Peripheral neuropathy and ADCETRIS® (brentuximab vedotin) dose modification

Peripheral neuropathy (PN)—ADCETRIS trial experience1

  • ADCETRIS treatment causes PN that is predominantly sensory
    • Cases of peripheral motor neuropathy have also been reported
  • ADCETRIS-induced PN is cumulative

Incidence of PN observed in relapsed classical HL, relapsed sALCL, and classical HL post auto-HSCT consolidation trials*†1:

 
  Grade 1 or Grade 2 Grade 3 Grade 4
Relapsed Classical HL patients (n=102)1 Sensory 44% 8% -
Motor 12% 4% -
Relapsed sALCL patients (n=58)1 Sensory 43% 10% -
Motor 4% 3% -
Classical HL patients post auto-HSCT (n=167)1 Sensory 46% 10% -
Motor 17% 6% -
 
In the relapsed classical HL and relapsed sALCL trials, PN was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Published August 9, 2006. Accessed September 30, 2015.1
In the classical HL post auto-HSCT consolidation trial, PN was graded using the NCI CTCAE, Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_5x7.pdf. Published June 14, 2010. Accessed September 30, 2015.1

 

Incidence of PN observed in relapsed classical HL, relapsed sALCL, and classical HL post auto-HSCT consolidation trials*†1:

 
  Grade 1 or Grade 2 Grade 3 Grade 4
Relapsed Classical HL (n=102)1 Sensory 44% 8% -
Motor 12% 4% -
Relapsed sALCL (n=58)1 Sensory 43% 10% -
Motor 4% 3% -
Classical HL post auto-HSCT (n=167)1 Sensory 46% 10% -
Motor 17% 6% -
 

PSN=peripheral sensory neuropathy; PMN=peripheral motor neuropathy.

In the relapsed classical HL and relapsed sALCL trials, PN was graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Published August 9, 2006. Accessed September 30, 2015.1
In the classical HL post auto-HSCT consolidation trial, PN was graded using the NCI CTCAE, Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_5x7.pdf. Published June 14, 2010. Accessed September 30, 2015.1

 

Median time to observed onset of PN (any grade)1-3

A timeline chart illustrating the median time to onset of PN. PN can occur as early as the first dose. In the classical HL trial, median was 12 weeks, and range 0 to 41 weeks. In the relapsed sALCL trial, median was 15 weeks and range 0 to 52 weeks. In the classical HL post auto-HSCT consolidation trial, median was 14 weeks, and range was 0.1 to 47 weeks.

Improvement or resolution of PN was observed in the majority of patients during follow-up1

Incidence & resolution of PN (any grade) in the relapsed classical HL and relapsed sALCL trials

A bar chart depicting incidence and resolution of PN. 46% of patients had no PN. Of the 54% that had PN, 49% were resolved completely, 31% showed partial improvement, and 20% showed no improvement at the time of last follow-up.

 

At the time of last follow-up.

 

Incidence & resolution of PN (any grade) in the post auto-HSCT classical HL consolidation trial

A bar chart depicting incidence and resolution of PN. 33% of patients had no PN. Of the 67% that had PN, 59% were resolved completely, 26% showed partial improvement, and 15% showed no improvement at the time of last follow-up.

 

At the time of last follow-up.

 

Throughout treatment, patients should be monitored for PN symptoms, which include1:

  • Hypoesthesia
  • Hyperesthesia
  • Paresthesia
  • Discomfort
  • Burning sensation
  • Neuropathic pain
  • Weakness

It is important to be proactive in monitoring your patients. PN is best managed by close monitoring and timely dose modification.1

Grading PN

  • In the relapsed classical HL and relapsed sALCL trials of ADCETRIS, PN symptoms were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.01
  • In the post auto-HSCT consolidation trial of ADCETRIS, PN symptoms were assessed using the CTCAE Version 4.01
  • PN should be graded using the definitions in the chart below, which come from CTCAE Version 4.04  
 
NCI CTCAE v4 Criteria for Peripheral Sensory Neuropathy1,4 ADCETRIS Dose Modification
Grade Criteria
1 Asymptomatic; loss of deep tendon reflexes or paresthesia No dose modification required; continue monitoring
2 Moderate symptoms; limiting instrumental activities of daily living (ADL) New or worsening symptoms: hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg
3 Severe symptoms; limiting self-care ADL New or worsening symptoms: hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg
4 Life-threatening consequences; urgent intervention indicated Discontinue ADCETRIS
 
 
NCI CTCAE v4 Criteria for Peripheral Motor Neuropathy1,4 ADCETRIS Dose Modification
Grade Criteria
1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated No dose modification required; continue monitoring
2 Moderate symptoms; limiting instrumental ADL New or worsening symptoms: hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg
3 Severe symptoms; limiting self-care; assistive device indicated New or worsening symptoms: hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg
4 Life-threatening consequences; urgent intervention indicated Discontinue ADCETRIS
 

ADL=activities of daily living; PN=peripheral neuropathy.

These grading descriptions are from the NCI CTCAE Version 4.0. In the relapsed classical HL and relapsed sALCL trials of ADCETRIS, peripheral sensory neuropathy and peripheral motor neuropathy were graded using the NCI CTCAE Version 3.0. In the consolidation trial of ADCETRIS, peripheral sensory neuropathy and peripheral motor neuropathy were graded using the NCI CTCAE Version 4.0.1

Discontinuation due to PN in the clinical trials1

  • In the relapsed classical HL and relapsed sALCL trials, 8% of patients discontinued due to peripheral sensory neuropathy and 3% due to peripheral motor neuropathy
  • In the classical HL post auto-HSCT consolidation trial, 14% of patients discontinued due to peripheral sensory neuropathy and 7% of patients discontinued due to peripheral motor neuropathy

Dose delays due to PN in the clinical trials1

  • In the relapsed classical HL and relapsed sALCL trials, 11% of patients experienced a dose delay due to peripheral sensory neuropathy
  • In the classical HL post auto-HSCT consolidation trial, 16% of patients experienced a dose delay due to peripheral sensory neuropathy and 6% due to peripheral motor neuropathy

Download a tool to help your patients track PN symptoms »

Please see Important Safety Information, including BOXED WARNING, and read full Prescribing Information.

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Important Safety Information

Indications

ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with:

Classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

Classical HL at high risk of relapse or progression as post auto-HSCT consolidation treatment.

Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

Boxed Warning

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS® (brentuximab vedotin).

Contraindication:

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions:

  • Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
  • Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
  • Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
  • Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
  • Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
  • Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
  • Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
  • Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
  • Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
  • Pulmonary toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
  • Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
  • Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus, have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
  • Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after final dose of ADCETRIS.

Adverse Reactions:

In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, the most common adverse reactions (≥20%), regardless of causality, were: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post auto-HSCT, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:

Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

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Reference
1.
ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc.; September 2016.
2.
Data on file. Seattle Genetics, Inc.
3.
Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30:2183-2189.
4.
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Published June 14, 2010. Accessed August 26, 2015.