Blood & lymphatic system disorders

As part of your assessment and management of a potential adverse reaction, evaluate whether LYNPARZA dosing should be interrupted, reduced, or discontinued.

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) has occurred in patients treated with LYNPARZA and some cases were fatal. In clinical studies, among 2219 patients with various BRCAm, gBRCAm, HRR gene–mutated or HRD-positive cancers who received LYNPARZA as a single agent or as part of a combination regimen, consistent with approved indications, the cumulative incidence of MDS/AML was approximately 1.2% (26/2219). Of these, 54% (14/26) had a fatal outcome. The median duration of therapy with LYNPARZA in patients who developed MDS/AML was 2 years (range: <6 months to >4 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA-damaging agents including radiotherapy.

In SOLO-1, patients with newly diagnosed advanced BRCAm ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received LYNPARZA and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received LYNPARZA and 2.3% (3/131) in the control arm.

In SOLO-2, patients with BRCAm platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received LYNPARZA and 4% (4/99) in patients who received placebo. The duration of LYNPARZA treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years.

• Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (CTCAE ≤Grade 1)
• Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment
• For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery
• If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics
• If MDS/AML is confirmed, discontinue LYNPARZA

Venous Thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with LYNPARZA. In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received LYNPARZA, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5%, including pulmonary embolism in 1.5%.

• Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated

Advise patients that:

• Anemia was one of the most common side effects reported in clinical studies with LYNPARZA
• Management strategies exist to aid in the alleviation of the symptoms of anemia³
• Regular blood tests are necessary to monitor for hematological ARs, including anemia
  • Blood tests should occur before treatment with LYNPARZA, every month during treatment with LYNPARZA, and weekly in case of low blood cell counts that last a long time. Treatment with LYNPARZA may need to be stopped until blood cell counts improve
• There is the possibility that a blood transfusion may be required
• Communication with their care team may inform their experience on therapy^3,4
• They should contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), which have been reported in patients treated with LYNPARZA
• Patients should immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia
• They should report to their healthcare provider any new or worsening symptoms they experience while taking medication

As part of your clinical evaluation, consider potential causes, including if the patient’s cancer has progressed or recurred, and evaluate appropriately.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) recommendations include investigating causality and treating underlying conditions as indicated:

First perform:

• Detailed history and physical exam

Check:

• CBC with differential, peripheral blood smear, and reticulocyte count

Then consider possible causes, including:

• Hemorrhage
• Hemolysis
• Nutrition
• Inherited
• Renal dysfunction
• Treatment-induced myelosuppression
• Hormone dysfunction
• Anemia of chronic inflammation

See NCCN Guidelines^® for Hematopoietic Growth Factors for further information.

NCCN Guidelines recommendations for intervention include:

If the cause is identified, treat as indicated. If no cause is identified, perform risk assessment and consider transfusion if indicated.

Observe with periodic reevaluation:

• Asymptomatic patients without significant comorbidities*

Consider RBC transfusion per AABB Guidelines^†:

• High-risk patients (ie, progressive decline in Hb with recent intensive chemotherapy or radiation)

OR

• Asymptomatic patients with comorbidities*:
  • Cardiac disease
  • Chronic pulmonary disease
  • Cerebral vascular disease

RBC transfusion per AABB Guidelines^†:

• Symptomatic (physiologic) patients:
  • Sustained tachycardia
  • Tachypnea
  • Chest pain
  • Dyspnea on exertion
  • Lightheadedness
  • Syncope
  • Severe fatigue preventing work and usual activity^‡

See NCCN Guidelines for Hematopoietic Growth Factors for further information.

*Degree of severity of comorbidities in combination with the degree of severity of anemia should be taken into consideration when initiating RBC transfusion.

^†The AABB has made recommendations regarding appropriate indications for RBC transfusion. Further details are included in the NCCN Guidelines.

^‡Fatigue (FACT-F) and Anemia (FACT-An) subscales of the Functional Assessment of Cancer Therapy (FACT) and Brief Fatigue Inventory (BFI) are examples of standardized measures for assessing patient-reported fatigue.

NCCN Guidelines also include information on the use of ESAs or evaluation of iron deficiency. Refer to the NCCN Guidelines for more information.

Advise patients that:

• Leukopenia and neutropenia are potential side effects with LYNPARZA
• Regular blood tests are necessary to monitor for hematological ARs, including leukopenia and neutropenia
  • Blood tests should occur before treatment with LYNPARZA, every month during treatment with LYNPARZA, and weekly in case of low blood cell counts that last a long time. Treatment with LYNPARZA may need to be stopped until blood cell counts improve
• Communication with their care team may inform their experience on therapy⁴
• They should contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), which has been reported in patients treated with LYNPARZA
• Patients should immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia
• They should report to their healthcare provider any new or worsening symptoms they experience while taking medication

As part of your clinical evaluation, consider potential causes, including if the patient’s cancer has progressed or recurred, and evaluate appropriately.

NCCN Guidelines recommendations include evaluation and risk assessment for febrile neutropenia in patients with certain cancers based on clinical presentation and treatment history.

• If fever and/or neutropenia is present, perform a complete history and physical examination and laboratory assessment
• Perform blood cultures, urine culture, site-specific diagnostics, and viral diagnostics as appropriate
• Consider chest x-ray

See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for further information.

NCCN Guidelines recommend initial risk assessment for febrile neutropenic patients, including:

Factors indicating low risk, which include most of the following, and none of the high-risk factors:

• Outpatient status when fever develops
• No associated acute comorbid illness, independently indicating inpatient treatment or close observation
• Anticipated short duration of severe neutropenia (≤100 cells/mcL for <7 days)
• Good performance status (ECOG 0-1)
• No hepatic or renal insufficiency
• MASCC* Risk-Index Score of ≥21 or CISNE score of <3

A factor indicating high risk, which includes any of the following factors:

• Inpatient when fever develops
• Significant medical comorbidity or clinically unstable
• Anticipated prolonged severe neutropenia (≤100 cells/mcL and ≥7 days)
• Hepatic or renal insufficiency
• Pneumonia or other complex infections
• Mucositis grade 3–4
• MASCC* Risk-Index Score of <21 or CISNE score of ≥3
• Allogeneic HCT
• Uncontrolled/progressive cancer
• Use of immune or targeted treatments

If febrile neutropenia is confirmed:

• Consider appropriateness of hospitalization vs outpatient management
• Consider appropriate pharmaceutical interventions and supportive care

See NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections for further information.

Advise patients that:

• Thrombocytopenia is a potential adverse reaction reported in patients receiving LYNPARZA
• Regular blood tests are necessary to monitor for hematological ARs, including thrombocytopenia
  • Blood tests should occur before treatment with LYNPARZA, every month during treatment with LYNPARZA, and weekly in case of low blood cell counts that last a long time. Treatment with LYNPARZA may need to be stopped until blood cell counts improve
• There is the possibility that a platelet transfusion may be required³
• Communication with their care team may inform their experience on therapy^3,4
• They should contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), which has been reported in patients treated with LYNPARZA
• Patients should immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia
• They should report to their healthcare provider any new or worsening symptoms they experience while taking medication

As part of your clinical evaluation, consider potential causes, including if the patient’s cancer has progressed or recurred, and evaluate appropriately.

NCCN Guidelines recommendations for evaluation include investigating causality as follows:

First perform:

• Detailed history and physical exam

Check:

• CBC with differential, including evaluations for other cytopenias
• Blood smear morphology, including evaluation for platelet clumping

Consider possible causes, including but not limited to:

• Nutritional deficiencies
• Medications and supplements suppressing platelet production
• Infection
• Immune thrombocytopenia

See NCCN Guidelines for Hematopoietic Growth Factors for further information.

Underlying conditions should be treated as indicated. If a patient has chemotherapy-induced thrombocytopenia, consider platelet transfusion per AABB guidelines, change in chemotherapy regimen/dose reduction, or clinical trial of a thrombopoietin receptor agonist, or romiplostim.

See NCCN Guidelines for Hematopoietic Growth Factors for further information.