligible
  • Determine Child-Pugh Class status and make appropriate recommendation for therapy
  • If underlying hypertension exists or developed while on sorafenib, ensure appropriate blood pressure control prior to starting regorafenib
  • Refer to Regorafenib (Stivarga®) In the Treatment of Hepatocellular Carcinoma PQI for managing adverse effects

Patient Centered Activities:

Counseling for sorafenib

Counseling for regorafenib

 

Supplemental Information:

Table 1: Dose Adjustments for Baseline Hepatic Dysfunction15*

Degree of Hepatic ImpairmentCriteriaSorafenib Dose
MildBilirubin >1 to ≤1.5 times ULN and/or AST >ULN400 mg twice daily
ModerateBilirubin >1.5 to ≤3 times ULN; any AST200 mg twice daily
SevereAlbumin <2.5 g/dL with any bilirubin/AST200 mg once daily
Bilirubin >3 to 10 x ULN with any ASTNo tolerable dose identified

*Reference used differs slightly from sorafenib prescribing information reference

Table 2: Dose Adjustments for Baseline Renal Dysfunction15

Baseline Creatinine ClearanceSorafenib Dose
40-59 mL/min400 mg twice daily
20-39 mL/min200 mg twice daily
< 20 mL/minUnable to define dose
Hemodialysis200 mg once daily

 

Table 3: Dose Reduction Levels for Adverse Effects*

Dose ReductionSorafenib Dose
Starting400 mg twice daily
1200 mg twice daily
2200 mg once daily or 400 mg every other day
3Discontinue

Patient Assistance

Sorafenib patients can utilize the REACH support program while on therapy

  • Nurse counselors are available for answering questions and providing patient education including Patient Starter Kits
  • Service counselors are available to discuss patient access services including co-pay assistance

References:

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34.
  2. Cronin KA, Lake AJ, Scott S, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer. 2018 Jul 1;124(13):2785-2800.
  3. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004; 127: S87–96.
  4. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.e1.
  5. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018 Aug;68(2):723-750.
  6. National Comprehensive Cancer Network. Hepatobiliary cancers version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf.
  7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.
  8. Nexavar® (sorafenib) [prescribing information]. Wayne, NJ: Bayer Healthcare Pharmaceuticals Inc.
  9. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56-66.
  10. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMat 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492-2502.
  11. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952.
  12. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.
  13. Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):282-296.
  14. Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma. Merck. Published February 19, 2019. https://bit.ly/2SQ6J45.
  15. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009 Apr 10;27(11):1800-5.
  16. Finn RS et. Al Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC. J Hepatol.2018 Aug;69(2):353-358. doi: 10.1016/j.jhep.2018.04.010.
Important notice: NCODA has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

 

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Written by: Bryan J. Brinda, PharmD
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Description: This PQI will discuss proper patient selection and management of adverse events related to the administration of oral gilteritinib pharmacotherapy in patients with relapsed/refractory AML that have an FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an  FDA-approved test. Optimal patient identification, dosing, and follow-up are essential to help patients benefit fully while taking this medication.

Background: Gilteritinib is a tyrosine kinase inhibitor that has demonstrated activity in patients with relapsed/refractory (R/R) AML who have mutations in the internal tandem duplication (ITD) and/or tyrosine kinase domain (TKD) of FLT3 (found in 30% of AML population). This represents a treatment paradigm shift as the first oral monotherapy option for this particular subset of FLT3- mutated AML patients who, if interested in further treatment, would traditionally utilize IV salvage chemotherapy. Clinicians should be aware of the need for molecular testing and identifying therapy options with the highest level of evidence. In the final analysis of the ADMIRAL study, Overall Survival (OS) was reported as 9.3 months for patients receiving gilteritinib versus 5.6 months for those receiving salvage chemotherapy (Hazard Ratio = 0.64 (95% CI 0.49, 0.83), P=0.0004). The rate of complete response (CR/CRh) was reported at 22.6%. The median time to first response was 2 months and transfusion-independence was observed in 34.5% of patients, representing a potential improvement in quality of life. Gilteritinib is actively being studied in other AML settings including front-line therapy with induction chemotherapy, maintenance therapy after transplant, and in combination with hypomethylators.

PQI Process: Upon receipt of new prescription for gilteritinib:

  • Verify genetic testing is complete with positive FLT3 mutation and appropriate prior lines of therapy
  • Ensure that the correct dose is prescribed (3 x 40 mg oral tablets (120 mg total)) by mouth daily
  • Verify that baseline blood counts, chemistries, as well as creatine phosphokinase (CPK) have been assessed prior to initiation of gilteritinib
    • Schedule these labs for every week for the first month, every other week for the second month, and once monthly thereafter for the duration of therapy
  • Ensure ECG results obtained prior to initiation of gilteritinib as well as appointments scheduled to receive follow-up ECGs on days 8 and 15 of the first cycle and consider for the next two cycles
  • Monitor for any signs/symptoms of pancreatitis, PRES, differentiation syndrome
    • Fever, dyspnea, hypoxia, pulmonary infiltrates, pleural effusions, edema
  • Call office at first sign of fever (temperature >100.4F)
  • Consider the use of antidiarrheals
  • Important: Upon refill, check and clarify dosing, quantity, and instructions to the patient (number of tablets per dose, etc.)

Patient Centered Activities:

  • Provide Oncology Chemotherapy Education (OCE) sheet
  • Ensure patient knows the appropriate drug dose and schedule (3 x 40 mg oral tablets )120 mg total) once daily continuously)
  • Ensure patient knows that the drug may be taken without regard to meals and that the tablets should not be broken or crushed
  • Patients should take their dose as soon as possible if missed on the same day if at least 12 hours before next scheduled dose followed by a return to normal dosing schedule *Patient should not take two doses within 12 hours
  • Counsel female patients of childbearing age to use effective contraception during treatment and for at least six months after the last dose of gilteritinib; male patients should utilize contraception during treatment and for at least 4 months after the last dose of gilteritinib
  • Dosage modifications as described in Table in Supplemental Information

References:

  1. XOSPATA® (gilteritinib) [package insert].
  2. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicenter, first-in-human, open-label, phase 1-2 study. Lancet Oncology. 2017;18(8):1061-1075.
  3. Usuki K, Sakura T, Kobayashi Y, et al. Clinical profile of gilteritinib in Japanese patients with relapsed/refractory acute myeloid leukemia: an open-label phase 1 study. Cancer Science. 2018;109(10):3235-3244.
  4. Perl AE, Cortes JE, Strickland SA, et al. An open-label, randomized phase III study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation- positive acute myeloid leukemia. Journal of Clinical Oncology. DOI: 10.1200/JCO.2017.35.15_suppl.TPS7067.

Supplemental Information

Dose Modifications

Adverse EventRecommended Action
·  Differentiation Syndrome· Systemic steroids until resolved for 3 days (interrupt gilteritinib if signs remain >48H)

· Resume when symptoms improve to Grade 2

·  Posterior reversible encephalopathy syndrome (PRES)· Discontinue gilteritinib
·  QTc interval > 500 msec· Interrupt gilteritinib and resume at reduced dose of 80 mg
(2 x 40 mg tablets) daily when

QTc interval returns within 30 msec of baseline or ≤480 msec

·  QTc interval increased by > 30 msec on ECG on day 8 of cycle 1· Confirm with ECG on day 9

· If confirmed, consider gilteritinib dose reduction to 80 mg (2 x 40 mg tablets) daily

·  Pancreatitis· Interrupt gilteritinib until pancreatitis is resolved and resume at a reduced dose of 80 mg (2 x 40 mg tablets) daily
·  Other grade 3 or higher toxicity (related to treatment)· Interrupt gilteritinib until toxicity resolves or improves to grade 1 and reduce dose to 80 mg (2 x 40 mg tablets) daily

 

Co-Pay Assistance

  • Patients with commercial paying insurance are eligible for co-pay support
    • Patients pay as little as $0 per prescription
    • Enrollment is for a 12 month period and the program benefit covers up to a maximum of $25,000 per calendar year
    • Contact XOSPATA® support solutions (1-844-632-9272) OR your preferred network specialty

Common adverse events (all grade >30%):

  • Transaminase increase (51%)
  • Fatigue/malaise (44%)
  • Fever (41%)
  • Mucositis (41%)
  • Edema (40%)
  • Rash (36%)
  • Diarrhea (35%)
  • Dyspnea (35%)
  • Nausea (30%)

Rare and serious adverse events:

  • Electrocardiogram QT prolonged (9%)
  • Hypersensitivity (8%)
  • Pancreatitis (5%)
  • Cardiac Failure (4%)
  • Pericardial Effusion (4%)
  • Differentiation syndrome (3%) [Boxed Warning]
  • Posterior reversible encephalopathy syndrome (1%)

*AE reported from 319 gilteritinib patients across 3 clinical trials

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