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doi:10.1182/blood-2013-01-4777292013 121: 1928-1930

V. Koneti Rao

Les MisrablesITP: hematology's Cosette from

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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 blood-

2011-04-348896 [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. 23.6 802.

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 overallsurvival 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: hematologys Cosette

from Les Mis

erables-----------------------------------------------------------------------------------------------------V. Koneti Rao1 1NATIONAL 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 pri-

mary immune thrombocytopenia (ITP), addition of rituximab (RTX) to high-dose

dexamethasone (DEX) as first-line therapy yields higher sustained response rates.

If all the ailments covered under hematology

were characters in Victor Hugos novel Les

Miserables, 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 Cosettes 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-

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

thoughrare in adultsoften 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 withno 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 first-

line 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 failuresa 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

1928 BLOOD, 14 MARCH 2013 x VOLUME 121, NUMBER 11

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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 (n5 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 persistenthypogammaglobulinemia 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 risk-

benefit 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, Cosettes fortunes do change during

the course of Les Miserablesfrom an abused

and orphaned urchin to a millionaire heiress

of Jean Valjeans wealth and she lives happily

ever after married to Marius.11

Let us hope

Cosette as depicted in a painting on the cover of the novel Les Miserables11

Table 1. Prices of all currently available medications used for ITP

Commonly used ITP drugs UnitSuggested warehouseprice per unit (US $)

Price for 1 month ora 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

The splenectomy procedure itself costs approximately US $20 000.2

BLOOD, 14 MARCH 2013 x VOLUME 121, NUMBER 11 1929


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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 Intra-

mural Research Program of the National

Institute of Allergy and Infectious Diseases,

National Institutes of Health.

Conflict-of-interest disclosure: The author

declares no competingfinancial 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, dApuzzo 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 fornonsplenectomized 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 Miserables. New York: Barnes and

Noble Classics; 2003.

l l l LYMPHOIDNEOPLASIA

Comment on Heideman et al, page 2038

Too much or too little, how muchHDAC activity is good for you?-----------------------------------------------------------------------------------------------------

Patrick Matthias1 1FRIEDRICH 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.

Acetylation 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

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 pan-

inhibitors 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 slower-

appearing 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 studyand of another recently

published study with similar conclusions5is

1930 BLOOD, 14 MARCH 2013 x VOLUME 121, NUMBER 11


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