Written by: Kelly Valla, PharmD, BCOP, Emory Healthcare Winship Cancer Institute

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Description: The purpose of this PQI is to discuss the clinical considerations around the use of loncastuximab tesirine-lply (Zynlonta®) to optimize the outcomes for patients with relapsed/refractory large B-cell lymphoma.

Background: Loncastuximab tesirine-lply is a CD19 directed antibody-drug conjugate with a pyrrolobenzodiazepine (PBD) dimer payload.1, 2 The PBD dimer acts as an alkylating agent and has a relatively short half-life, decreasing likelihood of accumulation and reducing overall systemic toxicity. On April 23, 2021, loncastuximab tesirine-lply received FDA-approval for the management of relapsed/refractory large B-cell lymphoma (including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, or high-grade B-cell lymphoma) following 2 or more lines of prior systemic therapy. Approval was based on data from the phase 2, multicenter, single-arm LOTIS-2 study demonstrating an overall response rate of 48.3% in 145 treated patients, half of whom had a complete response.

Other key findings:

  • Median time to response = 41 days; median duration of response = 10.3 months
  • Median treatment cycles = 3 (range 1 – 15)
  • Overall acceptable safety profile with a few notable considerations:
    • Hematologic toxicities: neutropenia (26%), thrombocytopenia (18%)
    • Effusions and edema related to the PBD dimer did occur in 31% of patients, but were generally low grade; see below for considerations around preventative corticosteroid use
    • Grade ≥3 elevations of gamma-glutamyltransferase (17%)
    • Infusion-related reactions were uncommon (5%)
  • No signal indicating CD19-loss after loncastuximab tesirine-lply was found in a small cohort of progressing patients who were able to proceed to CAR T-cell therapy

PQI Process: Use of loncastuximab tesirine-lply should include the following safety considerations

  • Verification of dosage, schedule, and concomitant conditions
    • Recommended dosage is 0.15 mg/kg IV over 30 minutes of Day 1 of cycles 1 and 2, then 0.075 mg/kg IV over 30 minutes on Day 1 of cycles 3 and onward; cycle length is 21 days
      • Use total body weight to determine dose, unless BMI ≥ 35 kg/m2 then use adjusted body weight
    • Pregnancy testing is recommended in women of childbearing potential
  • Ensure appropriate supportive care accompanies orders for loncastuximab tesirine-lply
    • Dexamethasone 4 mg by mouth orally or intravenously twice daily x 3 days (day prior to infusion, day of infusion, and day after infusion) to reduce the risk of edema and effusions
      • If patient forgets to take doses the day prior to loncastuximab tesirine-lply, then dexamethasone dose should be given at least 2 hours prior to infusion
  • Preparation and administration
    • Follow appropriate precautions for NIOSH Hazardous Agents with respect to handling and disposal and prepare in an environment that is USP 800 compliant
    • Add loncastuximab tesirine-lply in a 50 mL infusion bag containing 5% Dextrose Injection, USP
      • Diluted product may be stored in the refrigerator (2°C to 8°C) for up to 24 hours or room temperature (20°C to 25°C) for up to 8 hours
    • Administer as a 30-minute intravenous infusion through a dedicated infusion line using a sterile, non-pyrogenic, low-protein binding in-line filter (0.2 – 0.22 micron pore size)
  • Review patient’s medications for drug-drug interactions
    • The PBD dimer component is a substrate of P-glycoprotein (P-gp), but otherwise does not inhibit any key enzyme

Adverse Events and Management1

ToxicitySeverityAction
Hematologic Toxicities
Neutropeniaa≥ Grade 3

Absolute Neutrophil Count (ANC) < 1000

Withhold loncastuximab tesirine-lply until ANC ≥ 1000
Thombocytopenia≥ Grade 3

Platelet Count < 50,000

Withhold loncastuximab tesirine-lply until Platelet Count ≥ 50,000
Non-Hematologic Toxicities
Edema / Effusionb≥ Grade 2Withhold loncastuximab tesirine-lply until toxicity resolves to ≤ Grade 1
Cutaneous Reactions / Rashc≥ Grade 3Withhold loncastuximab tesirine-lply until resolved
Infection≥ Grade 3
Other Adverse Reactions≥ Grade 3Withhold loncastuximab tesirine-lply until toxicity resolves to ≤ Grade 1
a Use of granulocyte colony stimulating factors (as management and/or as prevention) can be considered for neutropenia
b Consider diagnostic imaging and medical management
c Consider dermatology consult

Dose Modifications1

  • Reduce dose by 50% if treatment is delayed 3 weeks or longer due to treatment-related toxicity
    • If toxicity requiring dose reduction occurs following 0.15 mg/kg (Cycle 2), proceed with planned dose of 0.075 mg/kg

 

Patient Centered Activities:

  • Patient Education:
    • Provide written and verbal education
      • Consider providing treatment calendar and include dosing for dexamethasone for the day before, day of, and day after each infusion
    • Educate patients on the signs of fluid overload (edema and effusions) and to contact their healthcare provider for swelling, weight gain, and shortness of breath or labored breathing
    • Encourage patient to report and signs or symptoms of infection including fever, chills, and upper respiratory symptoms such as cough or difficulty breathing
  • Advise patient to minimize sun exposure, wear sun-protective clothing, and to use sunscreen
  • Inform patients of reproductive risks and importance of appropriate contraception to avoid becoming pregnant or fathering a child while receiving loncastuximab tesirine-lply
  • ADC Advancing Patient Support program (https://www.advancingpatientsupport.com)
    • Benefits investigation
    • Financial support
      • Copay program for commercially insured, eligible patients
      • Patient assistance program for uninsured and underinsured patients
    • Nursing support
      • Free service offered Monday – Friday (8 am – 5 pm EST) staffed with nurses to answer questions and connect patients with available resources

References:

  1. Zynlonta (loncastuximab tesirine-lply) [package insert]. Murray Hill, NJ: ADC Therapeutics America; 2021.
  2. Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi: 10.1016/S1470-2045(21)00139-X. PubMed PMID: 33989558.
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: Kirollos Hanna, PharmD, BCPS, BCOP, Mayo Clinic College of Medicine and M Health Fairview and Kayla Randle, PharmD, BCOP, Kaiser Permanente – Southwood Oncology Clinic
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Description: Brentuximab vedotin is a CD30-directed antibody drug conjugate (ADC) indicated as front-line treatment for patients with classical stage III/IV Hodgkin’s Lymphoma (cHL) or CD30-expressing peripheral T-cell lymphomas (PTCL) in combination with multiagent chemotherapy.1 This PQI will review how to safely manage select toxicities associated with brentuximab vedotin.

Background: ADCs offer a unique modality of drug delivery to cancer cells expressing specific targets. In the case of brentuximab vedotin (BV), a monomethyl auristatin E (MMAE) is attached via a linker to a mAb directed against CD30.  Upon binding to CD30 on the cell surface, BV is internalized and the linker is cleaved to release MMAE, which then exerts its cytotoxic effect.1 The efficacy of brentuximab vedotin for cHL and CD30-expressing PTCL was established from the Echelon-1 and Echelon-2 trials, respectively.2,3 In both trials, outcomes favored the BV + chemotherapy combination over standard of care chemotherapy. For PTCL, only a positive expression of CD30 is required for patients to be eligible for therapy.1 Adverse events included neuropathy and hematologic toxicities.1-3 Clinicians need to be aware of recommended interventions to optimally and safely manage neuropathy and neutropenia in patients receiving brentuximab vedotin. This is particularly important in patients with HL as they can be treated with curative intent.

PQI Process:

  • Neutropenia Prevention and Management
    • Patients initiating front-line therapy with brentuximab vedotin for HL or PTCL should receive granulocyte colony-stimulating factor (G-CSF) beginning with Cycle 1, Day 1
    • The choice of G-CSF therapy should follow institutional standard and formulary. The use of long acting G-CSF agents is appropriate when indicated as both treatment regimens are administered every 14 or 21 days
    • Brentuximab vedotin for HL offers a bleomycin-free treatment option for patients
    • All patients who experience Grade ≥3 neutropenia who did not receive primary G-CSF prophylaxis should receive it with subsequent cycles
    • CBC with differential should be assessed prior to each dose of brentuximab vedotin
  • Neuropathy Prevention and Management
    • Neuropathies, primarily sensory rather than motor, may be seen in approximately >50% of patients. In clinical trials, most patients experienced only Grade 1 or 2 neuropathy and majority improved with intervention
    • Symptoms of hypo- or hyperesthesia, paresthesia, discomfort, burning sensation, weakness, tingling and neuropathic pain should be assessed with each cycle
    • Counsel patients to report any numbness or tingling in their hands or feet or muscle weakness

Table: Dose Adjustments for Neuropathy

Brentuximab Vedotin Dose1GradeIntervention
1.8 mg/kg (max 180 mg) every 3 weeks + CHP*2Sensory: Continue

Motor: Reduce to 1.2 mg/kg

3Sensory: Reduce to 1.2 mg/kg

Motor: Discontinue

4Discontinue
1.2 mg/kg (max 120 mg) every 2 weeks + AVD**2Reduce to 0.9mg/kg
3Hold until recovers to ≤ grade 2 and restart at 0.9 mg/kg

Consider modifying other neurotoxic chemo

4Discontinue

* PTCL indication in combination with cyclophosphamide, doxorubicin and prednisone

**HL indication in combination with doxorubicin, vinblastine, and dacarbazine

Patient Centered Activities:

  • Educate patients to report any fevers or signs of an infection such as coughing or congestion to their healthcare provider immediately
    • Some patients may require supportive care with G-CSF agents for neutropenia; supplemented with antihistamines if associated bone pain occurs (ex. Loratadine)
    • Patients should contact their provider if they utilize the Neulasta On-Pro device and have any warning sounds/lights or if the device is removed
  • Many patients (especially those with HL) may under report symptoms due to a concern of diminished efficacy with interventions. Building a rapport with these patients and helping them understand the balance between safety and efficacy is important
    • Tests to help assess for neuropathy include buttoning a shirt or picking up a coin off of a flat surface
    • Colder temperatures may exacerbate the neuropathies
    • Patients who initially do not report with a caregiver and later do could be underreporting symptoms

 References:

  1. Adcetris (brentuximab vedotin) [prescribing information]. Bothell, WA: Seattle Genetics; November 2018.
  2. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med. 2018;378(4):331-344.t
  3. Horwitz S, O’connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240.
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: Katie Carter, PharmD, BCPS, Indiana University Health
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Description: Olaparib is a poly ADP-ribose polymerase (PARP) enzyme inhibitor and is FDA approved as a targeted therapy for BRCA-mutated breast cancer, ovarian, pancreatic cancer, as well as prostate cancer.  This PQI will highlight its place in therapy in these disease states, safety profiles, and clinical pearls regarding dose adjustment.

Background:  Breast Cancer – About 5-10% of breast cancers can be associated with gene mutations inherited from a parent, most common mutations in the BRCA1 and BRCA2 genes.12

Lifetime Risk of Developing Breast Cancer
MutationWomenMen
BRCA1Up to 72%6.8%
BRCA269%Less frequent cause

Ovarian CancerCurrently, ovarian cancer is primarily treated with surgery and systemic chemotherapy. About 25% of ovarian cancer cases are related to a BRCA mutation (15% germline and 7% somatic).14,15

Pancreatic Cancer – Up to 7% of patients with pancreatic cancer have a gBRCA mutation.16,17

Prostate Cancer – Olaparib approved in May 2020 for patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer in combination with gonadotropin-releasing hormone analog or prior bilateral orchiectomy (full indication list in supplemental information).7

PQI Process: 

  • Verify the dosage form is correct
  • Olaparib was previously available as both a tablet and a capsule, and the two dosage forms had different bioavailability and therefore were not interchangeable on a milligram-per-milligram basis
      • Capsules were discontinued August 2018 and only the tablets are currently available
  • Olaparib is available as 100 mg and 150 mg tablets
  • Verify the dose is correct
  • Typical starting dose for all FDA-approved indications: 300 mg orally twice daily
      • See Supplemental Information Section for current FDA-approved indications
  • The dose of olaparib must be adjusted to 200 mg twice daily for renal dysfunction when creatinine clearance is <50 mL/minute. Olaparib has not been studied in patients with creatinine clearance < 30 mL/minute
  • Dose adjustments for adverse reactions
  • Consider holding treatment or dose reductions if patients experience adverse reactions
Dose reductionRecommended DoseHow to Supply
1st dose reduction250 mg BIDOne 150 mg tablet + one 100 mg tablet BID
2nd dose reduction200 mg BIDTwo 100 mg tablets BID

 

  • Drug interactions
  • Avoid concomitant use with moderate and/or strong CYP3A4 inhibitors
  • If a strong CYP3A4 inhibitor must be used concomitantly, the olaparib dose should be reduced to 100 mg twice daily
  • If a moderate CYP3A4 inhibitor must be used concomitantly, the olaparib dose should be reduced to 150 mg twice daily
  • Avoid concomitant strong CYP3A inducers; if a moderate CYP3A inducer must be used, there is the potential for reduced efficacy of olaparib
  • Laboratory monitoring
  • Complete blood counts should be performed at baseline and monthly thereafter
  • Renal function should be verified at baseline and periodically thereafter
  • Taking other anticancer agents may cause a potentiation/prolongation of myelosuppression

Patient Centered Activities:

  • Provide Oral Chemotherapy Education (OCE) sheet
  • Counsel patient on side effect profile (see supplemental information)
  • Instruct patient to avoid grapefruit, grapefruit juice, Seville oranges, and/or Seville orange juice

Copay Assistance:

  • Commercially insurance patients who qualify can enroll in a $0 copay card assistance program through AstraZeneca’s Access 360 program

References:

  1. Birrer, M. Ask an expert: how do PARP inhibitors work? Cancer Updates, Research & Education. Published March 27, 2018.
  2. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203.
  3. How common are BRCA mutations? INSIGHT from Dana-Farber Cancer Institute. Updated March 1, 2018. Available at: https://blog.dana-farber.org/insight/2018/03/brca-mutations-common.
  4. How do PARP inhibitors work in cancer? INSIGHT from Dana-Farber Cancer Institute. July 2016. Available at: https://blod.dana-farber.org/insight/2016/07/how-do-parp-inhibitors-work-in-cancer.
  5. Key statistics for ovarian cancer. American Cancer Society. Last updated January 8, 2019. Accessed April 8, 2019. Available at: https://www.cancer.org/cancer/ovarian-cancer/ about/key-statistics.html.
  6. Lexicomp Online, Hudson, Ohio: Lexi-Comp, Inc.; updated 2/22/19; accessed 2/25/19.
  7. LYNPARZA® (olaparib) [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.
  8. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med2018; 379:2495-2505.
  9. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2018. Available at: https://www.nccn.org/professionals/physician_gls/default.aspx#ovarian.
  10. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2mutation (SOLO2/ENGOT-Ov21): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncology; 2017:18(9):1274-1284.
  11. Robson M, Im A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCAmutation (OlympiAD trial). N Engl J Med. 2017; 377:523-533.
  12. S. Breast Cancer Statistics. Breastcancer.org. Last updated Feb 13,2019. Accessed Mar 19, 2019. Available at: www.breastcancer.org/symptoms/understand_bc/statistics.
  13. Konstantinopoulos et al. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer. J Clin Oncol
  14. Pal T et al. Cancer. 2005;104(12):2807-2816.
  15. Pennington KP et al. Clin Cancer Res. 2014;20(3):764-775.
  16. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma. V.1.2020. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 20, 2020.
  17. SEER Cancer Stat Fact Sheets: Pancreatic Cancer. National Cancer Institute website. https://seer.cancer.gov/statfacts/html/pancreas.html.  Accessed March 20, 2020.

Supplemental Information:

Current FDA-approved indications: (Starting dose is 300 mg twice daily for all indications)

IndicationEfficacySafety
Ovarian cancer
First-line maintenance treatment for deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to first-line platinum-based chemotherapy (SOLO-1 trial)
  • mPFS results: olaparib 56 months vs placebo 13.8 months
    (p-value <0.0001)
  • 5-Year PFS: olaparib 48% vs placebo 21%
  • Most common AEs with olaparib: nausea, vomiting, fatigue, anemia, diarrhea
  • Serious AEs occurred in 21% of olaparib patients vs 12% of placebo patients, most commonly anemia
In combination with bevacizumab for maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:

  • Deleterious or suspected deleterious BRCA mutation and/or
  • Genomic instability

PAOLA-1 trial

  • Reduced the risk of disease progression or death by 67% (equal to HR of 0.33) and improved progression-free survival to a median of 37.2 months vs 17.7 months with bevacizumab alone
  • Higher Risk: mPFS olaparib 36.0 vs. 16.0 bevacizumab
  • Lower Risk: mPFS olaparib Not Reached vs. 22.1 bevacizumab
  • Adverse reactions (Grade 1-4) occurring in ≥10% of patients treated with olaparib/bevacizumab in PAOLA-1 compared with the placebo/bevacizumab arm were nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%), diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%)
Maintenance treatment for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to platinum-based chemotherapy – 2 randomized trails completed10

SOLO-2 trial

Study 19

SOLO-2:

  • PFS: olaparib 19.1 months vs placebo 5.5 months, p-value <0.0001
  • OS: olaparib 51.7 months vs placebo 38.8 months, p-value 0.0537

Study 19:

  • PFS: olaparib 8.4 months vs placebo 4.8 months, p-value <0.0001

OS: olaparib 29.8 months vs placebo 27.8 months (p-value 0.73)PFS (p-value <0.0001): olaparib vs placebo: 19.1 months vs 5.5 months

SOLO-2:

  • Most common grade 1-2 AEs in both groups: nausea, fatigue, vomiting, abdominal pain, and diarrhea
  • Most common grade 3 or higher AE with olaparib: anemia

Study 19:

  • Most common AEs of all grads in olaparib arm included nausea (71%), fatigue (63%), vomiting (35%), diarrhea (28%), anemia (23%), constipation (22%), respiratory tract infection (22%), decreased appetite (21%), and headache (21%)
Deleterious or suspected deleterious gBRCAm advanced ovarian cancer after > 3 prior lines of chemotherapySingle arm trial PFS results:

  • ORR: 34%
  • Median DoR: 7.9 months
  • Serious AEs reported in 30% of patients, most frequently anemia, abdominal pain
Breast Cancer
Deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer after treatment with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting (OlympiAD trial)
  • PFS:   olaparib 7 months vs chemotherapy 4.2 months (p-value 0.0009)
  • Rate of grade 3 or higher AEs was lower with olaparib (36.6%) vs chemotherapy (50.5%)
  • AEs that occurred more frequently with olaparib: anemia, nausea, vomiting, fatigue, headache, and cough
Pancreatic Cancer
Maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen (POLO trial)
  • PFS results: olaparib vs. placebo: median 7.4 months vs. 3.8 months (p-value 0.0035)
  • ORR: 23% in olaparib arm (12% in placebo arm)
  • OS: olaparib 19.3 months vs placebo 17.1 months (p-vale NS)
  • Most common AE at grades 3-4 for olaparib: anemia (11%)
  • All grades AE >30% for olaparib: Fatigue (60%), nausea (45%), abdominal pain (34%)
  • All grade diarrhea occurred at a rate of 29%
Prostate Cancer
Treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone (PROfound trial)
  • Reduced risk of disease progression or death by 66% (HR 0.34, p-value <0.0001)
  • Radiographic PFS median of 7.4 months vs. 3.6 months with enzalutamide or abiraterone in men with BRCA1/2 or ATM gene-mutated mCRPC
  • OS: olaparib 19.1 months vs placebo 14.7 months (p-value 0.0175)
  • Most common AE (Grade 1-4) occurring in ≥10% in the olaparib arm (N=256) were anemia (46%), nausea (41%), fatigue including asthenia (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%) and dyspnea (10%)
  • Venous thromboembolic events, including pulmonary embolism occurred in 7% of patients with mCRPC who received olaparib plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT

PFS – progression free survival; AEs – adverse events; ORR – objective response rates; DoR – duration of response

Based on current February 2020 ASCO Guidelines13:

  • Women diagnosed with epithelial ovarian cancer
    • Offer germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes at time of diagnoses
    • Preform somatic tumor testing for BRCA1/2 and other likely pathogenic variants in women who are negative for a germline mutation
    • First/second-degree blood relatives with a known germline susceptible gene mutation/variant should be offered individualized genetic risk evaluation/counseling and genetic testing
    • Genetic evaluations can be conducted in conjunction with health care professionals including genetic counselors
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: Anna Howard, PharmD, BCOP, Billings Clinic
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Description: The purpose of this PQI is to discuss the option of using liposomal daunorubicin-cytarabine for patients with newly diagnosed therapy-related Acute Myeloid Leukemia (AML) or AML with myelodysplasia-related changes (AML-MRC).1

Background: Liposomal daunorubicin-cytarabine is a combination of daunorubicin and cytarabine in a fixed molar ratio of 1:5 (44mg daunorubicin and 100mg cytarabine) encapsulated together in liposomes.1 Daunorubicin and cytarabine are commonly used together in the “7+3” regimen for AML induction. However, in the “7+3” regimen, the drugs are mixed and administered separately. Daunorubicin is given as a bolus on days 1 through 3 and cytarabine is administered as a continuous infusion on days 1 through 7. Liposomal daunorubicin-cytarabine, in contrast, while including the same core medications, is administered as 90-minute infusion days 1, 3, and 5 or days 1 and 3 (depending on whether used for induction or consolidation). In a randomized clinical study in patients 60 to 75 years of age with newly-diagnosed therapy-related AML (t-AML) or AML-MRC observed all-cause day-30 mortality was 6% in the liposomal daunorubicin-cytarabine arm and 11% in the control arm utilizing standard 7+3 combination. During the first 60 days of the study, 14% (21/153) of patients died in the liposomal daunorubicin-cytarabine arm vs. 21% (32/151) of patients in the 7+3 treatment group.1 Animal studies have shown that the pharmacokinetics are changed due to the liposomal formulation of daunorubicin/cytarabine1,2

  • Liposomes persist in the bone marrow
  • Liposomes favor uptake into leukemia cells more than normal bone marrow cells
  • Once intracellular, liposomes degrade and release daunorubicin and cytarabine to intracellular environment
  • Half-life of daunorubicin and cytarabine is significantly longer in liposomal daunorubicin-cytarabine compared to non-liposomal formulations of each drug

PQI Process:

  • Patient eligibility
    • Confirmation of t-AML or AML-MRC
    • Anthracycline eligibility:1
      • Calculate patient’s previous lifetime anthracycline dose. If approaching or over recommended lifetime maximum, consider alternative therapy. Liposomal daunorubicin-cytarabine is not recommended for patients who have reached maximum lifetime anthracycline dose
      • Evaluate baseline echocardiogram for signs of cardiac dysfunction. If patient exhibits significant cardiac dysfunction at baseline, discuss risks/benefits of continuing this therapy vs. choosing alternative. Re-evaluate echocardiogram prior to consolidation with liposomal daunorubicin-cytarabine and as clinically necessary
    • Consolidation with liposomal daunorubicin-cytarabine is only preferred if given in induction3
  • Premedications1
    • Follow institutional practice for moderate emetic risk IV chemotherapy
  • Preparation1
    • Calculate the volume of reconstituted Liposomal daunorubicin-cytarabine required based on daunorubicin dose: [volume required (mL) = daunorubicin dose (mg/m2) X BSA (m2) ÷ 2.2 (mg/mL)]
    • Review PI for complete admixture details which must be followed to increase homogeneity of product
  • Compatible with NS or D5W
  • Resulting product will be a purple, opaque, homogeneous dispersion with no visible particulates
  • Dosing1
    • Dose adjustments:
      • Renal: not required. Not studied in severe renal impairment or end-stage renal disease
      • Hepatic: not required. Not studied in patients with bilirubin >2.92 mg/dL
    • Induction:
      • 44mg/m2 daunorubicin + 100mg/m2 cytarabine IV infusion over 90 minutes on Days 1, 3, and 5
    • Second induction (administered 2 to 5 weeks after first induction, if remission is not achieved with first induction cycle):
      • 44mg/m2 daunorubicin + 100mg/m2 cytarabine IV infusion over 90 minutes on Days 1 and 3
    • First consolidation cycle (administered 5 to 8 weeks after start of last induction cycle) and second consolidation cycle (administered 5 to 8 weeks after start of first consolidation cycle):
      • 29 mg/m2 daunorubicin + 65mg/m2 cytarabine IV infusion over 90 minutes on Days 1 and 3
      • Do not administer consolidation until neutrophils and platelets have recovered to 5 Gi/L and 50 Gi/L respectively1
    • Administration
      • May be administered as outpatient in an infusion center if patient is clinically stable4,5
      • Due to risk for tissue necrosis from extravasation, only administer through central line1
      • Review the PI regarding specifics surrounding infusion filtration1
    • Adverse events
      • Some common events include (>25%): hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, arrhythmia, pneumonia
      • Differences in adverse events compared to standard 7+3 regimen1,2
        • Prolonged high-grade cytopenias in absence of active leukemia (lasting past cycle day 42) were more frequent in liposomal daunorubicin-cytarabine than 7+3 regimen
        • Prolonged neutropenia in liposomal daunorubicin-cytarabine vs. 7+3 regimen (neutrophils < 0.5 Gi/L): 17% vs 3% (induction), 10% vs 3% (consolidation)
        • Prolonged thrombocytopenia (Platelets < 50 Gi/L): 28% vs 12% (induction), 25% vs 16% (consolidation)
        • Hemorrhage: In an observed clinical study, fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in liposomal daunorubicin-cytarabine (2%) vs 7+3 (0.7%)
          • Grade 3 or higher hemorrhagic events from severe thrombocytopenia in liposomal daunorubicin-cytarabine (12%) vs 7+3 (8%)
        • Grade 5 infection related events: 7.2 % liposomal daunorubicin-cytarabine vs 2.6% 7+3. Rates of febrile neutropenia: 68.0% vs 70.9%2
      • Copper Overload Risk1
        • When reconstituted for infusion, contains 5 mg/mL copper gluconate, of which 14% is elemental copper
  • If a patient has a history of Wilson’s disease or other copper-related metabolic disorder, evaluate risk/benefit
    • Monitor total serum copper, serum nonceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological examinations in this patient population
    • If signs or symptoms of acute copper toxicity develop, discontinue

Patient Centered Activities:

  • Patient monitoring1
    • May cause severe neutropenia, anemia, and thrombocytopenia. Monitor blood counts during therapy
    • Monitor liver function
      • Daunorubicin is metabolized by the liver. No dose adjustments are recommended by manufacturer at this time but has not been studied in patients with total bilirubin greater than 3mg/dL
    • Monitor cardiac function due to daunorubicin
    • Monitor daunorubicin lifetime cumulative dose from liposomal daunorubicin-cytarabine and other therapies
  • Patient education
    • Monitor and educate patient for signs and symptoms for:
  • Heart failure
  • Infection
  • Bleeding
  • Rash
  • GI side effects: Nausea, Vomiting, Diarrhea, Abdominal pain, Colitis

Supplemental Information

  • Billing Information
    • Permanent, product specific HCPCS J-code: J9153
    • Dosage: Injection, liposomal, 1 mg daunorubicin and 2.27 mg cytarabine
    • Billing unit per dose: 1
    • Billing unit per vial: 44 units
    • See manufacturer website for further billing information including NTAP designation

References:

  1. Daunorubicin and cytarabine liposome for injection (Vyxeos®) [Package insert]. Jazz Pharmaceuticals, Inc, Palo Alto, CA; July 2019.
  2. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. JCO 2018;36(26):2684-2692.
  3. National Comprehensive Cancer Network. Acute Myeloid Leukemia (Version 3.2020). https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed April 21, 2020.
  4. Kubal TE, Salamanca C, Komrokji RS, et al. Safety and feasibility of outpatient induction chemotherapy with CPX-351 in selected older patients with newly diagnosed AML. J Clin Oncol. 2018:36(15)(suppl):e19013.
  5. Deutsch YE, Presutto JT, Brahim A, et al. 3559 Safety and feasibility of outpatient liposomal daunorubicin and cytarabine (Vyxeos) induction and management in patients with secondary AML. Paper presented at: American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA.
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: Jody Agena, PharmD, MBA, BCOP
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Description: Ibrutinib is a small molecule that acts as a potent, irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK), a key component of the B-cell receptor and cytokine receptor signaling pathway.  BTK inhibition is vital for decreased malignant B-cell proliferation and survival.  This molecule disrupts the proliferation of B-cell cancers such as Mantle Cell Lymphoma (MCL), Chronic/Small Lymphocytic Leukemia (CLL/SLL), Marginal Zone Lymphoma (MZL), Waldenström’s Macroglobulinemia (WM), and chronic Graft Versus Host Disease (cGVHD). Management of both medication dosing and adverse effects are prime examples of key areas for additional intervention opportunities for improved patient health outcomes within the medically integrated team.

Background: Dosing of ibrutinib varies by disease and indication and should therefore be carefully assessed. Lymphocytosis is a noted adverse effect of ibrutinib which results in an increased lymphocytes count. This adverse drug reaction is a common and expected occurrence which is does not reflect progression of the disease. Monitoring patient laboratory values must be considered and evaluated based on patient-specific need.

PQI Process: Upon receiving new ibrutinib prescription:

  • Confirm appropriate indication and dosing
  • Monitor CBC at baseline, monthly and as clinically necessary
  • Monitor CMP, uric acid levels at baseline, monthly and as clinically necessary
  • ECG at baseline (patients with a positive cardiac history/risk factors) and periodically as clinically necessary
  • Evaluate patients on anticoagulation, including low-dose aspirin, for bleeding risk. The use of anticoagulation with ibrutinib should be assessed with each patient based on risk versus benefit. It is recommended to withhold ibrutinib 3 days pre/post minor surgical procedures and pre/post 7 days for major surgical procedures
  • Consider Pneumocystis Jirovecii Pneumonia (PJP) prophylaxis in patients with increased risk of opportunistic infections
  • Upon initiation of ibrutinib, lymphocytosis commonly occurs in first weeks and resolves by week 8 (median) of therapy *Does not reflect disease progression*
  • Monitor adherence and compliance

Dosing Guidelines

Indication

Dose (Daily)

CLL

420 mg

Mantle Cell Lymphoma

560 mg

Marginal Zone Lymphoma

560 mg

Waldenstroms Macroglobulinemia

420 mg

cGVHD

420 mg

 Adverse Effects

Adverse Reaction

Grade ≥3 (%)

Hemorrhage

6

Infections

29

Cytopenias

13-39

Cardiac Arrhythmia

6

Hypertension

17

 

Adverse Reaction

All Grades (%)

Diarrhea

51

Fatigue

41

Musculoskeletal Pain

37

Peripheral Edema

35

Upper Respiratory Tract Infection

34

Nausea

31

Bruising

30

Secondary Malignancies

16

 

Recommended Dose Modifications for Toxicity Occurrences

Toxicity Occurrence

MCL and MZL After Recovery Starting Dose = 560 mg

CLL/SLL, WM, and cGVHD After Recovery Starting Dose = 420 mg

First

Restart at 560 mg daily

Restart at 420 mg daily

Second

Restart at 420 mg daily

Restart at 280 mg daily

Third

Restart at 280 mg daily

Restart at 140 mg daily

Fourth

Discontinue

Discontinue

 

Drug Interactions:

  • CYP3A4 Inducers (Strong): May decrease the serum concentration of ibrutinib. (ex. carbamazepine, rifampin, phenytoin, St. John’s Wort)Risk: Avoid combination
  • CYP3A4 Inhibitors (Strong): May increase the serum concentration of ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (ex. anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued (ex. ketoconozole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin). Risk: Avoid combination
  • Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of vaccines. Immunosuppressants may diminish the therapeutic effect of vaccines. Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.Risk: Avoid combination
  • Warfarin and anticoagulation: Increased bleeding risk: Consider risk versus benefit
    • Secondary analysis of RESONATE trial and Phase I study participants on anticoagulation and ibrutinib showed that among 175 patients receiving concomitant anticoagulant or antiplatelet agents, 5 had major bleeding events (3%), and Grade 1 bleed in occurred in 10-20%. These events were typically observed in conjunction with other factors, such as coexisting medical conditions and/or concurrent medications6

Patient Centered Activities:

  • Provide Oncology Chemotherapy Education (OCE) sheet
  • Ensure patients understand the formulation prescribed and how to take their dose
    • Varying dosage forms: capsules – 70 mg, 140 mg; tablets – 140 mg, 280 mg, 420 mg, 560 mg
  • Administer orally once daily with a glass of water
  • Swallow whole; do not break, crush, chew
  • If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day
  • Proper sign/symptom monitoring
    • If any abnormal bruising or bleeding especially those on anticoagulation or aspirin
    • If there are any new medications (assess for risk of QT prolongation or drug-drug interactions)
    • Evaluate if patients have missed any doses between cycles to determine if interventions are needed such as reminders, calendars, pill boxes, etc

References:

  1. Dimopoulos MA, Tedeschi A, Trotman J, et al; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med. 2018;378(25):2399-2410
  2. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223
  3. Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129(16):2224-2232
  4. Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126(6):739-745
  5. Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Blood. 2016;128(22)
  6. Jones JA, Hillmen P, Coutre S, et al. Use of anticoagulants and antiplatelet in patients with chronic lymphocytic leukaemia treated with single-agent ibrutinib. Br J Haematol. 2017;178(2):286-291.
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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