Download ITP: hematology`s Cosette from Les Mis ´erables

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with refractory multiple myeloma who have received
lenalidomide and bortezomib. Blood. 2013;121(11):
1961-1967. Prepublished on 2012/12/18 as DOI
10.1182/blood-2012-08-450742.
3. Kumar SK, Rajkumar SV, Dispenzieri A, et al.
Improved survival in multiple myeloma and the
impact of novel therapies. Blood. 2008;111(5):
2516-2520.
4. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of
progression and survival in multiple myeloma relapsing
after therapy with IMiDs and bortezomib: a multicenter
international myeloma working group study. Leukemia:
official journal of the Leukemia Society of America,
Leukemia Research Fund, UK. 2012;26(1):149-157.
Prepublished on 2011/07/30 as DOI 10.1038/
leu.2011.196.
5. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide
plus low-dose dexamethasone in myeloma refractory to
both bortezomib and lenalidomide: comparison of 2 dosing
strategies in dual-refractory disease. Blood. 2011;118(11):
2970-2975. Prepublished on 2011/06/22 as DOI blood2011-04-348896 [pii]10.1182/blood-2011-04-348896.
6. Lacy MQ, Hayman SR, Gertz MA, et al.
Pomalidomide (CC4047) plus low-dose dexamethasone
as therapy for relapsed multiple myeloma. J Clin
Oncol. 2009;27(30):5008-5014. Prepublished on
2009/09/02 as DOI JCO.2009.23.6802 [pii] 10.1200/
JCO.2009.23.6802.
7. Lacy MQ, Hayman SR, Gertz MA, et al.
Pomalidomide (CC4047) plus low dose dexamethasone
(Pom/dex) is active and well tolerated in lenalidomide
refractory multiple myeloma (MM). Leukemia. 2010;
24(11):1934-1939. Prepublished on 2010/09/10 as DOI
leu2010190 [pii]10.1038/leu.2010.190.
8. Leleu X, Attal M, Arnulf B, et al. High response rates
to pomalidomide and dexamethasone in patients with
refractory myeloma, final analysis of IFM 2009-02. ASH
Annual Meeting Abstracts. 2011;118(21):812.
9. Schuster SR, Kortuem KM, Zhu YX, et al. Cereblon
expression predicts response, progression free and overall
survival after pomalidomide and dexamethasone therapy in
multiple myeloma. ASH Annual Meeting Abstracts. 2012;
120(21):194.
10. Schey SA, Fields P, Bartlett JB, et al. Phase I study of
an immunomodulatory thalidomide analog, CC-4047, in
relapsed or refractory multiple myeloma. J Clin Oncol.
2004;22(16):3269-3276.
11. Streetly MJ, Gyertson K, Daniel Y, et al. Alternate
day pomalidomide retains anti-myeloma effect with
reduced adverse events and evidence of in vivo
immunomodulation. Br J Haematol. 2008;141(1):41-51.
12. Mark TM, Boyer A, Rossi AC, et al. ClaPD
(clarithromycin, pomalidomide, dexamethasone) therapy in
relapsed or refractory multiple myeloma. ASH Annual
Meeting Abstracts. 2012;120(21):77.
13. Lacy MQ, Kumar SK, LaPlant BR, et al.
Pomalidomide plus low-dose dexamethasone (Pom/Dex)
in relapsed myeloma: long term follow up and factors
predicing outcome in 345 patients. ASH Annual Meeting
Abstracts. 2012;120(21):201.
l l l CLINICAL TRIALS & OBSERVATIONS
Comment on Gudbrandsdottir et al, page 1976
ITP: hematology’s Cosette
from
Les Misérables
----------------------------------------------------------------------------------------------------V. Koneti Rao1
1
NATIONAL INSTITUTES OF HEALTH
In this issue of Blood, Gudbrandsdottir et al from Denmark report that in the
largest multicenter cohort to date comprising newly diagnosed adults with primary immune thrombocytopenia (ITP), addition of rituximab (RTX) to high-dose
dexamethasone (DEX) as first-line therapy yields higher sustained response rates.
I
f all the ailments covered under hematology
were characters in Victor Hugo’s novel Les
Misérables, ITP might rank as someone like
Cosette, who is considered by some literary
critics as an inconsequential character that
adorns the cover while serving as a mere prop
for imbibing parental and romantic love with
changing fortunes (see figure). After
recalling orphaned Cosette’s rescue by Jean
Valjean from wily innkeeper Thenardier and
their tumultuous journey through the course
of the novel with its historical backdrop of
revolutionary 19th-century France, one should
ponder the plight of a patient with ITP today.
German physician and poet Paul Gottlieb
Werlhof originally described ITP in a 16-year-
1928
old girl in 1735, more than 100 years before
Victor Hugo published his novel in 1862.
Others have astutely summarized the intriguing
history of ITP consisting of fascinating
observations and game-changing discoveries, an
approximate incidence of 6 per 100 000, and
good paradigms for its treatment following the
licensing of thrombopoietin mimetic agents.1,2
However, any patient with leukemias—
including chronic myeloid leukemia or even
the rarer acute promyelocytic leukemia—
presenting to hematology clinics in the
developed world today is likely to be offered
a more definitive and targeted treatment as
part of a randomized clinical trial in
a cooperative group than if he or she has
newly diagnosed ITP. There are no collaborative
clinical groups or registries for prospectively
diagnosing, observing (as spontaneous remissions
though rare in adults often occur in children), and
treating newly diagnosed ITP patients as part of
a clinical trial. Corticosteroids and intravenous
immunoglobulin introduced in 1951 and 1981,
respectively, are the mainstays of immediate
intervention. Splenectomy, in use for almost
100 years, is the only therapy with a curative
potential.3,4
Despite its widespread use for more than
a decade, because of lack of data from
randomized trials that can satisfy the US
Food and Drug Administration, rituximab
use in ITP has remained off-label in North
America.5 Evidence-based guidelines offer
a grade 2C recommendation for its use as
a reasonable second-line option.6 The premise
of using B-cell depletion therapy in ITP with
no consistent antibody to follow as a surrogate
marker of disease activity poses challenges.
Although the majority of B cells reside in
bone marrow and lymphoid tissue, RTX
mostly depletes circulating peripheral blood
B cells.7 Current regimens of RTX borrowed
from the lymphoma clinics may not be optimal
in depleting B cells from lymphoid tissues in
nonmalignant conditions. Long-lived plasma
cells, the source of most autoantibodies, do not
express CD20 and are not depleted by RTX.
Gudbrandsdottir and colleagues from
9 hospitals in Denmark report the largest
prospective, randomized cohort study to date
of newly diagnosed primary ITP patients with
a 4-year follow-up.8 Their study compares
concurrent use of RTX and high-dose DEX
(n 5 49) with DEX alone (n 5 52) as firstline therapy, with a median follow-up of 921
and 922 days, respectively. At 12-month
follow-up, sustained partial or complete
response was achieved in 53% in the RTX1
DEX group and 33% in DEX monotherapy
group (P , .05). By combining high-dose
DEX with RTX, this study avoided
immediate RTX “failures”—a result of
responses lagging by 6 to 8 weeks when RTX
is used as a single agent, often requiring
concurrent rescue medications. Based on their
study, the authors propose instead to use
RTX early in the course of the treatment of
ITP, even before splenectomy.
Similar studies to determine the feasibility
of recruitment, protocol adherence, and
blinding of a larger trial of RTX vs placebo to
evaluate role of adjuvant RTX in
BLOOD, 14 MARCH 2013 x VOLUME 121, NUMBER 11
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Cosette as depicted in a painting on the cover of the novel Les Misérables11
Table 1. Prices of all currently available medications used for ITP
Commonly used ITP drugs
Suggested warehouse
price per unit (US $)
Unit
Price for 1 month or
a single-course treatment
in an adult (US $)
Prednisone
20 mg (100 tablets)
$8 from Costco Pharmacy
$16
Dexamethasone
4 mg (40 tablets)
$13.20 from Costco Pharmacy
$52.80
IVIG (Gamunex 10%)
40 g
$4824
$9648
WinRho
5000 IU
$1351.72
$1351.72
Rituximab
500 mg
$3899.16
$15 596.64
Romiplostim
250 mg SDV 0.5 mL
$1433.10
$5732.40
Eltrombopag
50 mg (30 tablets)
$5934.54
$5934.54
2
The splenectomy procedure itself costs approximately US $20 000.
BLOOD, 14 MARCH 2013 x VOLUME 121, NUMBER 11
nonsplenectomized adults with ITP saw no
difference in the outcome with or without
RTX. After recruiting 60 patients over 46
months, this study from Canada closed because
of insufficient accrual. Rate of refusal was high
(42%) because of patients’ unwillingness to be
randomized to the placebo arm.9
One of the secondary end points of the
study by Gudbrandsdottir et al was time to
rescue treatment. Significant difference was
noted between the 2 groups, favoring those
receiving RTX1DEX. More serious adverse
events (n 5 16 vs 9) and infections (n 5 11 vs
9) were noted in the RTX1DEX cohort than
DEX single-agent cohort. Serum
immunoglobulin-G and -A levels were
decreased in all that could be tested, but were
still within the normal range, similar to what
was observed by others.9 However, there are
publications cautioning against persistent
hypogammaglobulinemia following rituximab
exposure in patients that received rituximab for
autoimmune and autoinflammatory conditions.10
Designing appropriate trials addressing
rituximab dosage and scheduling in ITP is
imperative and using it concurrently with
corticosteroids might actually confer some
benefit by minimizing infusion reactions.
Using this Danish design as a template, future
clinical trials in newly diagnosed ITP patients
should study its natural history,
pathophysiology, and T- and B-cell
dysfunction that can lead to identification and
validation of appropriate biomarkers of ITP as
the disease evolves in an individual patient.
This would allow us to move forward from
the prevailing empiricism in ITP therapeutics
to effective targeting and appropriate riskbenefit assessment with different classes of
medications while being wary of the cost
structure for all of them (Table 1).
Findings reported in the current issue of
Blood do underscore that a multicenter
clinical trial in adult ITP with long-term
follow-up is feasible.8 The time has come for
clinicians that care for patients with newly
diagnosed ITP to enroll them in controlled
trials to investigate the role of
immunosuppression in relation to newer
agents such as thrombopoietin agonists. After
all, despite insipid characterization by Victor
Hugo, Cosette’s fortunes do change during
the course of Les Misérables—from an abused
and orphaned urchin to a millionaire heiress
of Jean Valjean’s wealth and she lives happily
ever after married to Marius.11 Let us hope
1929
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
for a comparable outcome for all the new
patients with ITP, a relatively common
medical condition benevolently neglected by
clinical trialists until now.
Acknowledgment
Drug prices were researched and provided by
Dr Timothy Jancel, Pharmacy Department,
National Institutes of Health Clinical Center.
The author is grateful to Dr Michael Sneller
for reviewing the manuscript and providing
valuable comments.
This research was supported by the Intramural Research Program of the National
Institute of Allergy and Infectious Diseases,
National Institutes of Health.
Conflict-of-interest disclosure: The author
declares no competing financial interests. n
REFERENCES
1. Stasi R, Newland AC. ITP: a historical perspective. Br
J Haematol. 2011;153(4):437-450.
2. Ghanima W, Godeau B, Cines DB, Bussel JB.
How I treat immune thrombocytopenia: the
choice between splenectomy or a medical therapy
as a second-line treatment. Blood. 2012;120(5):960-969.
3. Wintrobe MM, Cartwright GE, Palmer JG, Kuhns
WJ, Samuels LT. Effect of corticotrophin and cortisone on
the blood in various disorders in man. AMA Arch Intern
Med. 1951;88(3):310-336.
4. Imbach P, Barandun S, d’Apuzzo V, et al. High-dose
intravenous gammaglobulin for idiopathic
thrombocytopenic purpura in childhood. Lancet. 1981;1
(8232):1228-1231.
5. Saleh MN, Gutheil J, Moore M, et al. A pilot study of
the anti-CD20 monoclonal antibody rituximab in patients
with refractory immune thrombocytopenia. Semin Oncol.
2000;27(6 Suppl 12):99-103.
6. Neunert C, Lim W, Crowther M, Cohen A, Solberg L,
Jr., Crowther MA. The American Society of Hematology
2011 evidence-based practice guideline for immune
thrombocytopenia. Blood. 2011;117(16):4190-4207.
7. Reff ME, Carner K, Chambers KS, et al. Depletion of
B cells in vivo by a chimeric mouse human monoclonal
antibody to CD20. Blood. 1994;83(2):435-445.
8. Gudbrandsdottir S, Birgens HS, Frederiksen H, et al.
Rituximab and dexamethasone vs dexamethasone
monotherapy in newly diagnosed patients with primary
immune thrombocytopenia [published ahead of print
January 8, 2013]. Blood. 2013;121(11):1976-1981.
9. Arnold DM, Heddle NM, Carruthers J, et al. A pilot
randomized trial of adjuvant rituximab or placebo for
nonsplenectomized patients with immune
thrombocytopenia. Blood. 2012;119(6):1356-1362.
10. Rao VK, Price S, Perkins K, et al. Use of rituximab
for refractory cytopenias associated with autoimmune
lymphoproliferative syndrome (ALPS). Pediatr Blood
Cancer. 2009;52(7):847-852.
11. Hugo V. Les Misérables. New York: Barnes and
Noble Classics; 2003.
l l l LYMPHOID NEOPLASIA
Comment on Heideman et al, page 2038
Too much or too little, how much
HDAC
activity is good for you?
----------------------------------------------------------------------------------------------------Patrick Matthias1
1
FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH
In this issue of Blood, Heideman and colleagues show that the major class I
histone deacetylases (HDACs) HDAC1 and HDAC2 can act to suppress tumors
in mouse thymocytes.
A
cetylation of proteins on lysine
residues has been recognized as a crucial
posttranslational modification that is now second
only to phosphorylation in its prevalence.1
Histone deacetylases are a family of enzymes
that remove acetyl groups from histone
N-terminal tails, thereby contributing to
chromatin condensation and the modulation of
gene expression and of other chromatin-based
processes.2 In addition, HDACs also can
deacetylate an increasing number of nonhistone
proteins, impinging on diverse cellular processes.
Inhibitors of HDACs, such as trichostatin
A, were identified more than 20 years ago and
were rapidly shown to have remarkable
1930
biological properties, such as induction of
differentiation in cellular systems and
a marked antiproliferative potential when
applied to transformed cells in culture.3
These early observations sparked an
enormous interest in HDAC inhibition as
a novel therapeutic modality; today 2 paninhibitors are approved for treatment of
cutaneous T-cell lymphoma (CTCL). HDAC
inhibition represents the first available
epigenetic therapy and it is currently
considered for a variety of other cancers in
addition to CTCL, as well as for
neurodegeneration and autoimmunity.
However, it has not yet been established
which HDAC(s) have to be inhibited under
which condition. It is generally assumed that
specific inhibitors might have fewer side
effects, although their clinical efficacy remains
to be demonstrated.
Heideman et al4 generated genetically
modified mice lacking HDAC1 and HDAC2
in thymocytes. By making a systematic
combination of alleles, they created a series of
mice expressing a gradient of deacetylase
activity as a function of HDAC1/HDAC2
levels. Unexpectedly, they found that in
mice lacking HDAC1 and having a single
HDAC2 allele, immature thymocytes
accumulated in great numbers, and
monoclonal lymphoblastic lymphomas were
observed, which led to death of the animals at
age 5 to 15 weeks. A similar but slowerappearing phenotype was observed in mice of
other genotypes: in the absence of HDAC1,
most mice developed lymphomas between
ages 15 and 25 weeks, and mice having 1 copy
of HDAC1 but no HDAC2 developed
lymphoma between ages 18 and 28 weeks. In
contrast, when both enzymes were fully
ablated, lymphomagenesis was abrogated,
owing to a block in early thymocyte
development. Using thymocytes of the
different genotypes, the authors showed that
the various HDAC1/HDAC2 combinations
result in different levels of overall deacetylase
activity, with HDAC1 contributing to more
activity than HDAC2. Based on the remarkable
correlation between the time of lymphoma
development and the level of overall HDAC
activity detected in the thymocytes, the authors
postulate that in this system, lymphomagenesis
is the outcome of an insufficient level of
HDAC activity, elicited by deletion of either
HDAC1 or HDAC2 (see Figure).
The authors go on to show that in the
T-cell lymphomas, the p53 pathway is
functionally inactivated, although p53 does
not appear to be mutated. They demonstrate
that the Myc gene is overexpressed in the
lymphomas due to chromosomal amplification.
Furthermore, they show that Myc-collaborating
genes, such as the p53 suppressor Jdp2, are
overexpressed in an HDAC1/HDAC2–
dependent manner. Finally, the authors provide
evidence that Jdp2 overexpression is critical for
the survival of these lymphoma cells.
Beyond these novel mechanistic insights,
which are very relevant, the main merit of this
important study—and of another recently
published study with similar conclusions5—is
BLOOD, 14 MARCH 2013 x VOLUME 121, NUMBER 11
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
2013 121: 1928-1930
doi:10.1182/blood-2013-01-477729
ITP: hematology's Cosette from Les Misérables
V. Koneti Rao
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