ASH News Daily 2017 - Issue 3 - A-10

Page A-10

ASH News Daily

Monday, December 11, 2017

LY M P H O M A

Looking for Aggressive Needles in Indolent Haystacks
By Peter Forsberg, MD, and
Nina Shah, MD

t seems like everyone wants
to get personal. I'm not taking about the chatty hospitalist
who has somehow been telling you
about his three-day lemon juice and
cayenne pepper cleanse for a full 30
minutes - I mean that buzziest of
all oncologic movements: personalized medicine. And yes, immunotherapy, I did just call personalized
medicine "the buzziest oncologic
remained generally constant over the follow-up
period in both cohorts. All patients who tested
positive for anti-recombinant human hyaluronidase
antibodies at any point during the study were
negative for neutralizing antibodies.
In the SAWYER study, where previously
untreated patients with CLL were treated with
RITUXAN HYCELA or rituximab in combination
with FC, the incidence of treatment-induced/
enhanced anti-rituximab antibodies was 2.4%
in the RITUXAN HYCELA group vs. 6.7% in
rituximab group. The incidence of treatmentinduced/enhanced anti- recombinant human
hyaluronidase antibodies was 10.6% in the
RITUXAN HYCELA treatment arm. None of the
patients who tested positive for anti-recombinant
human hyaluronidase antibodies tested positive
for neutralizing antibodies.
The clinical relevance of the development
of anti-rituximab or anti-recombinant human
hyaluronidase antibodies after treatment with
RITUXAN HYCELA is not known.
6.3 Postmarketing Experience
The following adverse reactions have been identified
during post-approval use of rituximab-containing
products. 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.
* Hematologic: prolonged pancytopenia, marrow
hypoplasia, Grade 3-4 prolonged or lateonset neutropenia, hyperviscosity syndrome in
Waldenstrom's macroglobulinemia, prolonged
hypogammaglobulinemia
* Cardiac: fatal cardiac failure
* Immune/Autoimmune Events: uveitis, optic
neuritis, systemic vasculitis, pleuritis, lupus-like
syndrome, serum sickness, polyarticular arthritis,
and vasculitis with rash.
* Infection: viral infections, including progressive
multifocal leukoencephalopathy (PML), increase in
fatal infections in HIV-associated lymphoma, and
a reported increased incidence of Grade 3 and 4
infections
* Neoplasia: disease progression of Kaposi's
sarcoma.
* Skin: severe mucocutaneous reactions.
* Gastrointestinal: bowel obstruction and perforation.
* Pulmonary: fatal bronchiolitis obliterans and fatal
interstitial lung disease.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on human data, rituximab-containing
products can cause adverse developmental
outcomes including B-cell lymphocytopenia in
infants exposed to rituximab in-utero (see Clinical
Considerations). There are no available data on
RITUXAN HYCELA use in pregnant women to
inform a drug-associated risk of major birth defects
and miscarriage. In animal reproduction studies,
intravenous administration of a rituximab product to
pregnant cynomolgus monkeys during the period
of organogenesis caused lymphoid B cell depletion
in the newborn offspring at doses resulting in 80%
of the exposure (based on AUC) of those achieved
following a dose of 2 grams in humans. Reduced
fetal weight and increased fetal lethality were
observed following subcutaneous administration
of hyaluronidase human in mice at a dose > 2700
times higher than the human dose. Comparable
systemic exposure levels could occur in a
pregnant patient following accidental intravenous
administration of an entire vial of RITUXAN HYCELA
(see Data). Advise pregnant women of the risk to
a fetus.
Adverse outcomes in pregnancy occur regardless of
the health of the mother or the use of medications.
The background risk of major birth defects and
miscarriage for the indicated population is unknown.
The estimated background risk in the U.S. general
population of major birth defects is 2%-4% and of
miscarriage is 15%-20% of clinically recognized
pregnancies.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Observe newborns and infants for signs of infection
and manage accordingly.
Data
Human Data
Postmarketing data indicate that B-cell
lymphocytopenia generally lasting less than six
months can occur in infants exposed to rituximab
in-utero. Rituximab was detected postnatally in
the serum of infants exposed in-utero.
Animal Data
RITUXAN HYCELA for subcutaneous injection
contains rituximab and hyaluronidase human [see
Description (11)].

movement," but I promise you're
only one more standing-roomonly oral abstract session from the
top spot. During the education
program session "Indolent Lymphoma: How Understanding Disease Biology is Influencing Clinical
Decision-Making," Drs. Brad Kahl,
Jorge Castillo, and Catherine Thieblemont endeavored to describe
the current landscape of personalized treatment in a set of these diverse diseases. Their focus was on
the evolving intersection between
Rituximab Product:
* An embryo-fetal developmental toxicity study
was performed on pregnant cynomolgus
monkeys. Pregnant animals received rituximab
via the intravenous route during early gestation
(organogenesis period; post coitum days 20
through 50). Rituximab was administered as
loading doses on post coitum (PC) Days 20, 21
and 22, at 15, 37.5 or 75 mg/kg/day, and then
weekly on PC Days 29, 36, 43 and 50, at 20, 50
or 100 mg/kg/week. The 100 mg/kg/week dose
resulted in 80% of the exposure (based on AUC)
of those achieved following a dose of 2 grams in
humans. Rituximab crosses the monkey placenta.
Exposed offspring did not exhibit any teratogenic
effects but did have decreased lymphoid tissue
B cells.
* A subsequent pre-and postnatal reproductive
toxicity study in cynomolgus monkeys was
completed to assess developmental effects
including the recovery of B cells and immune
function in infants exposed to rituximab in utero.
Animals were treated with a loading dose of 0,
15, or 75 mg/kg every day for 3 days, followed
by weekly dosing with 0, 20, or 100 mg/kg dose.
Subsets of pregnant females were treated from
PC Day 20 through postpartum Day 78, PC
Day 76 through PC Day 134, and from PC Day
132 through delivery and postpartum Day 28.
Regardless of the timing of treatment, decreased
B cells and immunosuppression were noted in the
offspring of rituximab-treated pregnant animals.
The B-cell counts returned to normal levels,
and immunologic function was restored within
6 months postpartum.
Hyaluronidase Human:
* In an embryo-fetal study, mice have been dosed
daily by subcutaneous injection during the period
of organogenesis with hyaluronidase human at
dose levels up to 2,200,000 U/kg, which is > 2700
times higher than the human dose. The study
found no evidence of teratogenicity. Reduced fetal
weight and increased numbers of fetal resorptions
were observed, with no effects found at a daily
dose of 360,000 U/kg, which is > 450 times higher
than the human dose.
* In a peri-and post-natal reproduction study, mice
have been dosed daily by subcutaneous injection,
with hyaluronidase human from implantation
through lactation and weaning at dose levels up
to 1,100,000 U/kg, which is > 1,300 times higher
than the human dose. The study found no adverse
effects on sexual maturation, learning and memory
or fertility of the offspring.
8.2 Lactation
There are no data on the presence of rituximab
or hyaluronidase human in human milk, the effect
on the breastfed infant, or the effect on milk
production. However, rituximab is detected in the
milk of lactating cynomolgus monkeys, and IgG is
present in human milk. Since many drugs including
antibodies are present in human milk, advise a
lactating woman not to breastfeed during treatment
and for at least 6 months after the last dose of
RITUXAN HYCELA due to the potential for serious
adverse reactions in breastfed infants.
8.3 Females and Males of Reproductive
Potential
Rituximab-containing products can cause fetal
harm [see Use in Specific Populations (8.1)].
Contraception
Females
Females of childbearing potential should use
effective contraception while receiving RITUXAN
HYCELA and for 12 months following treatment.
8.4 Pediatric Use
The safety and effectiveness of RITUXAN HYCELA
in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of subjects in the SABRINA,
MabEase, and SAWYER studies, 37% were 65
and over, while 10% were 75 and over. No overall
differences in safety or effectiveness were observed
between these subjects and younger subjects, and
other reported clinical experience has not identified
differences in responses between the elderly and
younger patients, but greater sensitivity of some
older individuals cannot be ruled out.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Severe Mucocutaneous Reactions
Advise patients to contact their healthcare provider
immediately for symptoms of severe mucocutaneous
reactions, including painful sores or ulcers on the lips
or mouth, blisters, peeling skin, rash, and pustules
[see Warnings and Precautions (5.1)].

recent biologic advances and individualized patient care.
Dr. Kahl, focused on follicular
lymphoma (FL). He reviewed how
the heterogeneity of FL and the excellent outcomes experienced by
many patients combine to make
risk estimation for individual patients at diagnosis challenging. He
discussed the limitations in tools
currently available to inform clinicians in the "goldilocks approach"
currently used to select initial treatment, striving to be "not too cold

Hepatitis B Virus Reactivation
Advise patients to contact their healthcare provider
immediately for symptoms of hepatitis including
worsening fatigue or yellow discoloration of skin or
eyes [see Warnings and Precautions (5.2)].
Progressive Multifocal Leukoencephalopathy (PML)
Advise patients to contact their healthcare provider
immediately for signs and symptoms of PML,
including new or changes in neurological symptoms
such as confusion, dizziness or loss of balance,
difficulty talking or walking, decreased strength
or weakness on one side of the body, or vision
problems [see Warnings and Precautions (5.3)].
Hypersensitivity and Other Administration Reactions
Inform patients about the signs and symptoms of
hypersensitivity and administration-related reactions.
Advise patients to contact their healthcare provider
immediately to report symptoms of administrationrelated reactions including dizziness, nausea, chills,
fever, vomiting, diarrhea, urticaria, angioedema,
breathing problems, or chest pain [see Warnings
and Precautions (5.4)].
Tumor Lysis Syndrome (TLS)
Advise patients to contact their healthcare provider
immediately for signs and symptoms of tumor lysis
syndrome such as nausea, vomiting, diarrhea, and
lethargy [see Warnings and Precautions (5.5)].
Infections
Advise patients to contact their healthcare provider
immediately for signs and symptoms of infections
including fever, cold symptoms (e.g., rhinorrhea or
laryngitis), flu symptoms (e.g., cough, fatigue, body
aches), earache or headache, dysuria, cold sores,
and painful wounds with erythema [see Warnings
and Precautions (5.6)].
Cardiovascular Adverse Reactions
Advise patients of the risk of cardiovascular
adverse reactions, including ventricular fibrillation,
myocardial infarction, and cardiogenic shock.
Advise patients to contact their healthcare provider
immediately to report chest pain and irregular
heartbeats [see Warnings and Precautions (5.7)].
Renal Toxicity
Advise patients of the risk of renal toxicity. Inform
patients of the need for healthcare providers
to monitor kidney function [see Warnings and
Precautions (5.8)].
Bowel Obstruction and Perforation
Advise patients to contact their healthcare provider
immediately for sign and symptoms of bowel
obstruction and perforation, including severe
abdominal pain or repeated vomiting [see Warnings
and Precautions (5.9)].
Embryo-Fetal Toxicity
Advise a pregnant woman of the potential risk
to a fetus. Advise female patients that rituximab
containing products can cause fetal harm if taken
during pregnancy and to use effective contraception
during treatment with RITUXAN HYCELA and for
at least 12 months after the last dose of RITUXAN
HYCELA. Advise patients to inform their healthcare
provider of a known or suspected pregnancy [see
Warnings and Precautions (5.11) and Use in Specific
Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment
with RITUXAN HYCELA and for 6 months after the
last dose [see Use in Specific Populations (8.2)].

RITUXAN HYCELA™
[rituximab and
hyaluronidase human]
Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco,
CA 94080-4990
U.S. License No.: 1048

RITUXAN HYCELA™ is
a trademark of Biogen.
Jointly marketed by: Biogen
and Genentech USA, Inc.
©2017 Biogen and
Genentech USA, Inc.
RSC/062017/0061

06/17

and not too hot". He emphasized
the importance of maintaining response for greater than 24 months
(POD24) following chemoimmunotherapy as likely the most powerful current indicator of disease
behavior, and ultimately, survival
endpoints. Observations from multiple large data sets that the 20 percent of patients who don't achieve a
POD24 have a five-year overall survival lower than 50 percent while
the remaining 80 percent have a
survival approaching disease-free
controls, highlight the power of
this endpoint to identify the true
patients representing "an unmet
need." Unfortunately, as a posttreatment factor, the POD24 is unable to inform upfront therapy.
Acknowledging the difficulties
that have come from attempts to
augment historical risk stratification tools with biologically based
approaches, Dr. Kahl highlighted
a few encouraging recent developments. These include a recently
described 26 gene expression tool
that appears to stratify disease behavior, so keep your eyes on Lancet
Oncology where this will be published soon. He also reviewed two
clinicogenetic risk models, the m7FLIPI and POD24-PI, that integrate
the mutation status of a set of genes
with the FLIPI.
Dr. Castillo then provided an update on the diagnosis, evaluation,
and initial management of Waldenström macroglobulinemia, describing the impact of new insights into
disease biology and targeted therapeutic approaches. He stated that
"the identification of recurrent mutations in the MYD88 and CXCR4
genes in patients with WM represents clear opportunities to personalize treatment approaches in these
patients." Dr. Castillo presented an
algorithmic approach to treatment
in newly diagnosed patients based
on MYD88 and CXCR4 mutation
status as well as pertinent clinical
features. He emphasized the role
for ibrutinib in MYD88-mutated
patients given its virtually 100 percent response rate in patients with
isolated MYD88 mutations and 80
percent response rate in those with
MYD88 and CXCR4 mutations. He
did caution that responses in the
latter group were slower and less
durable and recommended against
ibrutinib use in MYD88 wild-type
patients given its limited efficacy.
Dr. Castillo sees even more innovation on the horizon, "Overall, I consider these developments just the
first steps. Ongoing clinical trials
»» LYMPHOMA Page A-20

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 3