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AMERICAN SOCIETY of HEMATOLOGY
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53rd ASH
Annual Meeting
and Exposition
M E ETI N G DATE S:
December 10-13, 2011
December 10-13, 2011
San Diego Convention Center U San Diego, CA
E X P OS ITI ON DATE S:
December 10-12, 2011
FR I DAY SATE LLITE SYM P OS IA:
December 9, 2011
4Please note that this year’s
meeting will take place the second
weekend in December.
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BIOMED, and BIOSIS.
Hodgkin lymphoma—
≈10% refractory rates1
≈ 30% relapse rates after complete response1
≈50% of transplants fail2,3
Long-term health complications4
Reduced survival in some patients initially cured5
NoGoodCancer.com
References
1. Quddus F, Armitage JO. Salvage therapy for Hodgkin’s lymphoma. Cancer J. 2009;15(2):161-163.
2. Sureda A, Constans M, Iriondo A, et al; The Grupo Español de Linfomas/Transplante Autólogo de Médula Osea (GEL/TAMO) Cooperative Group. Prognostic factors affecting long-term outcome
after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16(4):625-633.
3. Majhail NS, Weisdorf DJ, Defor TE, et al. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma. Biol Blood Marrow Transplant.
2006;12(10):1065-1072.
4. Aleman BMP, van den Belt-Dusebout AW, Klokman WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE. Long-term cause-specific mortality of patients treated for Hodgkin’s disease.
J Clin Oncol. 2003;21(18):3431-3439.
5. Martinez C, Canals C, Alessandrino E, et al; Lymphoma Working Party of the EBMT. Relapse of Hodgkin’s lymphoma (HL) after autologous stem cell transplantation (ASCT): prognostic factors in
462 patients registered in the database of the EBMT. J Clin Oncol. 2010;28(15)(suppl):8060.
Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc.
© 2011 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved
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Bayer and the Bayer Cross are trademarks of Bayer.
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© 2010 Bayer Schering Pharma AG. All rights reserved.
Bayer and the Bayer Cross are trademarks of Bayer.
G.PH.SM.Hem.2010-08-03.0180
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®
53rd ASH Annual Meeting and Exposition
December 10-13, 2011 U San Diego Convention Center U San Diego, CA
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Important Safety Information
Warnings and Precautions
FOLOTYN may suppress bone marrow function, manifested
by thrombocytopenia, neutropenia, and anemia. Monitor
blood counts and omit or modify dose for hematologic
toxicities.
Mucositis may occur. If ≥Grade 2 mucositis is observed,
omit or modify dose. Patients should be instructed to take
folic acid and receive vitamin B12 to potentially reduce
treatment-related hematological toxicity and mucositis.
H
W
D
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H
U
SUDODW
Fatal dermatologic reactions may occur. Dermatologic
reactions may be progressive and increase in severity with
further treatment. Patients with dermatologic reactions
should be monitored closely, and if severe, FOLOTYN
should be withheld or discontinued.
Tumor lysis syndrome may occur. Monitor patients and
treat if needed.
FOLOTYN can cause fetal harm. Women should avoid
becoming pregnant while being treated with FOLOTYN
and pregnant women should be informed of the
potential harm to the fetus.
Use caution and monitor patients when administering
FOLOTYN to patients with moderate to severe renal
function impairment.
Elevated liver function test abnormalities may
occur and require monitoring. If liver function test
abnormalities are ≥Grade 3, omit or modify dose.
11080 CirclePoint Road, Suite 200
Westminster, CO 80020
www.allos.com
©2011 Allos Therapeutics, Inc.
5/11
Printed in USA
FOL-1183-11
Please see accompanying brief
s
FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell
lymphoma. The indication for FOLOTYN is based on overall response rate. Clinical benefit such
as improvement in progression-free survival or overall survival has not been demonstrated.
Demonstrated
response in relapsed
or refractory PTCL1
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Adverse Reactions
The most common adverse reactions were mucositis
(70%), thrombocytopenia (41%), nausea (40%), and
fatigue (36%). The most common serious adverse events
were pyrexia, mucositis, sepsis, febrile neutropenia,
dehydration, dyspnea, and thrombocytopenia.
Use in Specific Patient Populations
Nursing mothers should be advised to discontinue nursing
or the drug, taking into consideration the importance of
the drug to the mother.
Drug Interactions
Co-administration of drugs subject to renal clearance
(e.g., probenecid, NSAIDs, and trimethoprim/
sulfamethoxazole) may result in delayed renal clearance.
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Reference: 1. FOLOTYN Prescribing Information.
Allos Therapeutics, Inc., 2011.
Please see FOLOTYN Full Prescribing Information.
*Per independent central review
summary of Prescribing Information.
www.FOLOTYN.com
Brief summary of Full Prescribing Information for FOLOTYN®
(pralatrexate injection)—Please consult Full Prescribing
Information.
N=111
Total
INDICATIONS AND USAGE
FOLOTYN is indicated for the treatment of patients with relapsed or refractory
peripheral T-cell lymphoma (PTCL). This indication is based on overall
response rate. Clinical benefit such as improvement in progression-free
survival or overall survival has not been demonstrated.
WARNINGS AND PRECAUTIONS
Bone Marrow Suppression
FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia,
neutropenia, and anemia. Dose modifications are based on ANC and platelet
count prior to each dose.
Mucositis
Treatment with FOLOTYN may cause mucositis. If ≥Grade 2 mucositis is
observed, omit dose and follow guidelines in Table 1.
Dermatologic Reactions
FOLOTYN has been associated with severe dermatologic reactions, which may
result in death. These dermatologic reactions have been reported in clinical
studies (14/663 patients [2.1%]) and post marketing experience, and have
included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN).
These reactions may be progressive and increase in severity with further
treatment, and may involve skin and subcutaneous sites of known lymphoma.
Patients with dermatologic reactions should be monitored closely, and if severe,
FOLOTYN should be withheld or discontinued.
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported in patients with lymphoma receiving
FOLOTYN. Patients receiving FOLOTYN should be monitored closely and treated
for complications.
Folic Acid and Vitamin B12 Supplementation
Patients should be instructed to take folic acid and receive vitamin B12 to
potentially reduce treatment-related hematological toxicity and mucositis.
Pregnancy Category D
FOLOTYN can cause fetal harm when administered to a pregnant woman.
FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.
Decreased Renal Function
Although FOLOTYN has not been formally tested in patients with renal
impairment, caution is advised when administering FOLOTYN to patients
with moderate to severe impairment. Monitor patients for renal function and
systemic toxicity due to increased drug exposure.
Elevated Liver Enzymes
Liver function test abnormalities have been observed after FOLOTYN
administration. Persistent liver function test abnormalities may be indicators
of liver toxicity and require dose modification. Monitor patients for liver
function.
ADVERSE REACTIONS
The most common adverse reactions observed in patients with peripheral t-cell
lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia,
nausea, and fatigue.
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions,
adverse reaction rates observed in the clinical studies of a drug cannot be
directly compared to rates in the clinical studies of another drug and may not
reflect the rates observed in practice.
The safety of FOLOTYN was evaluated in 111 PTCL patients in a single-arm
clinical study in which patients received a starting dose of 30 mg/m2 once weekly
for 6 weeks in 7-week cycles. The median duration of treatment was 70 days
(range 1-540 days).
Most Frequent Adverse Reactions
Table 4 summarizes the most frequent adverse reactions, regardless of
causality, using the National Cancer Institute-Common Terminology Criteria for
Adverse Events (NCI CTCAE, version 3.0).
Table 4 Adverse Reactions Occurring in PTCL Patients
(Incidence ≥10% of patients)
N=111
Total
Preferred Term
Grade 3
Grade 4
N
%
N
%
N
%
Any Adverse Event
111
100
48
43
34
31
Mucositisa
78
70
19
17
4
4
Thrombocytopeniab
45
41
15
14
21
19b
Nausea
44
40
4
4
0
0
Fatigue
40
36
5
5
2
2
Anemia
38
34
17
15
2
2
Constipation
37
33
0
0
0
0
Pyrexia
36
32
1
1
1
1
Edema
33
30
1
1
0
0
Cough
31
28
1
1
0
0
Epistaxis
29
26
0
0
0
0
Vomiting
28
25
2
2
0
0
Neutropenia
27
24
14
13
8
7
Diarrhea
23
21
2
2
0
0
Dyspnea
21
19
8
7
0
0
Anorexia
17
15
3
3
0
0
a
b
c
Grade 3
Grade 4
Preferred Term
N
%
N
%
N
Hypokalemia
17
15
4
4
1
%
1
Rash
17
15
0
0
0
0
Pruritus
16
14
2
2
0
0
Pharyngolaryngeal
pain
15
14
1
1
0
0
Liver function test
abnormalc
14
13
6
5
0
0
Abdominal pain
13
12
4
4
0
0
Pain in extremity
13
12
0
0
0
0
Back pain
12
11
3
3
0
0
Leukopenia
12
11
3
3
4
4
Night sweats
12
11
0
0
0
0
Asthenia
11
10
1
1
0
0
Tachycardia
11
10
0
0
0
0
Upper respiratory
tract infection
11
10
1
1
0
0
Stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts
Five patients with platelets <10,000/µL
Alanine aminotransferase, aspartate aminotransferase, and transaminases increased
Serious Adverse Events
Forty-four percent of patients (n=49) experienced a serious adverse event while
on study or within 30 days after their last dose of FOLOTYN. The most common
serious adverse events (>3%), regardless of causality, were pyrexia, mucositis,
sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.
One death from cardiopulmonary arrest in a patient with mucositis and
febrile neutropenia was reported in this trial. Deaths from mucositis, febrile
neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on
all FOLOTYN trials at doses ranging from 30 to 325 mg/m2.
Discontinuations
Twenty-three percent of patients (n=25) discontinued treatment with FOLOTYN
due to adverse reactions. The adverse reactions reported most frequently as
the reason for discontinuation of treatment were mucositis (6%, n=7) and
thrombocytopenia (5%, n=5).
Dose Modifications
The target dose of FOLOTYN was 30 mg/m2 once weekly for 6 weeks in 7-week
cycles. The majority of patients (69%, n=77) remained at the target dose for
the duration of treatment. Overall, 85% of scheduled doses were administered.
Post Marketing Experience
Toxic epidermal necrolysis has been identified during post approval use of
FOLOTYN. 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 (see Warnings and
Precautions).
DRUG INTERACTIONS
In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or
inducer of CYP450 isoenzymes and has low potential for drug-drug interactions
at CYP450 isoenzymes. No formal clinical assessments of pharmacokinetic
drug-drug interactions between FOLOTYN and other drugs have been
conducted. The effect of co-administration of the uricosuric drug probenecid
on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical
study. Co-administration of increasing doses of probenecid resulted in delayed
clearance of pralatrexate and a commensurate increase in exposure.
Due to the contribution of renal excretion (approximately 34%) to the overall
clearance of pralatrexate, concomitant administration of drugs that are subject
to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole)
may result in delayed clearance of pralatrexate.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D (see Warnings and Precautions).
FOLOTYN can cause fetal harm when administered to a pregnant woman.
Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/
day (0.36 mg/m2/day or about 1.2% of the clinical dose on a mg/m2 basis)
given on gestation days 7 through 20. Treatment with pralatrexate caused
a dose-dependent decrease in fetal viability manifested as an increase in
late, early, and total resorptions. There was also a dose-dependent increase
in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/
m2/day) or greater given on gestation days 8 through 21 also caused abortion
and fetal lethality. This toxicity manifested as early and total resorptions,
post-implantation loss, and a decrease in the total number of live fetuses.
If this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the fetus.
Nursing Mothers
It is not known whether pralatrexate is excreted in human milk. Because many
drugs are excreted in human milk, and because of the potential for serious
adverse reactions in nursing infants from this drug, a decision should be made
whether to discontinue nursing or to discontinue FOLOTYN, taking into account
the importance of FOLOTYN to the mother.
Pediatric Use
Pediatric patients were not included in clinical studies with FOLOTYN. The safety
and effectiveness of FOLOTYN in pediatric patients have not been established.
Geriatric Use
In the PTCL efficacy study, 36% of patients (n=40) were 65 years of age and
over. No overall differences in efficacy and safety were observed in patients
based on age (<65 years compared with ≥65 years).
No dosage adjustment is required in elderly patients with normal renal function.
Hepatic Impairment
Formal studies have not been performed with FOLOTYN in patients with hepatic
impairment. Patients with the following laboratory values were excluded from
the pralatrexate lymphoma clinical trials: total bilirubin >1.5 mg/dL; aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × upper limit
of normal (ULN); and AST or ALT >5 × ULN if documented hepatic involvement
with lymphoma.
Renal Impairment
See Warnings and Precautions.
OVERDOSAGE
No specific information is available on the treatment of overdosage of FOLOTYN.
If an overdose occurs, general supportive measures should be instituted as
deemed necessary by the treating physician. Based on FOLOTYN’S mechanism
of action the prompt administration of leucovorin should be considered.
PATIENT COUNSELING INFORMATION
See FDA-approved Patient Package Insert.
Patients should be instructed to read the Patient Package Insert carefully.
DOSAGE AND ADMINISTRATION
FOLOTYN should be administered under the supervision of a qualified physician
experienced in the use of antineoplastic agents. Appropriate management
of complications is possible only when adequate diagnostic and treatment
facilities are readily available.
Peripheral T-cell Lymphoma
The recommended dose of FOLOTYN is 30 mg/m2 administered as an
intravenous (IV) push over 3-5 minutes via the side port of a free-flowing 0.9%
Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles
until progressive disease or unacceptable toxicity.
Vitamin Supplementation
Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis.
Folic acid should be initiated during the 10-day period preceding the first dose
of FOLOTYN, and dosing should continue during the full course of therapy and
for 30 days after the last dose of FOLOTYN. Patients should also receive a
vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to
the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent
vitamin B12 injections may be given the same day as treatment with FOLOTYN
(see Warnings and Precautions).
Monitoring and Dose Modifications
Management of severe or intolerable adverse reactions may require dose
omission, reduction, or interruption of FOLOTYN therapy.
Monitoring
Complete blood cell counts and severity of mucositis should be monitored
weekly. Serum chemistry tests, including renal and hepatic function, should
be performed prior to the start of the first and fourth dose of a given cycle.
Dose Modification Recommendations
Prior to administering any dose of FOLOTYN:
• Mucositis should be ≤Grade 1.
• Platelet count should be ≥100,000/µL for first dose and ≥50,000/µL for all
subsequent doses.
• Absolute neutrophil count (ANC) should be ≥1,000/µL.
Doses may be omitted or reduced based on patient tolerance. Omitted doses
will not be made up at the end of the cycle; once a dose reduction occurs for
toxicity, do not re-escalate. For dose modifications and omissions, use the
guidelines in Tables 1, 2, and 3.
Table 1 FOLOTYN Dose Modifications for Mucositis
a
Mucositis Gradea on
Day of Treatment
Action
Dose upon Recovery
to ≤Grade 1
Grade 2
Omit dose
Continue prior dose
Grade 2 recurrence
Omit dose
20 mg/m2
Grade 3
Omit dose
20 mg/m2
Grade 4
Stop therapy
Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI
CTCAE, Version 3.0)
Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities
Blood Count on
Day of Treatment
Platelet
<50,000/µL
Duration of
Toxicity
1 week
Action
Omit dose
Dose upon Restart
Continue prior dose
2 weeks
Omit dose
20 mg/m2
3 weeks
Stop therapy
ANC 500-1,000/µL
1 week
and no fever
1 week
ANC 500-1,000/µL
with fever
2 weeks or
or
recurrence
ANC
<500/µL
3 weeks or
2nd recurrence
Omit dose
Continue prior dose
Omit dose, give
G-CSF or GM-CSF
support
Omit dose, give
G-CSF or GM-CSF
support
Continue prior
dose with G-CSF or
GM-CSF support
20 mg/m2 with
G-CSF or GM-CSF
support
Stop therapy
Table 3 FOLOTYN Dose Modifications for All Other
Treatment-related Toxicities
a
Toxicity Gradea on Day
of Treatment
Action
Dose upon Recovery to
≤Grade 2
Grade 3
Omit dose
20 mg/m2
Grade 4
Stop therapy
Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI
CTCAE, Version 3.0)
Manufactured for:
Allos Therapeutics, Inc.
Westminster, CO 80020
1-888-ALLOS88 (1-888-255-6788)
FOLOTYN, ALLOS, and the mobius triangle symbol are
all registered trademarks of Allos Therapeutics, Inc.
U.S. Patent: 6,028,071 and 7,622,470
Rev.3: January 2011
© 2011 Allos Therapeutics, Inc. All rights reserved.
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Author guide
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Immunobiology encompasses a wide spectrum of research, but
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scope of Blood. Papers on the immune response to specific microbioBLOOD, 18 AUGUST 2011 䡠 VOLUME 118, NUMBER 7
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xxi
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xxii
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BLOOD, 18 AUGUST 2011 䡠 VOLUME 118, NUMBER 7
Check out
ASH’s VIDEO LIBRARY
for Useful Teaching Tools
ASH offers a number of FREE videos
that are perfect for students.
ASH’s video library includes films on a variety of topics including:
Cancer Cells vs. Healthy Cells
Hereditary Spherocytosis
How Lymphoma Develops
How a Clot Becomes a Pulmonary Embolism
The Components of Blood
The Problem With Sickled Cells
The Role of Proteins in Blood Clotting
The Role of Red Blood Cells in Anemia
Von Willebrand Factor and ADAMTS13
Additionally, this library includes short videos about patients dealing with
various hematologic disorders, excerpted from the film “Blood Detectives.”
1772
BLOOD, 18 AUGUST 2011 䡠 VOLUME 118, NUMBER 7
SEKULOVIC et al
Tert⫺/⫺ HSCs in the absence of an additional stimulation of HSC
self-renewal divisions.
The absence of telomere loss by serially transplanted Tert⫺/⫺
HSCs may be explained by the possible existence of telomerelength-independent barriers, alternative mechanisms for lengthening telomeres in dividing HSCs, and insufficient HSC turnover
afterwhole bm transplantation. HSC replicative potential may be
limited by more than just the length of their telomeres, as the
expression of the catalytic component of telomerase was eventually
able to prevent telomere shortening in HSCs subjected to more
proliferation than that stimulated by 3 serial transplant cycles, but
was not sufficient to sustain their transplant capacity.18 Thus, it
cannot be excluded that HSC telomeres may stay long because of a
telomerase-independent mechanism active in HSCs. Telomeric
DNA may also be generated through recombination events, a
mechanism known as alternative lengthening of telomeres (ALT)36
and shown to occur in embryonic stem cells and during early
development.37 Recombination-based telomere elongation has also
been identified in human tumors, immortalized human cell lines,
telomerase-null mouse cell lines and late generation telomerasenull mice,38-40 and possibly occurs in other stem cells of Mus
musculus (with, on average, very long telomeres) as well. Finally, it
was recently shown that HSCs with the highest self-renewal
capacity are maintained in a dormant state with their stem cell
potential being subject to reversible activation on injury.41 Accordingly, it might be anticipated that the regeneration of hematopoiesis
that is stimulated to occur in transplanted irradiated mice would
involve a rapid induction and short-lived induction of HSC
turnover, insufficient to affect their telomere length. Another
explanation for the absence of detectable telomere shortening in
WT HSCs in spite of their extensively stimulatation to self-renew is
a potential up-regulation of endogenous telomerase levels by genes
active in HSCs, in line with recent reports demonstrating telomere
maintenance and elongation in induced pluripotent stem (iPS)
cells.42 In the current study, we detected no significant difference in
the telomere length in the progeny of GFP- and NA10hdtransduced WT BM cells cultured for up to 16-days after transduction (total of 20 days in culture) or transplanted immediately after
transduction into primary recipients. Moreover, preliminary affymetrix expression analysis showed no difference in telomerase
expression of nontransduced (fresh) and NUP98-HOXA10hdtransduced highly purified HSCs43 (data not shown). Thus our data
argue that NA10hd does not trigger up-regulation of endogenous
telomerase levels in HSCs.
The fact that our findings are in disagreement with previous
studies may also be explained in part by differences in the study
designs and methodologies used for telomere length measurements. Allsopp et al used Q-FISH to measure telomere lengths in
LSK cells and Southern blot analysis for whole BM cells; whereas,
we inferred effects on HSCs from measurements applied to their
granulocyte progeny and used flow-FISH for average telomere
length measurements at the single cell level. Q-FISH requires cells
to be stimulated in culture, arrested in metaphase and mounted onto
slides44 to enable telomere lengths of individual chromosomes to
be made on a limited number of cells. Accordingly, it is less
quantitative than Flow-FISH. The more precise measurements
possible with Flow-FISH indicate that self-renewal stress imposed
by serial transplantation even in the presence of stimulation by
NA10hd and in the absence of Tert does not result in significant
telomere length erosion. Nevertheless, highly significant telomere
length reduction (⬃ 10 kb) was apparent in the absence of Tert after
the forced stimulation of prolonged self-renewal divisions in vitro
and in vivo.
Consistent with the previous data, we did not observe any
difference in the frequency or competitive regenerative activity of
WT and early (first) generation Tert⫺/⫺ HSCs. However, we noted
levels of ␥-H2AX expression in the LSK population of later
(second) generation Tert⫺/⫺ BM cells, as well as after extensive
self-renewal induced by stimulating primitive NA10hd-transduced
Tert⫺/⫺ hematopoietic cell proliferation. Interestingly, this occurred
in cells that also showed an acquired deficiency in reconstituting
ability post transplantation and self-renewal ability in vitro. Indeed,
the appearance of this evidence of accumulating DNA damage in
primitive Tert⫺/⫺ hematopoietic cells paralleled their reduced
functional activity. Similar consequences of DNA damage accumulating in late generation aging Tert⫺/⫺ as well as WT HSCs has also
been reported.25
Recent evidence showing that TERT protein can have a
physiologic role independent of its canonical function in maintaining telomere homeostasis, suggests a broader involvement in the
control of cellular transformation, proliferation, stem cell biology,
survival and chromatin regulation.27-29,45-49 Furthermore, along
with recent findings of others,27-29 we showed that telomerase may
function as a regulator of the HSC self-renewal process, as our
results revealed significant (⬃ 7-fold) decrease in capacity of
Tert⫺/⫺ HSCs to expand in vitro in response to NA10hd stimulation,
relative to their WT counterparts. However, it is important to note
the lack of deleterious effects seen on the greatly expanded WT
HSC populations generated in the presence of intracellular NA10hd
in relatively short term (6-day) cultures. This included lack of
effects on both telomere homeostasis and overall genomic integrity.
Although the current findings cannot be safely extrapolated to
human HSCs, as inbred mice possess significantly longer telomeres
than humans,50 they do serve to underscore the importance of
elucidating the mechanisms linking the 2 roles of telomerase, in
telomere maintenance and in preserving HSC function, which are
likely to be relevant to the rational development of strategies for the
effective treatment of many patients with BM failure syndromes
(ie, dyskeratosis congenita and/or aplastic anemia) or conversely
with leukemia where this link may be uncoupled.
Acknowledgments
The authors acknowledge the expert technical assistance of Patty
Rosten, Courteney Lai, members of the flow core of the Terry Fox
Laboratory, Andy Johnson of the UBC shared FACS facility and
staff of the animal facilities of the Biomedical Research Center and
British Columbia Cancer Agency Research Center. The authors
thank Lea Harrington for providing the Tert⫺/⫺ mouse strain.
This work was supported by funds from a Canadian Institutes of
Health Research (CIHR) Team Grant in Stem Cell Expansion; a
CIHR Team Grant in Bone Marrow; CIHR operating grant
MOP82382; National Institutes of Health grant HL065430; the
Canadian Stem Cell Network; and the group grant from the Terry
Fox Foundation. Work in the laboratory of P.M.L. is supported by
grants from CIHR (MOP38075 and GMH79042).
Authorship
Contribution: S.S. and V.G. designed and performed the research
and analyzed the data; I.V. performed and analyzed flow-FISH
ADVATE
[Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method]
Brief Summary of Prescribing Information: Please see package insert for full prescribing information.
INDICATIONS AND USAGE
Clinical Trial Experience
Control and Prevention of Bleeding Episodes
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in clinical trials of another drug and may not
reflect the rates observed in clinical practice.
ADVATE is an antihemophilic factor (recombinant) indicated for control
and prevention of bleeding episodes in adults and children with
hemophilia A.
Perioperative Management
ADVATE is indicated in the perioperative management in adults and
children with hemophilia A.
ADVATE is not indicated for the treatment of von Willebrand’s disease.
CONTRAINDICATIONS
Known anaphylaxis to mouse or hamster protein or other constituents
of the product.
WARNINGS AND PRECAUTIONS
General
The clinical response to ADVATE may vary. If bleeding is not controlled
with the recommended dose, the plasma level of factor VIII should be
determined and a sufficient dose of ADVATE should be administered to
achieve a satisfactory clinical response. If the patient’s plasma factor
VIII level fails to increase as expected or if bleeding is not controlled
after the expected dose, the presence of an inhibitor (neutralizing
antibodies) should be suspected and appropriate testing performed.
Anaphylaxis and Hypersensitivity Reactions
Allergic-type hypersensitivity reactions, including anaphylaxis, are
possible and have been reported with ADVATE. Symptoms have
manifested as dizziness, paresthesias, rash, flushing, face swelling,
urticaria, dyspnea, and pruritis.
ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG;
maximum of 0.1 ng/IU ADVATE) and hamster (CHO) proteins (maximum
of 1.5 ng/IU ADVATE). Patients treated with this product may develop
hypersensitivity to these non-human mammalian proteins.
Discontinue ADVATE if hypersensitivity symptoms occur and administer
appropriate emergency treatment.
Neutralizing Antibodies
Patients treated with AHF products should be carefully monitored
for the development of factor VIII inhibitors by appropriate clinical
observations and laboratory tests. Inhibitors have been reported following
administration of ADVATE predominantly in previously untreated patients
(PUPs) and previously minimally treated patients (MTPs). If expected
plasma factor VIII activity levels are not attained, or if bleeding is not
controlled with an expected dose, an assay that measures factor VIII
inhibitor concentration should be performed.
Monitoring Laboratory Tests
s -ONITOR PLASMA FACTOR 6))) ACTIVITY LEVELS BY THE ONESTAGE CLOTTING
assay to confirm the adequate factor VIII levels have been achieved
and maintained, when clinically indicated.
s -ONITOR FOR DEVELOPMENT OF FACTOR 6))) INHIBITORS 0ERFORM THE
Bethesda assay to determine if factor VIII inhibitor is present. If
expected factor VIII activity plasma levels are not attained, or if
bleeding is not controlled with the expected dose of ADVATE. Use
Bethesda Units (BU) to titer inhibitors.
– If the inhibitor is less than 10 BU per mL, the administration of
additional antihemophilic factor concentrate may neutralize the
inhibitor, and may permit an appropriate hemostatic response.
– Adequate hemostasis may not be achieved if inhibitor titers are
above 10 BU per mL. The inhibitor titer may rise following ADVATE
infusion as a result of an anamnestic response to factor VIII. The
treatment or prevention of bleeding in such patients requires the
use of alternative therapeutic approaches and agents.
ADVERSE REACTIONS
The most serious adverse drug reactions (ADRs) seen with ADVATE are
hypersensitivity reactions and the development of high-titer inhibitors
necessitating alternative treatments to factor VIII.
The most common ADRs observed in clinical trials (frequency > 2% of
subjects) were: factor VIII inhibitor formation (observed predominantly
in PUPs) and headache (6.1)
Table 1. Adverse Events Reported by > 5%
Treated of Study Subjectsa
MedDRAb
System Organ Class
Number
of
Subjects
There were 2,507 adverse events (AEs) reported in 215 subjects. None
of the subjects withdrew from the studies due to adverse events. There
were no deaths. Nineteen treated subjects reported no AEs during their
participation. The most common AEs (product-related and unrelated,
according to the investigator’s opinion) occurring in at least 5% of
subjects who received at least 1 ADVATE study infusion are shown in
Table 1.
General disorders and
administration site
conditions
The majority of the events in Table 1 appear to have been related to
trauma, intercurrent mild respiratory or gastrointestinal disease or
well-described complications of hemophilia.
Ear pain
17
14
6.0
16
12
5.1
Diarrhoea
48
34
14.5
Nausea
25
19
8.1
Vomiting
53
38
16.2
Influenza like
illness
17
13
5.6
Pain
21
18
7.7
Pyrexia
173
76
32.5
Ear infection
40
25
10.7
Influenza
22
18
7.7
Nasopharyngitis
121
62
26.5
Otitis media
12
12
5.1
Sinusitis
21
14
6.0
Upper respiratory
tract infection
49
31
13.2
Accident
41
20
8.5
Fall
22
17
7.3
Joint sprain
16
14
6.0
Limb injury
141
44
18.8
Procedural pain
16
12
5.1
Arthralgia
79
40
17.1
5.6
Infections and
infestations
Fifty-six ADRs were reported in 27 subjects. Nearly all (53/56) were
isolated events or occurred once in one subject with numerous
subsequent infusions without reoccurrence. The most common ADRs
with a frequency greater than or equal to 2% are shown in Table 2. Of
all ADRs, none were reported in neonates, 16 were reported in infants,
7 were reported in children, 8 were reported in adolescents and 25
were reported in adults.
Injury, poisoning and
procedural
complications
IMMUNOGENICITY
The development of factor VIII inhibitors with the use of ADVATE was
evaluated in clinical studies with pediatric PTPs (<6 years of age with
>50 factor VIII exposures) and PTPs (*10 years of age with >150
factor VIII exposures). Of 198 subjects who were treated for at least
10 exposure days or on study for a minimum of 120 days, 1 adult
developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after
26 exposure days.
Musculoskeletal and
connective tissue
disorders
In clinical studies that enrolled previously untreated subjects (defined
as having had up to 3 exposures to a factor VIII product at the time of
enrollment, 5 (20%) of 25 subjects who received ADVATE developed
inhibitors to FVIII. Four patients developed high titer ( > 5 BU) and
one patient developed low-titer inhibitors. Inhibitors were detected
at a median of 11 exposure days (range 7 to 13 exposure days)
to investigational product. Immunogenicity was also evaluated by
measuring the development of antibodies to heterologous proteins.
182 treated subjects were assessed for anti-CHO cell protein
antibodies. Of these patients, 3 showed an upward trend in antibody
titer over time and 4 showed sustained but transient elevations of
antibodies. 182 treated subjects were assessed for muIgGl protein
antibodies. Of these 10 showed an upward trend in anti-mu IgG
antibody titer over time and 2 showed sustained but transient
elevations of antibodies. Four subjects who demonstrated antibody
elevations reported isolated events of urticaria, pruritus, rash, and
slightly elevated eosinophil counts. All of these subjects had numerous
repeat exposures to the study product without recurrence of the events
and a causal relationship between the antibody findings and these
clinical events has not been established.
Of the 181 subjects who were treated and assessed for the presence
of anti-human von Willebrand factor (VWF) antibodies, none displayed
laboratory evidence indicative of a positive serologic response.
Respiratory, thoracic
and
mediastinal disorders
13
22
15
6.4
Headache
205
64
27.4
29.1
Cough
150
68
Nasal congestion
64
33
14.1
Pharyngolaryngeal
pain
50
32
13.7
Rhinorrhoea
40
25
10.7
Rash
23
19
8.1
a
Includes data from 234 treated subjects from 5 completed studies in PTPs, and 1 ongoing
study in PUPs as of 27 March 2006.
b
MedDRA version 8.1 was used.
c
This percent is calculated relative to 234, the total number of treated subjects.
Table 2. Summary of Most Common Adverse Drug Reactions
(ADRs)a with a Frequency * 2%
MedDRA
System Organ Class
MedDRA
Preferred Term
Number of
Patients
ADR Rate
(% Patients)b
Investigations
Anti-factor VIII
antibody positive
5c
2.14%
Nervous System
Disorders
Headache
5
2.14%
a
ADR = Adverse Drug Reaction = adverse events considered by the investigator to be at
least possibly related to administration of the product.
b
The ADVATE clinical program included 234 treated subjects from 5 completed studies in PTPs,
and 1 ongoing study in PUPs as of 27 March 2006.
c
All 5 ADRs occurred in (PUPs) from an ongoing clinical study, and all were for the
development of factor VIII inhibitors with a titer * 0.6 BU that were to be reported as a
serious AE.
The following adverse reactions have been identified during post
approval use of ADVATE. 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.
Table 3. Post-Marketing Experience
a
U.S. License No. 140
15
Skin and
subcutaneous tissue
disorders
Post Marketing Experience
U.S. Patent Numbers: 4,757,006; 5,198,349; 5,250,421; 5,733,873; 5,919,766;
4,891,319; 5,955,448; 6,313,102; 5,891,873; 6,034,080; 6,649,386; 5,854,021;
5,470,954; 6,555,391; 6,936,441; 7,094,574; 6,100,061; 6,475,725; 6,586,573;
7,087,723
Joint swelling
Pain in extremity
Nervous system
disorders
Eight weeks later, the inhibitor was no longer detectable, and in
vivoo recovery was normal at 1 and 3 hours after infusion of another
marketed recombinant factor VIII concentrate. This single event results
in a factor VIII inhibitor frequency in PTPs of 0.51% (95% CI of 0.03 and
2.91% for the risk of any factor VIII inhibitor development). No factor VIII
inhibitors were detected in the 53 treated pediatric PTPs.
Percentc
of
Subjects
Constipation
Gastrointestinal
disorders
Table 3 represents the post-marketing adverse reactions as MedDRA
Preferred Terms.
Baxter, Advate, Baxject and Recombinate are trademarks of Baxter International Inc.
Baxter, Advate and Baxject are registered in the U.S. Patent and Trademark Office.
Number
of
Events
Ear and labyrinth
disorders
ADVATE has been evaluated in five completed studies in previously
treated patients (PTPs) and one ongoing study in PUPs with severe to
moderately severe hemophilia A (factor VIII ) 2% of normal). A total
of 234 subjects have been treated with ADVATE as of March 2006.
Total exposure to ADVATE was 84,539,784 IU (derived from 47 lots) in
44,926 infusions. The median duration of participation per subject was
370.5 (range: 1 to 1,256) days and the median exposure to ADVATE per
subject was 128.0 (range: 1 to 598) days.
Among patients treated with ADVATE, cases of serious allergic/
hypersensitivity reactions including anaphylaxis have been reported
and factor VIII inhibitor formation (observed predominantly in PUPs).
To enroll in the confidential, industry-wide Patient Notification System, call
1-888-UPDATE-U (1-888-873-2838).
MedDRA
Preferred Term
Organ System [MedDRA Primary SOC]
Preferred Term
Immune system disorders
Anaphylactic reactiona
Hypersensitivitya
Blood and lymphatic system disorders
Factor VIII inhibition
General disorders and administration site conditions
Injection site reaction
Chills
Fatigue
Malaise
These reactions have been manifested by dizziness, paresthesias, rash, flushing, face
swelling, urticaria, and/or pruritus.
Baxter Healthcare Corporation
Westlake Village, CA 91362 USA
A
Printed in USA
Issued October 2009
LE-07-12904
In recombinant FVIII therapy...
...ADVATE is a complete package
• Convenience — broad selection of dosage strengths (250 to
• Pathogen safety — ADVATE is the only recombinant FVIII
3000 IU), short infusion time (up to 10 mL/min), BAXJECT II device,
3‡
and room temperature storage for up to 6 months
therapy that is full-length and free of blood-based additives.
Because no blood-derived components are added at any stage of
the manufacturing process, the potential risk of pathogens that
1-3
may be carried in blood-based additives is eliminated
• Commitment — patient support programs and healthcare
professional (HCP) collaboration to stay at the forefront of
hemophilia care
There have been no confirmed reports of viral transmissions with
recombinant FVIII therapies.1
†
In clinical studies, ADVATE therapy demonstrated a low inhibitor rate with an
overall incidence rate of 0.51% (95% confidence interval [CI], 0.03%-2.91%).5
‡
Up to 30ºC/86ºF, not to exceed printed expiration date. After storage at room
temperature, ADVATE must not be returned to the refrigerator. Two-year shelf life
if refrigerated.3,6
• Efficacy — 93% of bleeds managed with 1 or 2 infusions in a
3,4*
clinical study
*
Pivotal study of 108 PTPs with FVIII ⱕ2%.4
• Low rate of inhibitor development — in completed clinical
studies, ⬍1% of previously treated patients (PTPs) developed an inhibitor
3-5†
The development of inhibitors has been detected in patients
receiving ADVATE.
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free
Method] is indicated for control and prevention of bleeding episodes in
adults and children with hemophilia A and for perioperative management
in adults and children with hemophilia A.
ADVATE is not indicated for the treatment of von Willebrand’s disease.
Important Risk Information for ADVATE therapy
ADVATE is contraindicated in patients with known anaphylaxis to mouse
or hamster proteins or other constituents of the product.
• If expected plasma factor VIII levels are not attained, or if bleeding is not
controlled with an expected dose, test for the presence of inhibitors
• The most serious adverse reactions seen with ADVATE are
hypersensitivity reactions and the development of high-titer inhibitors
necessitating alternative treatments to factor VIII
• The most common adverse reactions observed in clinical trials (frequency
ⱖ2% of subjects) were factor VIII inhibitor formation (observed
predominantly in PUPs) and headache
• Allergic-type hypersensitivity reactions, including anaphylaxis, are
possible and have been reported with ADVATE. Symptoms have
manifested as dizziness, paresthesia, rash, flushing, face swelling,
urticaria, dyspnea, and pruritus. Discontinue use if hypersensitivity
symptoms occur and administer appropriate emergency treatment
• Patients treated with AHF products should be monitored for the
development of factor VIII inhibitors. Inhibitors have been reported
following administration of ADVATE predominantly in previously untreated
patients (PUPs) and previously minimally treated patients (MTPs)
Please see US brief summary of Prescribing Information on adjacent page.
Licenses and licensing conditions may vary from country to country; therefore, please always consult your local full Prescribing Information.
References: 1. The National Hemophilia Foundation. MASAC Recommendations Concerning the Treatment of Hemophilia and Other Bleeding Disorders. MASAC Document #190.
June 2009. 2. McCormack PL, Plosker GL. Octocog alfa, plasma/albumin-free method. Drugs. 2005;65:2613-2620. 3. ADVATE Prescribing Information. Westlake Village, CA:
Baxter Healthcare Corporation; October 2009. 4. Tarantino MD, Collins PW, Hay CRM, et al, and the rAHF-PFM Clinical Study Group. Clinical evaluation of an advanced category
antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia.
2004;10:428-437. 5. Shapiro A, Gruppo R, Pabinger I, et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six
clinical studies in patients with hemophilia A. Expert Opin Biol Ther. 2009;9:273-283. 6. Data on file. Westlake Village, CA: Baxter Healthcare Corporation.
Baxter, Advate, and Baxject are trademarks of Baxter International Inc.
© Copyright (January 2010), Baxter Healthcare Corporation. All rights reserved. Printed in the U.S.A. HYL5133