Written by: Tammy McClellan, PharmD, Riverside Healthcare

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Positive Quality Intervention: Patient Screening for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Description:

            The purpose of this PQI is to assess the individualized characteristics of the Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) patient and important screening measures in order to achieve optimal pharmacological therapy.

Background:

CLL/SLL, a type of non-Hodgkin Lymphoma, is an indolent cancer in which immature lymphocytes (primarily B lymphocytes) are found in the blood and bone marrow and/or in the lymph nodes. CLL and SLL are the same disease, but in CLL cancer cells are found mostly in the blood and bone marrow6. In SLL cancer cells are found mostly in the lymph nodes1. CLL/SLL has been described as a disease of defective mechanisms of apoptosis and not hyper-proliferation. CLL/SLL is considered both a lymphoma and leukemia. There are multiple screening tests (ex. FISH, IgVH, TP53) that will help provide insight to an informed course of action. Predictive testing is important to provide an informed decision regarding therapy selection within CLL/SLL. When pharmacological therapy is warranted, the healthcare professional can now proceed in making a selection of the most appropriate therapies. In addition, testing for minimal residual disease (MRD) can additionally be utilized to determine depth of response along with detection of disease relapse.7

PQI Process:

General Screening Guide (Visit cllsociety.org for more in-depth information)6

  • Review B-lymphocyte count at ≥5000 monoclonal (genetically identical) B-lymphocytes in the blood for the duration of at least three months. Confirm utilizing flow cytometry.
  • For SLL confirm documented location of enlarged lymph nodes and/or an enlarged spleen with less than 5000 B-lymphocytes in the blood. Confirmed with lymph node biopsy.
  • Secondary Symptoms
    • Weight loss >10% of body weight in previous 6 months
    • Severe fatigue (ambulatory and capable of all self-care but unable to carry out any work activities
    • Fevers >38°C for at least 2 weeks without evidence of infection
    • Drenching night sweats for more than a month without evidence of infection

Tests to confirm to discuss with care team to determine course of action after screening5:

  • FISH (Interphase fluorescence in situ hybridization) test for genetic abnormalities
    • Test before every treatment
    • An abnormality such as deletion 17p can affect response to chemotherapy
  • IgVH mutation status.
    • Test mutation status before the 1st treatment
    • Patients with a “mutated” IgVH immunoglobulin will respond with FCR based therapies
  • TP53 genetic testing
    • Test before every treatment
    • A TP53 mutation can affect response to chemotherapy

Additional MRD Testing as needed:

  • Polymerase Chain Reaction laboratory test (PCR)
  • Flow Cytometry
  • Next Generation Sequencing

Patient Considerations:

  • Patient’s age (64 years old or younger & 65 years old or older)
  • Presence of Comorbidities/Performance Status
  • Genetic abnormalities to review4:
    • Deletion 17p
    • Deletion 13q
    • Deletion 11q
    • TP53 mutation
    • Complex karyotype
  • Tumor burden/Risk for Tumor Lysis syndrome: Clinical and Laboratory assessments3:
    • Review physical exam notes: presence of “bulky disease”
    • Laboratory values to review: increased potassium, uric acid, phosphorous, LDH, and decreased calcium
    • Clinical abnormalities to note: renal disease/failure, arrhythmias, seizures, muscle cramps and weakness
    • Drug selection examples: allopurinol, febuxostat, rasburicase; monitor serum creatinine and electrolytes)
    • Note to provide rigorous hydration

Prophylactic measures2:

  • Cytomegalovirus (CMV) by Polymerase Chain Reaction (PCR): Consider use of ganciclovir (note: patients at higher risk are those receiving idelalisib, alemtuzumab, fludarabine-based chemotherapy and some small-molecule inhibitors)
  • Herpes virus: Consider providing acyclovir or equivalent
  • Pneumocytis Jiroveci Pneumonia (PJP): Review usage of sulfamethoxazole and trimethoprim or equivalent
  • Hepatitis B virus (HBV): Hepatitis B surface antigen and Hepatitis B core antibody testing by PCR

Patient Centered Activities:

  • Note complications of Monoclonal Antibody Therapy: mucocutaneous reactions, Stevens-Johnson Syndrome, etc.
  • CLL/SLL patients are at higher risk for developing non-melanomatous skin cancer (annual dermatologic skin screening is recommended in addition to other screenings)
  • Irradiate all blood products to avoid transfusion-associated graft-versus-host disease (GVHD)
  • Counsel patient on disease state, treatment regimen, what to expect, upcoming appointments/toxicology checks and adherence.

References:

  1. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms. Assessed at: https://www.cancer.gov/publications/dictionaries/cancer-terms/search?contains=false&q=cll. 6-12-2020
  2. National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 4.2020-Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Accessed at: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf.
  3. Gupta, Arjun MD & Moore, Joseph A. MD. Tumor Lysis Syndrome [published online May 10, 2018]. JAMA Oncology. Doi:10.1001/jamaoncol.2018.0613. Accessed at: https://jamanetwork.com/journals/jamaoncology/fullarticle/2680750.
  4. National Institutes of Health (NIH): National Library of Medicine. Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia. Accessed at: https://pubmed.ncbi.nlm.nih.gov/11347338/.
  5. CLL Society. Test Before Treat. Accessed at: https://cllsociety.org/cll-101/test-before-treat/.
  6. CLL Society. Diagnosis of Chronic Lymphocytic Leukemia. Accessed at: https://cllsociety.org/cll-101/test-before-treat/.
  7. CLL Society. Minimal Residual Disease Testing 101: Definitions to Know. Accessed at: https://cllsociety.org/2020/09/mrd-glossary/.
Important notice: National Community Oncology Dispensing Association, Inc. (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: Julianna Darling, PharmD, Indiana University Health Simon Cancer Center

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Positive Quality Intervention: Fostamatinib (Tavalisse) use in Chronic Immune Thrombocytopenia

Description:

Fostamatinib is an oral spleen tyrosine kinase (Syk) inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. ITP is mediated by platelet antibodies that accelerate platelet destruction and inhibit their production. Common treatments for ITP include corticosteroids, rituximab, IVIG, splenectomy and/or thrombopoietin receptor agonists (TPO-RA).  This PQI will review appropriate use of fostamatinib in this setting.

Background:

Syk signaling is central to phagocytosis based, antibody mediated platelet destruction in adults with ITP. Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against SYK. The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B cell receptors, leading to decreased destruction of platelets.1 In two parallel, phase 3, multicenter, randomized, double blind, placebo-controlled trials (FIT1 and FIT2), adult patients with chronic ITP were randomized 2:1 to fostamatinib or placebo. Fostamatinib was dosed at 100mg BID for 24 weeks with a dose increase to 150mg BID in non-responders after 4 weeks. Primary endpoint was stable response, which was defined as platelet ≥50,000 x109/L at ≥4 of 6 biweekly visits, weeks 14 through 24, without rescue therapy. Stable responses occurred in 18% of patients in the fostamatinib group compared to 2% in the placebo group. The most common adverse events were diarrhea, hypertension, nausea, dizziness, and ALT increase.

PQI process:

Upon receipt of fostamatinib:

  • Confirm appropriate dosing: Typical starting dose is 100mg twice daily.2
  • May increase to 150mg twice daily if 100mg twice daily does not increase platelet count to >50,000/mm3 after 1 month
  • Use the lowest possible dose to achieve and maintain a platelet count of at least 50,000/mm3
  • Fostamatinib may be taken with or without food. In the case of a missed dose, instruct patients to take their next dose at its regularly scheduled time.
  • Obtain baseline LFTs and repeat monthly throughout therapy.
  • Obtain baseline CBC and repeat monthly with on therapy. If ANC drops below 1.0 x 109/L, dose reduce or discontinue fostamatinib
  • Monitor blood pressure every 2 weeks after starting therapy until patient is established on a stable dose, then obtain BP monthly
  • Screen for drug interactions with CYP3A4 inhibitors and inducers
    • Fostamatinib is a prodrug that is metabolized into its active metabolite, R406. Co-administration of ketoconazole caused a 2-fold increase in R406 exposure, verapamil increase R406 exposure by 39% and rifampicin co-administration decreased exposure by 75%.3
  • Discontinue fostamatinib after 12 weeks of therapy if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.

Patient Centered Activities:

  • Provide thorough verbal and written medication education; including, but not limited to, the OCE handout for fostamatinib
  • Ensure the patient understands the lab schedule for follow up CBC, LFTs, and BP monitoring
  • Avoid eating or drinking grapefruit and grapefruit juice while taking this medication
  • If patient is of child-bearing age, review pregnancy and contraception information with them. 

Supplemental Information:

Dose adjustments for toxicity2

Usual maximum dose150mg twice daily
First dose reduction100mg twice daily
Second dose reduction150mg once in the morning
Third dose reduction100mg once in the morning

References:

  1. Clemons Bankston P, Al-Horani RA. New small molecule drugs for thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations. Int J Mol Sci. 2019;20(12):3013
  2. Tavalisse (fostamatinib) [prescribing information]. South San Francisco, CA: Rigel Pharmaceuticals, Inc; April 2018.
  3. Martin P, Gillen M, Millson D, et al. Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies. Drugs R D. 2016;16(1):81-92. doi:10.1007/s40268-015-0118-4
Important notice: National Community Oncology Dispensing Association, Inc. (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: Houston Holmes, MD, Texas Oncology

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Positive Quality Intervention: Tazemetostat (Tazverik) management in Relapsed/Refractory Follicular Lymphoma 

Description:

This PQI will discuss the initiation and management of tazemetostat in the treatment of relapsed or refractory (r/r) follicular lymphoma (FL)

Background:

Tazemetostat is a methyltransferase inhibitor indicated for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for completed resection and adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test, such as via the cobas® EZH2 Mutation Test, and who have received at least 2 prior systemic therapies or who have no satisfactory alternative treatment options. For r/r follicular lymphoma, mutation status was determined using the cobas EZH2 mutation test to detect: Y646X [S,H,C], y646F, Y646N, A682G, and A692V. Patients in trials received 800mg of tazemetostat orally twice daily until disease progression or unacceptable toxicity with tumor assessments every 8 weeks. For EZH2 mutant FL patients the ORR was 69% (n=42) with a CR of 12% and PR of 57%. EZH2 wild-type FL patients had an ORR of 34% (n=53) with a CR of 4% and PR of 30%1,2.

In trial the median PFS was 13.8 months by both investigator and an independent review committee (IRC) assessment in patients with EZH2 mutations. In the EZH2 wild-type group, the median PFS was 5.6 months by investigator review and 11.1 months by IRC review. Main usage is currently within 3rd or greater line treatment with mutation typically seen in 2nd/3rd line r/r. Mutation is identified in 2nd or 3rd line if patient is positive. The treatment is fairly well tolerated; the most common adverse reactions (≥20%) in patients with r/r FL were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain1. Only 8% of patients permanently discontinued therapy due to adverse events, and 9% of patients required dose reductions. A well tolerated medication such as tazemetostat can be considered without testing for mutation if other alternatives are deemed too intolerable2,3.

PQI Process:

  • Confirm acceptable diagnosis and associated indication. EZH2 testing may not be required for all patients
    • Patient who has received 2 systemic therapies
      • Consider testing patient for EZH2, if positive, would be considered eligible candidate
    • No satisfactory alternative treatment options
      • Patient that has received 2 previous lines of therapy, and is evaluated to not to be a good candidate for additional chemoimmunotherapy or other treatments, testing for an EZH2 mutation would not be necessary
    • Speak with provider as a potential alternative treatment to current pathway
  • Recommended dosage of Tazverik is 800mg orally twice daily with or without food
  • Dose modifications for adverse reactions
    • First Dose Reduction -> 600mg orally twice daily
    • Second Dose Reduction -> 400mg orally twice daily
    • Patients unable to tolerate 400mg orally twice daily should permanently discontinue tazemetostat

PQI Process Continued1:

  • Cytopenia dose modifications
    • Neutropenia (Neutrophil count less than 1×109/L)
      • Withhold until neutrophil count is greater than or equal to 1×109/L or baseline
      • First occurrence, resume at same dose
      • Second and third occurrence resume at reduced dose
      • Permanently discontinue after third occurrence
    • Thrombocytpenia (Platelet count less than 50 x 109/L)
      • Withhold until platelet count is greater than or equal to 75 x 109/L or baseline
      • First and second occurrence, resume at reduced dose
      • Permanently discontinue after third occurrence
    • Anemia (Hemoglobin less than 8 g/DL)
      • Withhold until improvement to at least Grade 1 or baseline, then resume at same or reduced dose.
    • Other adverse reactions (Grades 3 and 4)
      • Grade 3
        • Withhold until improvement to at least Grade 1 or baseline
        • For first and second occurrence, resume at reduced dose
        • Permanently discontinue after third occurrence
      • Grade 4
        • Withhold until improvement to at least Grade 1 or baseline
        • For first occurrence, resume at reduced dose
        • Permanently discontinue after second occurrence

Patient Centered Activities1:

  • Provide Oral Chemotherapy Education Sheet and counsel patient on potential drug interactions with tazemetostat
  • Counsel patient on common side effects (>20%) including pain, fatigue, nausea, decreased appetite, vomiting, and constipation
  • Monitor patient’s laboratory values for decreased hemoglobin and decreased lymphocytes and increased glucose in r/r follicular lymphoma patients

Supplemental Information:

  • Information on FDA-approved tests for detection of EZH2 mutation in r/r follicular lymphoma: FDA.gov/CompanionDiagnostics

Patient Support:

  • Quick Start, Bridge Supply, Patient Assistance and Co-Pay Assistance Programs available for eligible patients
  • EpizymeNOW Patient & Product Support Website: www.tazverik.com/hcp/follicular-lymphoma/resources
  • Patient Support Contact: Monday-Friday (9 am to 6 pm ET) at: 1-833-4EPINOW (437-4669)

References:

  1. TAZVERIKTM (tazemetostat) [prescribing information]. Cambridge, MA: Epizyme, Inc.; July 2020.
  2. Morschhauser F, Tilly H, Chaidos A, et al. Phase 2 multicenter study of tazemetostat, an EZH2 Inhibitor, in patients with relapsed or refractory follicular  Blood. 2019;134(suppl 1):123. doi:10.1182/blood-2019-128096
  3. Burke, JM, Bucholtz, E, et al. New Developments in Follicular Lymphoma: Treatment Guidance and Clinical Resources. Clinical Care Options Oncology.
Important notice: National Community Oncology Dispensing Association, Inc. (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: Trey McNiel, PharmD, Georgia Cancer Specialists

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Description:

The purpose of this PQI is to discuss the clinical considerations around the use of acalabrutinib (Calquence) to optimize the outcomes for patients with CLL/SLL.

Background:

Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor initially indicated for mantle cell lymphoma (MCL) patients who have received one prior therapy. In late 2019, it received an indication for the treatment of CLL/SLL either as monotherapy or in combination with obinutuzumab.1

Efficacy in the front-line setting was established by the Elevate-TN trial, demonstrating progression-free survival advantage of acalabrutinib when administered with or without obinutuzumab, when compared to obinutuzumab plus chlorambucil.2

  • At a median follow up of 28.3. months, acalabrutinib plus obinutuzumab improved PFS and ORR compared with obinutuzumab plus chlorambucil in the ELEVATE-TN trial (ORR 93% vs. 78.5%, PFS 93% vs. 47% respectively)2

The ASCEND trial displayed advantage in progression-free survival of acalabrutinib monotherapy in the relapsed/refractory setting when matched against investigator’s choice of rituximab product plus idelalisib or bendamustine.3

  • As monotherapy, acalabrutinib significantly improved PFS, but not ORR, in both the ELEVATE-TN and in the ASCEND trial. ELEVATE trial ORR, 85% vs. 78.5%, ASCEND trial ORR 80 % monotherapy vs. 84% idelalisib plus rituximab (I-R) or bendamustine plus rituximab (B-R), ASCEND trial PFS: Not reached in monotherapy vs. 16.5 months for the I-R/B-R arm).3

PQI Process:

Upon the receipt of a new prescription of acalabrutinib for CLL/SLL:

  • Verify dosage: the recommended starting dose of acalabrutinib is 100 mg every 12 hours, taken whole with water and with or without food. If dose is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time.
    • Avoid in severe hepatic impairment.
    • No dose adjustment needed in mild to moderate hepatic or renal impairment (use in severe renal impairment has not yet been evaluated in patients with severe renal impairment or renal impairment with dialysis.)
  • Review patient medication list for possible drug-drug interactions
    • Taken with strong CYP3A4 inducer: if use cannot be avoided increase dosage to 200 mg every 12hours
    • Taken with strong CYP3A4 inhibitor: avoid use, but if the inhibitor is a short-term medication, (i.e. 7 days of anti-infective) stop acalabrutinib and resume after inhibitor is complete.
    • Taken with moderate CYP3A4 inhibitor: reduce dosage to 100 mg daily
  • Acalabrutinib should be avoided with proton pump inhibitors. If other gastric reducing agents are used, recommend taking acalabrutinib 2 hours prior to taking a H2 receptor antagonist, if using an antacid separate dosing by at least 2 hours.
  • If being used in combination with obinutuzumab, acalabrutinib should be taken BEFORE the obinutuzumab when taken the same day.

Adverse Events and Management1

CategoryOccurrenceAction
Fatal and serious infections, including opportunistic infections, have occurred.Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients in clinical trials.Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.
Fatal and serious hemorrhagic events have occurred in patientsMajor hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.Monitor patients for signs of bleeding. Consider the benefit-risk of withholding acalabrutinib for 3-7 days pre-and post-surgery depending on type of surgery and the risk of bleeding.

Caution in patients on antithrombotic agents

Grade 3 or 4 cytopeniasNeutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients. Grade 4 neutropenia developed in 12% of patients.Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.
Cardiac FactorsGrade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection.Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.
Skin CancerThe most frequent second primary malignancy was skin cancer, reported in 6% of patients.Monitor patients for skin cancers and advise protection from sun exposure.

Dose Modifications1

EventAdverse Reaction OccurrenceDose Modification

(Starting dose = 100 mg approximately every 12 hours)

Grade 3 or greater non-hematologic toxicities,

Grade 3 thrombocytopenia with bleeding,

Grade 4 thrombocytopenia,

or

Grade 4 neutropenia lasting longer than 7 days

First and SecondInterrupt Calquence

Once toxicity has resolved to Grade 1 or baseline level, Calquence may be resumed at 100mg approximately every 12 hours.

ThirdInterrupt Calquence

Once toxicity has resolved to Grade 1 or baseline level, Calquence may be resumed at a reduced frequence of  100 mg daily.

FourthDiscontinue Calquence

Patient Centered Activities:

  • Patient Education
    • Provide Oncology Chemotherapy Education (OCE) sheet and review with patient
    • Instruct patient to report any signs or symptoms of atrial fibrillation or flutter such as palpitations, dizziness, faint, chest discomfort
    • Patient should be made aware of the increased bleeding risk associated with acalabrutinib. Due to this risk, they may need to hold their medication prior to any procedures
    • Ensure patient has access to supportive medications for diarrhea such as loperamide
  • AstraZeneca Access 360™ Program
    • Calquence Co-Pay Savings Program (Commercially insured patients)
    • AZ&Me Prescription Savings Program
      • Provides AstraZeneca medicines at no cost to qualifying patients.
    • Patient Assistance foundations (Federally insured patients)
  • CALQUENCECares™
    • Service through AstraZeneca to provide education and support during treatment

References:

  1. Calquence (acalabrutinib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; November 2019.
  2. Sharman JP, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. 2020 Apr 18;395(10232):1278-1291.
  3. Ghia P, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020;
Important notice: National Community Oncology Dispensing Association, Inc. (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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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 for patients with GIST

Upon receiving a prescription for avapritinib:

  • Recommended dosage is 300mg orally once daily on an empty stomach, as least one hour before and two hours after a meal
    • No dose adjustment recommended with mild/moderate renal or mild/moderate hepatic impairment
    • Dose modifications:
First dose reduction200mg once daily
Second dose reduction100mg 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
  • 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: Withhold avapritinib until resolution and resume at reduced dose
        • Subsequent Occurrence: Discontinue
      • Grade 3 or 4: Permanently discontinue
    • Central Nervous System Effects:
      • Grade 1:
        • Continue avapritinib at same dose or withhold until improvement to baseline or resolution. Resume at same dose or reduced dose
      • Grade 2 or 3:
        • Withhold avaprintinib 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:
      • Withhold avapritinib 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 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 (as much as $0 per month)

References:

  1. AYVAKITTM (avapritinib) [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation; January 2020.
  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.
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