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2013 121: 1928-1930 doi:10.1182/blood-2013-01-477729

ITP: hematology's Cosette from Les Misrables

V. Koneti Rao

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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: of cial 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, nal 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: hematologys Cosette from Les Miserables ----------------------------------------------------------------------------------------------------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 rst-line therapy yields higher sustained response rates.

f all the ailments covered under hematology were characters in Victor Hugos novel Les Mis erables, 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 gure). 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 denitive 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 rstline 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

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

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

Suggested warehouse price per unit (US $) $8 from Costco Pharmacy $13.20 from Costco Pharmacy $4824 $1351.72 $3899.16 $1433.10 $5934.54
2

Commonly used ITP drugs Prednisone Dexamethasone IVIG (Gamunex 10%) WinRho Rituximab Romiplostim Eltrombopag

Unit 20 mg (100 tablets) 4 mg (40 tablets) 40 g 5000 IU 500 mg 250 mg SDV 0.5 mL 50 mg (30 tablets)

Price for 1 month or a single-course treatment in an adult (US $) $16 $52.80 $9648 $1351.72 $15 596.64 $5732.40 $5934.54

The splenectomy procedure itself costs approximately US $20 000.

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 insufcient 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. Signicant 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 autoinammatory conditions.10 Designing appropriate trials addressing rituximab dosage and scheduling in ITP is imperative and using it concurrently with corticosteroids might actually confer some benet 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 identication 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 riskbenet 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 Mis erablesfrom 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

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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.

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 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 Mis erables. New York: Barnes and Noble Classics; 2003.

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. Conict-of-interest disclosure: The author declares no competing nancial 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. 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.
cetylation of proteins on lysine residues has been recognized as a crucial posttranslational modication 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 identied 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 paninhibitors are approved for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibition represents the rst 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 specic inhibitors might have fewer side effects, although their clinical efcacy remains to be demonstrated. Heideman et al4 generated genetically modied 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 insufcient 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 amplication. 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

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