leukoencephalopathy
Two additional cases of progressive multifocal leukoencephalopathy (PML) have been reported with the lymphoma drug brentuximab vedotin (Adcetris), according to the US Food and Drug Administration (FDA).
So the agency has added a new boxed warning to the drug’s label highlighting the risk of PML. At the time of brentuximab vedotin’s approval in August 2011, only 1 case of PML was described in the warnings and precautions section of the label.
The label change also includes a contraindication warning against the use of brentuximab vedotin with bleomycin, as the combination appears to increase the risk of pulmonary toxicity.
Diagnosing PML
The FDA says healthcare professionals should consider a possible diagnosis of PML in any patient who is receiving or has received brentuximab vedotin and who presents with new signs or symptoms of central nervous system abnormalities.
Healthcare professionals should also instruct patients to report changes in mood or usual behavior, confusion, problems thinking, loss of memory, changes in walking or talking, decreased strength or weakness on one side of the body, or changes in vision.
Evaluation of PML may include consultation with a neurologist, a brain MRI, lumbar puncture with analysis of cerebrospinal fluid by polymerase chain reaction for John Cunningham (JC) virus, and/or a brain biopsy.
Healthcare professionals should hold brentuximab vedotin dosing for any suspected case of PML and discontinue brentuximab vedotin dosing if PML is confirmed.
PML case reports
To date, 3 patients have developed PML while receiving treatment with brentuximab vedotin.
A 48-year-old man with Hodgkin lymphoma (HL) was diagnosed with PML after receiving the drug. The patient’s medical history included prior treatment with multiple chemotherapeutic agents and targeted radiation therapy.
After the third dose of brentuximab vedotin, the patient presented with left-sided weakness and slurred speech. Cerebrospinal fluid was positive for JC virus. The patient’s condition deteriorated rapidly, resulting in death within 4 weeks of symptom onset.
A 50-year-old man with HL was also diagnosed with PML after receiving brentuximab vedotin. The patient’s medical history included prior treatment with multiple chemotherapeutic agents, targeted radiation therapy, and autologous stem cell transplant.
After 8 cycles of brentuximab vedotin, this patient presented to the local emergency room with complaints of changes in speech, difficulty writing with his right hand, and right lower extremity weakness. In addition, he had poor coordination, poor balance, and left-sided sensory deficits.
Although MRI results were inconclusive and cerebrospinal fluid analyses were negative for JC virus early in the course of the neurologic work-up, an immunostain of a spinal cord lesion biopsy was positive for JC virus.
The patient’s neurological condition continues to worsen. Most recently, he lost motor function of his lower extremities and deep tendon reflexes of his legs. He also has tremulousness of his hands and hypoactive arm reflexes.
Lastly, a 38-year-old female patient with a history of stage 4 cutaneous anaplastic large cell lymphoma was diagnosed with PML after receiving brentuximab vedotin. The patient’s medical history included prior treatment with multiple chemotherapeutic agents and targeted radiation therapy.
Prior to treatment with brentuximab vedotin, a baseline neurological examination was normal. After the second dose, the patient complained of the inability to read, inability to find words to express herself, memory lapses, and slight loss of balance.
A brain MRI revealed a demyelinating process, and a brain biopsy was positive for JC virus. The patient’s treatment with brentuximab vedotin was discontinued.
Pulmonary toxicity risk
In addition to the risk of PML, research has revealed that brentuximab vedotin can confer a risk of pulmonary toxicity when combined with bleomycin.
A clinical trial compared the combination of brentuximab vedotin plus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) to combination brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD) as front-line therapy for HL.
An excessive number of patients in the brentuximab vedotin plus ABVD treatment group experienced noninfectious pulmonary toxicity. The frequency of pulmonary toxicity in this group was approximately 40%, compared to a frequency of 10% to 25% previously observed with bleomycin-based regimens not containing brentuximab vedotin.
Researchers observed no pulmonary toxicity in the brentuximab vedotin plus AVD treatment group.
