ASH News Daily 2017 - Issue 1 - A-26

Severe Hematologic Toxicity in Patients Receiving ZEVALIN
Group 1
(n=270)
≥ 150,000/mm3

Group 2
(n=65 )
≥ 100,000 but
≤ 149,000/mm3

Study 4
(n=204)
≥ 150,000/mm3

0.4 mCi/kg
(14.8 MBq/kg)

0.3 mCi/kg
(11.1 MBq/kg)

0.4 mCi/kg
(14.8 MBq/kg)

Median nadir (per mm3)

800

600

721

Per Patient Incidence
ANC <1000/mm3

57%

74%

65%

Per Patient Incidence
ANC <500/mm3

30%

35%

26%

Median Duration (Days)*
ANC <1000/mm3

Median Time to Recovery**

Median nadir (per mm3)

41,000

24,000

42,000

Per Patient Incidence
Platelets <50,000/mm3

61%

78%

61%

Per Patient Incidence
Platelets <10,000/mm3

10%

14%

Median Duration (Days)#
Platelets <50,000/mm3

Median Time to Recovery**

Baseline Platelet Count

Y-90 ZEVALIN Dose
ANC

Platelets

* Day from last ANC ≥1000/mm3 to first ANC ≥1000/mm3 following nadir,
censored at next treatment or death
** Day from nadir to first count at level of Grade 1 toxicity or baseline
# Day from last platelet count ≥50,000/mm3 to day of first platelet count
≥50,000/mm3 following nadir, censored at next treatment or death
Cytopenias were more severe and more prolonged among eleven (5%) patients
who received ZEVALIN after first-line fludarabine or a fludarabine-containing
chemotherapy regimen as compared to patients receiving non-fludarabine
containing regimens. Among these eleven patients, the median platelet nadir
was 13,000/mm3 with a median duration of platelets below 50,000/mm3
of 56 days and the median time for platelet recovery from nadir to Grade
1 toxicity or baseline was 35 days. The median ANC was 355/mm3, with a
median duration of ANC below 1,000/mm3 of 37 days and the median time
for ANC recovery from nadir to Grade 1 toxicity or baseline was 20 days. The
median time to cytopenia was similar across patients with relapsed/refractory
NHL and those completing first-line chemotherapy, with median ANC nadir
at 61-62 days, platelet nadir at 49-53 days, and hemoglobin nadir at 68-69
days after Y-90-ZEVALIN administration. Information on hematopoietic
growth factor use and platelet transfusions is based on 211 patients with
relapsed/refractory NHL and 206 patients following first- line chemotherapy.
Filgrastim was given to 13% of patients and erythropoietin to 8% with
relapsed or refractory disease; 14% of patients receiving ZEVALIN following
first-line chemotherapy received granulocyte-colony stimulating factors and
5% received erythopoiesis-stimulating agents. Platelet transfusions were
given to approximately 22% of all ZEVALIN-treated patients. Red blood cell
transfusions were given to 20% of patients with relapsed or refractory NHL
and 2% of patients receiving ZEVALIN following first-line chemotherapy.
Infections: In relapsed or refractory NHL patients, infections occurred in
29% of 349 patients during the first 3 months after initiating the ZEVALIN
therapeutic regimen and 3% developed serious infections (urinary tract
infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea,
osteomyelitis, and upper respiratory tract infection). Life-threatening
infections were reported in 2% (sepsis, empyema, pneumonia, febrile
neutropenia, fever and biliary stent-associated cholangitis). From 3 months
to 4 years after ZEVALIN treatment, 6% of patients developed infections;
2% were serious (urinary tract infection, bacterial or viral pneumonia, febrile
neutropenia, perihilar infiltrate, pericarditis, and intravenous drug-associated
viral hepatitis) and 1% were life-threatening infections (bacterial pneumonia,
respiratory disease, and sepsis). When administered following first-line
chemotherapy, Grade 3-4 infections occurred in 8% of ZEVALIN treated
patients and in 2% of controls and included neutropenic sepsis (1%),
bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower
respiratory tract infection, sinusitis, and upper respiratory tract infection.
0102-017902
111114

Leukemia and Myelodysplastic Syndrome: Among 746 patients with relapsed/
refractory NHL, 19 (2.6%) patients developed MDS/AML with a median
follow-up of 4.4 years. The overall incidence of MDS/AML among the 211
patients included in the clinical studies was 5.2% (11/211), with a median
follow-up of 6.5 years and median time to development of MDS/AML of 2.9
years. The cumulative Kaplan-Meier estimated incidence of MDS/secondary
leukemia in this patient population was 2.2% at 2 years and 5.9% at 5
years. The incidence of MDS/AML among the 535 patients in the expanded
access programs was 1.5% (8/535) with a median follow-up of 4.4 years and
median time to development of MDS/AML of 1.5 years. Multiple cytogenetic
abnormalities were described, most commonly involving chromosomes 5
and/or 7. The risk of MDS/AML was not associated with the number of prior
treatments (0-1 versus 2-10). Among 204 patients receiving Y-90-ZEVALIN
following first-line treatment, 7 (3%) patients developed MDS/AML between
approximately 2 to 7 years after ZEVALIN administration.
Post-Marketing Experience: The following adverse reactions have been
identified during post-approval use of the ZEVALIN therapeutic regimen in
hematologic malignancies. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Decisions to include these reactions in labeling are typically based on one or
more of the following factors: (1) seriousness of the reaction, (2) frequency
of reporting, or (3) strength of causal connection to the ZEVALIN therapeutic
regimen.
* Cutaneous and mucocutaneous reactions: erythema multiforme, StevensJohnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and
exfoliative dermatitis. * Infusion site erythema and ulceration following extravasation. * Radiation injury in tissues near areas of lymphomatous involvement
within a month of ZEVALIN administration.
Immunogenicity: As with all therapeutic proteins, there is a potential for
immunogenicity. The incidence of antibody formation is highly dependent
on the sensitivity and specificity of the assay. Additionally, the observed
incidence of antibody (including neutralizing antibody) positivity in an
assay may be influenced by several factors including assay methodology,
sample handling, timing of sample collection, concomitant medications,
and underlying disease. For these reasons, comparisons of the incidence
of HAMA/HACA to the ZEVALIN therapeutic regimen with the incidence of
antibodies to other products may be misleading. HAMA and HACA response
data on 446 patients from 8 clinical studies conducted over a 10-year time
period are available. Overall, 11/446 (2.5%) had evidence of either HAMA
formation (N=8) or HACA formation (N=4). Six of these patients developed
HAMA/HACA after treatment with ZEVALIN and 5 were HAMA/HACA positive
at baseline. Of the 6 who were HAMA/HACA positive, only one was positive
for both. Furthermore, in 6 of 11 patients, the HAMA/HACA reverted to
negative within 2 weeks to 3 months. No patients had increasing levels of
HAMA/HACA at the end of the studies.
DRUG INTERACTIONS: No formal drug interaction studies have been
performed with ZEVALIN. Patients receiving medications that interfere
with platelet function or coagulation should have more frequent laboratory
monitoring for thrombocytopenia.
USE IN SPECIFIC POPULATIONS Pregnancy Category D:
Risk Summary Based on its radioactivity, Y-90 ZEVALIN may cause fetal
harm when administered to a pregnant woman. Immunoglobulins are known
to cross the placenta. There are no adequate and well-controlled studies in
pregnant women. Animal reproductive toxicology studies of ZEVALIN have
not been conducted. Advise women of childbearing potential to use adequate
contraception for a minimum of twelve months. Inform women who become
pregnant while receiving ZEVALIN of the potential fetal risks.
Nursing Mothers: Because human IgG is excreted in human milk, it is
expected that ZEVALIN would be present in human milk. Because of the
potential for adverse reactions in nursing infants from Y-90 ZEVALIN, a
decision should be made to discontinue nursing or not administer the
ZEVALIN therapeutic regimen, taking into account the importance of the drug
to the mother.
OVERDOSAGE: Severe cytopenias which may require stem cell support have
occurred at doses higher than the recommended maximum total dose of 32
mCi (1184 MBq).
© 2013 Spectrum Pharmaceuticals, Inc. All Rights Reserved.
SPECTRUM PHARMACEUTICALS, INC.® and ZEVALIN® are registered trademarks of
Spectrum Pharmaceuticals, Inc. and its subsidiaries.
The Spectrum Pharmaceuticals logo and ZEVALIN logo are trademarks owned by
Spectrum Pharmaceuticals, Inc. and its subsidiaries.

www.sppirx.com

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 1