Brentuximab Vedotin for the Treatment of Relapsed/Refractory HL and ALCL

Case Study

BS is a 63-year-old male who was well until the summer of 2008 when he developed right calf discomfort along with the sensation of his foot feeling cold. He had throbbing discomfort that led him to the emergency room. A Doppler ultrasound was completed of the right lower extremity that showed no evidence of a deep vein thrombosis. Due to evidence of a distinct mass on the right calf on MRI, an excisional biopsy was completed, and he was diagnosed with anaplastic large cell lymphoma (ALCL), stage IE. He was treated with 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Following CHOP, he received involved-field radiation therapy (XRT) and was noted to be in complete remission. In the fall of 2009 (approximately 6 months after the completion of his initial therapy), he developed right upper arm discomfort. A fluorodeoxyglucose-avid lesion was noted on PET/CT, and a biopsy was performed that demonstrated recurrent ALCL. He was treated with XRT to the right upper arm. While receiving XRT, he developed lymphadenopathy that was biopsied and found to be positive for ALCL. He was started on pralatrexate on a clinical trial but had progression of disease during the first cycle. He was then treated with mesna, ifosfamide, mitoxantrone, and etoposide (MINE) but experienced disease progression during the second cycle. He was started on brentuximab vedotin and achieved a complete response while on therapy. He reported numbness of his fingers and toes and experienced the sensation of his hands and feet feeling cold. He had a dose reduction after 10 cycles but completed 16 cycles. He remains in complete response 6 months after completion of therapy.

 

Brentuximab vedotin was ap - proved by the US Food and Drug Administration (FDA) on August 18, 2011, for the treatment of Hodgkin lymphoma (HL) that has relapsed after autologous stem cell transplant (ASCT) as well as for the management of relapsed anaplastic large cell lymphoma (ALCL).¹ It is an anticancer antibody conjugated to a cytotoxic agent, monomethyl auristatin E (MMAE). The antibody component is a chimeric antibody that targets CD30, a member of the tumor necrosis factor receptor superfamily. Because of its limited expression on healthy tissue, CD30 is an attractive target for monoclonal antibody therapy.¹ CD30 expression is restricted to activated B and T lymphocytes in healthy individuals; however, the function of CD30 is poorly understood. No diseases in humans have been linked to defects in CD30 genes.² The CD30 antigen is expressed in both benign and malignant disorders. The nonmalignant disorders in which CD30 is expressed include lymphomatoid papulosis and disorders with virally transformed B cells, such as infectious mononucleosis, hepatitis C, and HIV, and in human T-lymphotropic virus 1–associated lymphoma cells. Malignant disorders in which CD30 is expressed include ALCL, thyroid carcinoma, embryonal carcinomas, and select subtypes of B-cell–derived non-Hodgkin lymphomas and mature T-cell lymphomas. Other lymphoid malignancies in which CD30 is expressed include primary mediastinal B-cell lymphoma, primary effusion lymphoma harboring the human herpes virus 8, immunoblastic lymphoma and multiple myeloma, adult T-cell lymphoma/leukemia, and mycosis fungoides.² HL and ALCL are the 2 most common tumors expressing CD30.

Attempts to target the CD30 antigen with an unconjugated monoclonal antibody have demonstrated minimal activity. To enhance the antitumor effect of CD30-directed therapy, the monoclonal antibody SGN-30 was modified by the addition of a valine-citrulline dipeptide linker to enable attachment of the antitubulin agent MMAE, resulting in the CD30 antibody-drug conjugate (ADC) brentuximab vedotin (SGN- 35).¹ ADCs combine the specificity of targeting found with monoclonal antibodies with the ability to deliver a highly toxic chemotherapy agent that cannot be administered systemically.¹ Brentuximab vedotin is designed to be stable in the bloodstream but to release MMAE once it is internalized into CD30-expressing tumor cells. MMAE binds to tubulin and disrupts the microtubule network within the cell and induces cell cycle arrest and apoptotic cell death (Figure).^1,3 In vitro, the drug is potent and selective against CD30-positive tumor cell lines. The recommended dose is 1.8 mg/kg administered over 30 minutes every 3 weeks. The maximum dose is 180 mg. It is administered as an intravenous (IV) infusion, not as a bolus or IV push. Treatment can be continued to a maximum of 16 cycles.⁴

Two phase 1 clinical trials have been completed using different schedules including either 1- or 3-week intervals. In the initial phase 1 dose-escalation study in CD30-positive hematologic malignancies, brentuximab vedotin was administered to 45 patients (42 with HL, 2 with ALCL, and 1 with CD30-positive angioimmunoblastic T-cell lymphoma) every 3 weeks at dose levels from 0.1 to 3.6 mg/kg. The phase 2 dose was determined to be 1.8 mg/kg administered every 3 weeks. Objective responses, including 11 complete responses, were noted in 17 patients. Objective responses were noted in 6 patients (50%) who received the 1.8 mg/kg dose. Tumor regression was noted in 86% of evaluable patients. The median duration of response was at least 9.7 months. Most patients (88%) with objective responses demonstrated responses within 4 treatment cycles. Median progression-free survival (PFS) was at least 5.9 months, and a trend toward longer PFS was seen in patients who received doses of ≥1.2 mg/kg. The drug was well tolerated overall across dose levels. Dose-limiting toxicities included neutropenia and hyperglycemia. The most common treatment-related adverse events were fatigue (36%), pyrexia (33%), neutropenia (22%), peripheral neuropathy (PN) (22%), nausea (22%), and diarrhea (22%). The adverse events were primarily grade 1 or 2. Fatigue, neutropenia, and PN were considered to be dose related.⁵

In the second phase 1 study, brentuximab vedotin was administered weekly for 3 weeks with 1 week off (4-week cycle). A total of 44 patients were treated, with 38 of the patients having HL, 5 ALCL, and 1 peripheral T-cell lymphoma. Doses ranged from 0.4 to 1.4 mg/kg, with the maximum tolerated dose determined to be 1.2 mg/kg. The most common side effects were peripheral sensory neuropathy (66%), fatigue (52%), nausea (50%), diarrhea (32%), arthralgia (27%), and pyrexia (25%). Grade 3 adverse events occurring in ≥2 patients were peripheral sensory neuropathy, anemia, neutropenia, peripheral motor neuropathy, hyperglycemia, diarrhea, and vomiting. Grade 4 adverse events occurred in 3 patients and included hyperglycemia, low potassium and magnesium, and neutropenia. The overall objective response rate (ORR) was 59%, with 34% of patients attaining a complete response. Tumor regression occurred in 85% of patients.⁶

Two phase 2 clinical trials have been completed in patients with relapsed HL and relapsed ALCL. In the first study, the efficacy of brentuximab vedotin was evaluated in patients with relapsed or refractory HL who experienced disease progression after undergoing ASCT.⁷ Patients received brentuximab vedotin 1.8 mg/kg every 3 weeks as a 30-minute infusion. The maximum number of cycles was 16. The median age of the 102 patients treated was 31 years. Patients had received a median of 3.5 prior therapies and must have had failure with an ASCT. The ORR was 75%, with 34% achieving a complete response. Treatment-related toxicities included peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events that were grade 3 or higher and occurred in ≥5% of patients included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.⁷

In the second phase 2 study,⁸ 58 patients with relapsed systemic ALCL were treated with brentuximab vedotin 1.8 mg/kg every 3 weeks for up to 16 cycles. The median age of the patients was 52 years. Patients had received a median of 2 prior regimens. The majority of patients (62%) had primary refractory disease, and 50% were refractory to their most recent therapy. Seventy-two percent of the patients in the trial had ALK-negative disease. The ORR was 86%, with 53% of the patients achieving a complete response. The median duration of response had not been reached. Of the 15 patients with malignant cutaneous lesions at baseline, 93% had resolution of all lesions. The median time to resolution was about 5 weeks.⁸

Since a significant number of patients who receive brentuximab vedotin achieve a complete response, an important question is whether patients can be successfully re-treated with brentuximab vedotin. Bartlett and colleagues reported on patients who were re-treated with brentuximab vedotin in 3 multicenter studies.⁹ Patients who had any level of tumor response with prior brentuximab vedotin treatment and subsequently experienced relapse were retreated with brentuximab vedotin. Patients were treated at a dose of either 1 mg/kg once a week or 1.8 mg/kg every 3 weeks, depending on their original treatment schedule. Seven patients re-treated had a total of 8 retreatment experiences, with 2 complete responses, 4 partial responses, and 2 stable disease. Therefore, it is believed that no significant resistance is developed to brentuximab vedotin after the initial treatment.⁹ The most common side effects of brentuximab vedotin (≥20%) are neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting (Table 1).⁴ The most common grade 3/4 side effects include neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. MMAE is a strong inhibitor of CYP3A4. Administration of brentuximab vedotin along with ketoconazole caused increased exposure to MMAE of approximately 34%. Therefore, patients taking strong CYP3A4 inhibitors along with brentuximab vedotin should be closely monitored for adverse reactions.⁴ In January 2012, the FDA notified healthcare professionals that 2 additional cases of progressive multifocal leukoencephalopathy (PML) had been reported associated with brentuximab vedotin, now totaling 3 cases of PML.¹⁰ PML is a rare but serious brain infection that can result in death. Symptoms can include changes in mood or usual behavior; confusion; thinking problems; loss of memory; changes in vision, speech, and walking; and decreased strength or weakness in one side of the body. Due to its seriousness, the FDA required a Boxed Warning to highlight this risk. Additionally, a new contraindication warning was added against using brentuximab vedotin with bleomycin due to inceased risk of pulmonary toxicity.^4,10 This was noted in a clinical trial evaluating combination therapy in HL. Noninfectious pulmonary toxicity was more common with brentuximab vedotin plus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with an incidence of 40%, than with brentuximab plus AVD (doxorubicin, vinblastine, and dacarbazine) with an incidence of 0%. Other literature evaluating bleomycin-based regimens without brentuximab vedotin for HL have indicated the incidence of pulmonary toxicity to be between 10% and 25%.^10,11

Management of Toxicities

Management of side effects is of particular importance when caring for patients receiving brentuximab vedotin. Grade 3/4 side effects, including neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia, are among the most commonly occurring toxicities related to brentuximab vedotin,⁴ requiring close monitoring and early assessment to prevent complications.

Anemia is caused by the reduction of circulating red blood cells due to damage to existing stem cells in the bone marrow. Normally, when there is increased demand for red blood cell production, the bone marrow responds to the demand by increasing production. This compensatory response is diminished in patients receiving cytotoxic therapy (eg, brentuximab vedotin) because of damage to the precursor cells in the bone marrow.¹² Monitoring for side effects of anemia, including increased fatigue, lightheadedness, dizziness, palpitations, and shortness of breath, is important.

One important intervention in the management of chemotherapy-induced anemia is transfusion of packed red blood cells. Transfusion criteria vary by institution, but generally, transfusion of packed red blood cells is ordered to maintain hemoglobin between 7 g/dL and 9 g/dL in asymptomatic patients with no significant comorbidities or between 8 g/dL and 10 g/dL in patients with acute coronary syndrome, cerebrovascular disease, chronic obstructive pulmonary disease or hypoxemia, tachycardia, fever, or angina.¹² The most common risks related to red blood cell transfusions are transfusion reactions (including hemolytic, febrile, and nonhemolytic transfusion reactions as well as transfusion-related acute lung injury), congestive heart failure (especially if the patient has known cardiac disease), virus transmission (though this risk is extremely low), bacterial contamination, iron overload, and increased thrombotic events.¹³ Informed consent should be obtained prior to administering blood transfusions.¹³ In addition to transfusion of packed red blood cells, erythrocyte stimulating agents can be used in the palliative setting at provider discretion.¹³

Thrombocytopenia, caused by a reduction in the rate of platelet production, can be due to marrow injury from myelosuppressive medications that lead to destruction of the precursor megakaryocytes.¹⁴ Patients receiving brentuximab vedotin are at risk for thrombocytopenia during their treatment. Thrombocytopenia commonly occurs 10 to 14 days following the administration of chemotherapy. In some patients, dose decreases or delays are necessary due to delayed platelet recovery. Patients may not have any symptoms until platelets fall below 20,000/μL. Symptoms include petechiae, ecchymosis, hemorrhagic bullae on mucous membranes, gingival bleeding, epistaxis, menorrhagia, hematuria, GI bleeding, and bleeding from injection sites. In patients with prolonged thrombocytopenia, there is risk of cranial hemorrhage.¹⁵ Indications for prophylactic platelet transfusion are controversial. In general, evidence-based practice leads to a trigger for platelet transfusion at levels <10,000/μL unless there are other risk factors making this unreasonable, including fever, increased white blood cell (WBC) count, coagulopathy, bleeding, or invasive procedures.¹⁵

Neutropenia is also associated with brentuximab vedotin. Neutropenia is defined as an absolute neutrophil count (ANC) <500 neutrophils/μL or <1000 neutrophils/μL and a predicted decline to ≤500 neutrophils/μL over the next 48 hours.¹⁶ The severity and duration of neutropenia correlate with patient outcomes and influence the frequency and severity of infection as well as the response to chemotherapy.¹⁴ Patients with prolonged severe neutropenia are at significantly increased risk of developing severe bacterial, viral, and fungal infections.¹⁴

The management of neutropenia includes the use of growth factors to increase the WBC count, as well as preventing and treating infections related to neutropenia. Myeloid growth factors, including filgrastim and sargramostim, have been approved by the FDA for use in the prevention of neutropenia related to chemotherapy administration. Both effectively increase the ANC, but they have different side effect profiles. Filgrastim is a granulocyte colony-stimulating factor (G-CSF) and is more specific for activation of neutrophils.¹⁷ Filgrastim is available in a pegylated form (pegfilgrastim) that has a half-life of 46 to 62 hours, compared with the plasma half-life of 3 to 4 hours for filgrastim.¹⁸ Sargramostim is a granulocyte-macrophage colony-stimulating factor (GM-CSF) that stimulates monocytes, eosinophils, and neutrophils, prolongs their half-lives, and enhances their function.¹⁸ In patients who have had neutropenic complications during a prior cycle of brentuximab vedotin without CSF support, CSFs can be instituted to decrease the need for dose reductions or treatment delays. Dosing of filgrastim is 5 μg/kg/day subcutaneously until an ANC level >5000/μL is reached or pegfilgrastim 6 mg subcutaneously once, with both to be administered at least 24 hours after chemotherapy infusion. Administration of CSFs during chemotherapy or within 24 hours of chemotherapy may expose the rapidly dividing myeloid cells to the cytotoxic chemotherapy and result in more profound neutropenia. The most common side effect of CSFs is bone pain,¹⁸ which can be treated successfully with NSAIDs or acetaminophen if not contraindicated.¹⁹ Other, infrequent side effects include fever, petechiae, rash, splenomegaly, increased liver enzymes, epistaxis, hypertension or hypotension, cardiac arrhythmias, headache, nausea, vomiting, peritonitis, leukocytosis, and transfusion reactions.¹⁹

Of all the side effects of brentuximab vedotin noted, peripheral sensory neuropathy can affect quality of life the most. PN can require dose reductions or delays and can significantly impact daily life.²⁰ PN related to brentuximab vedotin is similar to that experienced by patients receiving microtubule-targeting agents (MTAs),⁵ such as vinca alkaloids, taxanes, and the recently introduced epothilone analog, ixabepilone.²¹ MTAs interfere with the normal function and structure of the microtubules in cells, leading to tumor cell death by arresting the cell cycle.²¹ This mechanism of action leads to interruption of the active transport of proteins and other components within the neurons, thereby affecting axonal transport in the neurons. Neurons depend on this transport of proteins for survival.²¹ Because the peripheral nerves have longer axon length and more permeability due to their structure, they are more frequently and quickly affected by this interruption, causing neuropathy.²¹

PN is manifested in most patients receiving brentuximab vedotin by sensory findings, including paresthesia, pain or burning, allodynia, hyperesthesia or numbness, decreased vibratory sensation, and reduced or absent deep tendon reflexes. There may also be motor findings consistent with neuropathy that include generalized muscle weakness, decreased fine motor skills, and vocal cord dysfunction. Lastly, autonomic findings, though less likely, can include abdominal cramping, constipation, severe ileus, and urinary retention. Grading usually takes into account the effect on quality of life and daily activities (Table 2).^21,22

Preexisting PN from any other causes increases the risk and severity of PN related to treatment.²² Certain conditions that put patients at increased risk of developing PN from brentuximab vedotin include diabetes, alcoholism, nutritional deficiencies, and infectious diseases such as AIDS or Lyme disease.²¹ Assessment of patients in whom there is suspicion of neuropathy should include evaluation for signs of decreased strength or diminished reflexes; symptoms including pain, paresthesia, or hyperesthesia; and any interference with activities of daily living.²⁰ In most cases of neuropathy, signs or symptoms will begin in the distal extremities and progress proximally in a stocking-glove distribution.²⁰

The only proven treatment methods for PN are discontinuation, delay, or dose reduction of brentuximab vedotin.⁵ In one study, resolution of PN was noted in 10 of 16 patients (63%) at the last safety assessment, approximately 30 days from the last dose of brentuximab vedotin; the only grade 3 event, which was observed in a patient in the 2.7-mg cohort, returned to grade 1 after approximately 4 months.⁵ In most cases, neuropathy will resolve after discontinuation of therapy or by decreasing the dose of brentuximab vedotin, but in some cases it becomes severe and irreversible.²¹

Other interventions have been used in the treatment of chemotherapy induced PN (CIPN), but none have been proven by prospective randomized clinical trial data, and none are FDA approved at this time. Some of these include tricyclic antidepressants, including amitriptyline, desipramine, and imipramine, that modulate sodium channels and inhibit reuptake of norepinephrine and serotonin, which leads to decreased pain.²³ Anti-convulsants, including gabapentin, are also often used, although there have been no data to show true reduction of pain.²⁰ Opioid pain medication has been used to treat CIPN, with good relief reported by patients. Opioids can be titrated to achieve maximal reduction of pain. Once maximal relief is achieved, the preferred plan of care includes a long-acting opioid analgesic with a short-acting medication used only for breakthrough pain.²⁰ Other compounds under investigation specifically for neuropathy caused by MTAs include amifostine, glutamine, and glutathione.²¹ There are no large randomized trials demonstrating efficacy of these agents and, in general, all evidence and current clinical guidelines do not recommend using amifostine.²¹ Glutamine and glutathione have shown some promise in reducing the severity of PN, but again, there are no large trials to support their use.²¹ In general, continued assessment and early intervention are key to preventing severe, irreversible PN, and patients should be advised to report symptoms immediately.²¹

Nursing management of patients receiving brentuximab vedotin includes good assessment and patient education. Patients should be educated to report symptoms early and should be asked about symptoms of PN or myelosuppression at each visit, as early intervention will prevent serious complications. Patients should be educated about early detection of PN and how to avoid falling or other harmful situations should they lose sensation, proprioception, or reflexes.²¹ Patient education should also include defining myelosuppression for the patient, listing symptoms to report, and explaining the routine of laboratory evaluations and chemotherapy treatments. Nurses should also take time before the start of treatment to teach patients about the potential for and consequences of neutropenia. They should tell patients to report signs and symptoms of infection or any fever immediately to their physician or nurses and let patients know about prevention of infection by way of hand washing and avoiding contact with anyone who appears ill.²⁴

Nurses can also help define fatigue fighting strategies such as prioritizing tasks and taking breaks to rest if necessary.²⁵ Many studies have been conducted to evaluate the use of exercise in combating fatigue. There is strong evidence supporting the benefits of exercise in managing fatigue.²⁶ Exercise can effectively reduce fatigue in many settings, including fatigue resulting from chemotherapy. In this case, home-based moderate exercise, both aerobic and strength training, has been proven to be beneficial.²⁶ The current recommendation from the National Comprehensive Cancer Network (NCCN) is to start with low-intensity exercise of short duration and then increase and modify the plan as conditions change.²⁷ Currently, data are insufficient to recommend specific amounts of time for activity, but the US Surgeon General does recommend 30 minutes of activity on most days for all populations.²⁷ With this in mind, caution should be taken in patients with comorbidities such as respiratory or cardiac disease and in those with bone metastasis, thrombocytopenia, anemia, and fever.²⁷ In these patients, activity regimens should be closely monitored and individualized based on current physical activity level and ability.²⁷

Brentuximab vedotin is a novel ADC that targets CD30. Responses have been shown in patients with Hodgkin lymphoma and anaplastic large cell lymphoma that is relapsed or refractory to prior therapy. Responses have also been shown in the retreatment setting. While overall the therapy is tolerable, significant side effects (grade 3 or greater) with brentuximab vedotin can include neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Nursing assessment to detect side effects early may be useful in attenuating their severity. In addition, interventions should be initiated to minimize the impact of therapy on the patient’s quality of life.

References

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