ASH News Daily 2016 - Issue 2 - A-22

ASH News Daily

Page A-22

Sunday, December 4, 2016

MAC

«« From Page A-1

session revealed, complement
disorders don't have to be a black
box. In the first talk, Dr. Parker conceded that PNH is indeed a complex
disease involving both intravascular hemolysis and bone marrow
failure, but he emphasized that understanding that PNH is ultimately
a clonal stem cell disorder can help
demystify the disease: "Because of
the PIGA mutation [in PNH], complement-regulatory proteins (CD55
and CD59) are not expressed on
progeny of mutated hematopoetic
stem cells. It's the red cells that suf-

fer the consequences of this deficiency."
In the second presentation, Dr. Vahid Afshar-Kharghan simplified the
pathophysiology of aHUS, pointing
out that ultimately, primary aHUS
is also merely due to an imbalance
in complement regulation. "Any
surface that cannot protect itself actively from complement attack becomes a target. In the case of aHUS,
this target is the endothelial surface
mainly in the kidney," he explained.
He also highlighted that the 2011
U.S. Food and Drug Administration
approval of eculizumab for aHUS
has revolutionized the treatment of
this disease and has made having a

INDICATIONS AND USAGE
ADCETRIS is a CD30-directed antibody-drug conjugate indicated for the treatment of patients with classical
Hodgkin Lymphoma (HL) at high risk of relapse or progression as post-auto-HSCT consolidation.

CONTRAINDICATIONS
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. In the relapsed classical HL and sALCL clinical trials,
54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution,
31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy,
51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms
of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation,
neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change
in dose, or discontinuation of ADCETRIS.
Anaphylaxis and Infusion Reactions
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during
infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS
and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should
be interrupted and appropriate medical management instituted. Patients who have 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 Grade 4 thrombocytopenia or anemia can occur with
ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. Complete blood counts
should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered
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 ADCETRIS doses.
Serious Infections and Opportunistic Infections
Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic
shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Patients should
be closely monitored during treatment for the emergence of possible bacterial, fungal or viral infections.
Tumor Lysis Syndrome
Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis
syndrome. Monitor closely and take appropriate measures.
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. Due to higher monomethyl auristatin E
(MMAE) exposure, ≥Grade 3 adverse reactions may be more frequent in patients with severe renal
impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with
severe renal impairment [creatinine clearance (CLcr) <30 mL/min].
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 (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
Hepatotoxicity
Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients receiving ADCETRIS.
Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin.
Cases have occurred after the first dose of ADCETRIS or after ADCETRIS 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
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 dosing for any suspected case of PML and discontinue
ADCETRIS dosing if a diagnosis of PML is confirmed.
Pulmonary Toxicity
Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute
respiratory distress syndrome (ARDS), 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 necrosis (TEN), including fatal outcomes, have
been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate
medical therapy.

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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. There are no adequate and well-controlled studies of ADCETRIS in
pregnant women. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased
embryo viability and fetal malformations, in animals at maternal exposures that were similar to the
clinical dose of 1.8 mg/kg every 3 weeks. Advise females of reproductive potential to avoid pregnancy
during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. If ADCETRIS
is used during pregnancy or if the patient becomes pregnant during ADCETRIS treatment, the patient
should be apprised of the potential risk to the fetus.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may
not reflect the rates observed in practice.
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, regardless
of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory
tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. The most common adverse
reactions occurring in at least 10% of patients, using the NCI CTC Version 4, are shown in Table 1.
Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation (Study 3)
ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-autoHSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting
dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks
or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 brentuximab vedotin, 160 placebo)
received at least one dose of study treatment. The median number of treatment cycles in each study arm
was 15 (range, 1-16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles.
Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV),
varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PCP) post-auto-HSCT. Overall, 312
patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0-20)
and 319 patients (98%) received PCP prophylaxis with a median duration of 6.5 months (range, 0-20).
Table 1: Most Commonly Reported (≥10% in the ADCETRIS arm) Adverse Reactions in Study 3
ADCETRIS
Total N = 167
% of patients
Adverse Reaction
Blood and lymphatic system disorders
Neutropenia*
Thrombocytopenia*
Anemia*
Nervous system disorders
Peripheral sensory neuropathy
Peripheral motor neuropathy
Headache
Infections and infestations
Upper respiratory tract infection
General disorders and administration site conditions
Fatigue
Pyrexia
Chills
Gastrointestinal disorders
Nausea
Diarrhea
Vomiting
Abdominal pain
Constipation
Respiratory, thoracic and mediastinal disorders
Cough
Dyspnea
Investigations
Weight decreased
Musculoskeletal and connective tissue disorders
Arthralgia
Muscle spasms
Myalgia
Skin and subcutaneous tissue disorders
Pruritus
Metabolism and nutrition disorders
Decreased appetite

Placebo
Total N = 160
% of patients

Any
Grade

Grade
3

Grade
4

Any
Grade

Grade
3

Grade
4

78
41
27

30
2
4

9
4
-

34
20
19

6
3
2

4
2
-

56
23
11

10
6
2

16
2
8

1
1
1

24
19
10

2
2
-

18
16
5

3
-

22
20
16
14
13

3
2
2
2
2

8
10
7
3
3

1
-

21
13

16
6

18
11
11

1
1

9
6
4

*Derived from laboratory values and adverse reaction data
Additional Important Adverse Reactions
Peripheral neuropathy
In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The median time
to first onset of any grade was 14 weeks (range, 0.1-47), of Grade 2 was 27 weeks (range, 0.4-52) and of
Grade 3 was 34 weeks (range, 7-106). The median time from onset to resolution or improvement of any
grade was 23 weeks (range, 0.1-138), of Grade 2 was 24 weeks (range, 1-108) and of Grade 3 was 25
weeks (range, 2-98). Of the patients who reported neuropathy, 59% had complete resolution and 41% had
residual neuropathy (26% partial improvement, 15% no improvement) at the time of their last evaluation.
Infusion reactions
Two cases of anaphylaxis were reported in the dose-finding trials. In Study 3, infusion-related reactions
were reported in 25 patients (15%) in the ADCETRIS-treated arm and 3 patients (2%) in the placebo arm.
Grade 3 events were reported in 3 of the 25 ADCETRIS-treated patients who experienced infusion-related
reactions. No Grade 4 infusion-related reactions were reported. The most common adverse reactions (≥2%)
associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), headache (2%),
pruritus (2%), rash (2%), back pain (2%), and vomiting (2%).
Pulmonary Toxicity
In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a combination
regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported

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DOSAGE AND ADMINISTRATION
Dosage Recommendations
Administer ADCETRIS as an intravenous infusion over 30 minutes every 3 weeks.
For classical HL post-auto-HSCT consolidation treatment, initiate ADCETRIS treatment within 4-6 weeks
post-auto-HSCT or upon recovery from auto-HSCT. These patients should continue treatment until a
maximum of 16 cycles, disease progression, or unacceptable toxicity.
The recommended dose is 1.8 mg/kg up to 180 mg. Reduce the dose in patients with mild hepatic
impairment (Child-Pugh A) to 1.2 mg/kg up to 120 mg. Avoid use in patients with moderate (Child-Pugh B)
or severe (Child-Pugh C) hepatic impairment or severe renal impairment (CLcr <30 mL/min).
Dose Modification
Peripheral Neuropathy: For new or worsening Grade 2 or 3 neuropathy, dosing should be held until
neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral
neuropathy, ADCETRIS should be discontinued.
Neutropenia: The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to
baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent cycles in patients who experience
Grade 3 or 4 neutropenia in the previous cycle. In patients with recurrent Grade 4 neutropenia despite the
use of G-CSF prophylaxis, consider discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg.

Dr. Naik indicated no relevant conflicts of interest.

LASERS PRINTED AT

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

ment-directed therapies may have
a role in the setting of acute intravascular hemolysis.
Still yearning to unlock the mystery of the MAC? Don't miss the encore presentation of this education
session tomorrow from 10:30 a.m.
to 12:00 noon in Room 29 of the San
Diego Convention Center.

70%

ADCETRIS (brentuximab vedotin) for injection, for intravenous use
Brief Summary: see package insert for complete prescribing information
®

working knowledge of the complement system more imperative for
the average hematologist.
The final talk by Dr. Sigbjörn
Berentsen shed light on primary
cold agglutinin disease as a clonal
lymphoproliferative disorder - a
fact often overlooked by hematologists and hematopathologists alike.
Dr. Berentsen emphasized that,
while many patients with cold agglutinins may never require treatment, clonally directed therapies
may be the key to long-term disease control. He also highlighted
the role of the complement system
in severe cases of cold agglutinin
disease and stressed that comple-

Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 2