Letters to the Editor 1096 1 Assistance Publique-Hoˆpitaux de Paris (AP-HP), References Service d’He´matologie Biologique, Hoˆpital Cochin-Hoˆtel-Dieu, Paris, France; 2 0 1 Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. De´partement d Immuno-He´matologie, Institut Cochin, IDH1 and IDH2 mutations in gliomas. NEnglJMed2009; 360: 765–773. Paris, France; 3 2 Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K Inserm U1016, CNRS UMR 8104FUniversite´ Paris et al. Recurring mutations found by sequencing an acute myeloid Descartes, Paris, France; leukemia genome. N Engl J Med 2009; 361: 1058–1066. 4 Centre National de la Recherche Scientifique (CNRS) Unite´ 3 Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W et al. Mixte de Recherche (UMR) 8104, Paris, France; Distinct clinical and biological characteristics in adult acute 5Faculte´ de Me´decine Rene´ Descartes, Universite´ Paris myeloid leukemia bearing isocitrate dehydrogenase 1 (IDH1) Descartes, Paris, France; mutation. Blood 2010. e-pub ahead of print 22 January 2010; doi: 6Laboratoire d’Oncologie Mole´culaire, Centre de Recherche 10.1182/blood-2009-11-253070. en Cance´rologie, Inserm UMR891, Institut Paoli-Calmettes, 4 Schnittger S, Haferlach C, Ulke M, Kaya L, Weiss T, Kern W et al. Marseille, France; IDH1 mutations are detected in 9.3% of all AML and are strongly 7AP-HP, Unite´ Fonctionnelle d’He´matologie, De´partement de associated with intermediate risk karyotype and unfavourable Me´decine Interne, Hoˆpital Cochin, Paris, France; prognosis: a study of 999 patients. Blood 2009; 114 (abstract LBA-3). 8Service de Me´decine Interne, CHU Purpan, Toulouse, 5 Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E et al. Structures of France; human cytosolic NADP-dependent isocitrate dehydrogenase 9Service des Maladies du Sang, Hoˆpital Huriez Centre de reveal a novel self-regulatory mechanism of activity. J Biol Chem 2004; 279: 33946–33957. Recherche Inserm 837, Institut pour la Recherche sur le 6 Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang Cancer de Lille (IRCL), Lille, France; 10 HG et al. Cancer-associated metabolite 2-hydroxyglutarate accu- Service des Maladies du Sang, CHU, Angers, France; mulates in acute myelogenous leukemia with isocitrate dehydro- 11Service de Me´decine, CHR Avignon, Avignon, France; 12 genase 1 and 2 mutations. J Exp Med 2010; 207: 339–344. Service d’He´matologie, Institut Paoli Calmettes, 7 Green A, Beer P. Somatic mutations of IDH1 and IDH2 in the Marseille, France; leukemic transformation of myeloproliferative neoplasms. N Engl J 13 Inserm U1009, Institut Gustave Roussy, Universite´ Paris XI, Med 2010; 362: 369–370. Villejuif, France and 8 Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, 14Inserm U985, Universite´ Paris Descartes, Paris, France Masse´ A et al. Mutation in TET2 in myeloid cancers. N Engl J Med E-mail: [email protected] 2009; 360: 2289–2301.

Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP

Leukemia (2010) 24, 1096–1098; doi:10.1038/leu.2010.45; secondary ITP, the activity of these new drugs in CLL-associated published online 25 March 2010 ITP has not been reported. Thus, we present two patients with CLL and secondary ITP who responded to eltrombopag. We identified two patients followed at MD Anderson Cancer In the course of active, progressive chronic lymphocytic Center with CLL and ITP who received the TPO-R agonist leukemia (CLL), patients have infiltration of peripheral lymphoid eltrombopag (Table 1). A third patient was identified who tissue and bone marrow with the malignant, monoclonal B cells received eltrombopag, but did not respond. coexpressing CD5, CD19 and CD23. This is manifest as Patient 1 was a 74-year-old female diagnosed with Rai stage 0 lymphocytosis, progressive lymphadenopathy and hepato- CLL in December 1995. She received multiple previous splenomegaly, and can be associated with progressive treatment regimens for her CLL, and then developed severe neutropenia, anemia and thrombocytopenia. Up to 25% of thrombocytopenia in May 2009, 5 months after her third course patients with CLL, including those with stable disease, develop of combined oxaliplatin, fludarabine, cytarabine and rituximab secondary autoimmune disorders, which can confound cyto- (OFAR). She was noted to have 17p del in 72% of leukemia cells penias, complicate the course of their CLL, compromise their by fluorescence in situ hybridization (FISH), which is a high-risk quality of life, and in some cases can be fatal.1 The most feature in CLL. Her platelet count dropped from 89 Â 103 to common among autoimmune disorders in CLL are autoimmune 1 Â 103/ml and she received infrequent platelet transfusions for hemolytic anemia (AIHA), immune thrombocytopenic purpura minor bleeding without improvement in platelet counts. (ITP) and pure red cell aplasia (PRCA).2 Indeed, CLL is one of the Patient 2 was a 49-year-old male who presented in October most common secondary causes of ITP.3 2004 with thrombocytopenia and was concurrently diagnosed Historically, it was hypothesized that rapid splenic and hepatic with CLL and ITP. He was initially treated with prednisone for clearance of autoantibody-loaded platelets from the circulation his ITP, then with one course of fludarabine with cyclo- was the primary mechanism for decreased platelet count in ITP.4 phosphamide and then with single-agent rituximab. Following However, recent studies showed that impaired platelet production this, in December 2004, his CLL was in partial remission with also contributes to the pathogenesis of ITP.5 Consistent with these residual CLL in his marrow, and his platelets were stable at findings, two second-line thrombopoietin receptor (TPO-R) approximately 100 Â 103/ml. FISH analysis of leukemia cells agonists, romiplostim (Nplate, Amgen, Thousand Oaks, CA, showed 11q deletion in 16.5% of cells. Subsequently, despite USA) and eltrombopag (Promacta, GlaxoSmithKline, Research stable CLL by other parameters, over several months his platelet Triangle Park, NC USA),6 showed remarkable efficacy in patients count dropped to 30 Â 103/ml when treatment for ITP was with primary ITP.7,8 As these trials excluded patients with considered.

Leukemia Letters to the Editor 1097 Table 1 Patient characteristics

Patient 1 Patient 2

Date of CLL diagnosis December 1995 October 2004 Tx for CLL 1997–fludarabine (3 courses) 2004–1 course FC 2002–FCR (6 courses) 2004–rituximab 2004–autologous T cells 2004–rituximab+GM-CSF 2006–lenalidomide 2008–OFAR (3 courses) Fludarabine-refractory Yes No Date of ITP diagnosis May 2009 October 2004 ITP Tx before eltrombopag 2009–prednisone 2004–2005–prednisone 2006–cyclosporine A 2006–2008–rituximab

Characteristics immediately before eltrombopag WBC ( Â 103/ml) 16.9; 80% lymphs 15.6; 71% lymphs HGB (gm per 100 ml) 12.5 15.3 PLT ( Â 103/ml) 16 (transfused) 36 Lymphadenopathy Cervical (1 cm) and inguinal (1 cm) Cervical (1 cm) Hepato-splenomegaly No No Last bone marrow evaluation before Hypercellular; 70% of cellularity compromised of Mildly hypercellular; 5–10% of cellularity eltrombopag CLL; megakaryocytes slightly decreased with normal compromised of CLL; megakaryocytes morphology (May 2009) normal number and morphology (April 2006) FISH: 17p del (72% cells) FISH: 11q del (16.5% cells) Time since last ITP Tx F 7 months Start of eltrombopag May 2009 March 2009 Concurrent ITP Tx Prednisone taper None Days on eltrombopag treatment 180+ 37 Abbreviations: CLL, chronic lymphocytic leukemia; FC, fludarabine and cyclophosphamide; FCR, fludarabine, cyclophosphamide and rituximab; FISH, fluorescence in situ hybridization; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGB, hemoglobin; lymphs, lymphocytes; ITP, immune thrombocytopenic purpura; OFAR, oxaliplatin, fludarabine, cytarabine, and rituximab; PLT, platelet; Tx, treatment; WBD, white blood count.

Figure 1 Platelet count (a) for patients 1 and 2 from the beginning of eltrombopag treatment. Patient 1 recovers her platelet count from 16 Â 103/ml (transfused) to 4100 Â 103/ml (transfusion independent). Patient 2 has a rapid response in platelet count, reaching high enough count to perform laparoscopic splenectomy. The platelet count of patient 2 dropped after splenectomy and off eltrombopag; he has not been retreated. ANC, ALC and HGB for patients 1 (b)and2(c) are shown from the start of eltrombopag. There was an overall reduction in ALC and HGB for patient 1.

Leukemia Letters to the Editor 1098 Neither patient had splenomegaly or rapid change in CLL infectious complications are common, additional suppression tumor burden before onset of thrombocytopenia, making ITP the of the immune system can be detrimental. TPO-R agonists are most reasonable diagnosis for both. Neither was evaluated for non-immunosuppressive, can be administered over a long antiplatelet antibodies. Initially, both patients were treated with period of time, help to keep platelet counts continually above prednisone (1 mg/kg) and re-evaluated after 1 week. Patient 1 life-threatening levels and therefore preserve immune function. continued to have a low platelet count (PLT: 13 Â 103/ml, Indeed, these agents are intended for long-term administration; transfused) after 4 weeks on prednisone and was started on however, long-term safety data are lacking in both primary and eltrombopag 50 mg daily. Prednisone was tapered off over 1 secondary ITP. week. From that time on, patient 1 has only been on These case reports show the activity of the TPO-R agonist eltrombopag and has not received anti-CLL treatment. Patient eltrombopag in two patients with CLL-associated ITP who were 2 did not respond to prednisone after 1 week and additionally refractory to standard treatment for ITP and therefore support received cyclosporine A (300 mg daily). After 5 months on further study of this and similar compounds in patients with cyclosporine A and prednisone with a platelet count of secondary ITP. 23 Â 103/ml, patient 2 received weekly standard-dose rituximab for 8 weeks and cyclosporine A and prednisone were tapered off over a month. He reached a platelet count of 167 Â 103/ml2 Conflict of interest months after rituximab but then only 5 months later he lost his response, and he received four additional weekly doses of Michael J Keating is a consultant for GlaxcoSmithKline. William rituximab, and again had a normal platelet count. Rituximab G Wierda received research funding from and has served as a ( Â 4) was repeated twice, each 6 months, before he agreed to consultant for GlaxcoSmithKline. Stefan Koehrer has no conflict splenectomy. To increase his platelet count from 36 Â 103/mlto of interest to disclose. a safer level for laparoscopic splenectomy, patient 2 received eltrombopag 50 mg daily. Author contributions Figure 1a shows the platelet count for patients 1 and 2 from Stefan Koehrer reviewed, analyzed, summarized patient data, start of eltrombopag treatment. Patient 1 has not received any wrote paper and approved the final version of the paper. antileukemia treatment and remains on eltrombopag 6 months Michael J Keating was the treating physician for patients and after starting with her most recent blood count showing a approved the final version of the paper. William G Wierda was platelet level of 77 Â 103/ml. The platelet count of patient 2 rose the treating physician for patients, and reviewed, analyzed, from 36 Â 103 to 134 Â 103/ml after 31 days on eltrombopag, summarized patient data, wrote paper and approved the final before splenectomy. Eltrombopag was stopped shortly after version of the paper. 3 splenectomy and his platelet count peaked at over 300 Â 10 /ml. 1 The peak platelet count was likely secondary to the combined S Koehrer, MJ Keating and WG Wierda Division of Cancer Medicine, Department of Leukemia, effects of eltrombopag and splenectomy. As shown in Figure 1a, University of Texas MD Anderson Cancer Center, stopping eltrombopag in patient 2 led to a decrease in platelet Houston, TX, USA count to pretreatment level. This reduction after stopping E-mail: [email protected] eltrombopag was also observed in phase 2 and phase 3 studies 1W.G. Wierda is a Leukemia and Lymphoma Society Clinical of eltrombopag for primary ITP. Neither patient 1, who is still Scholar. taking eltrombopag, nor patient 2 reported any eltrombopag- related side effects. In addition, neither had any change in lymphadenopathy while on eltrombopag. References Both patients experienced changes in blood counts, including significant increase in platelet count while on eltrombopag 1 Dearden C. Disease-specific complications of chronic lymphocytic (Figure 1). The presence of CLL cells in blood and bone marrow leukemia. Hematology 2008; 2008: 450–456. did not seem to have a negative effect on efficacy of 2 Diehl LF, Ketchum LH. Autoimmune disease and chronic lympho- cytic leukemia: autoimmune hemolytic anemia, pure red cell eltrombopag; even patient 1, who had 470% of her bone aplasia, and autoimmune thrombocytopenia. Semin Oncol 1998; marrow cellularity compromised of CLL cells at the beginning of 25: 80–97. her therapy, responded. In addition, for patient 1, there was a 3 Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP gradual decrease in hemoglobin (HGB) during treatment, but syndrome: pathogenic and clinical diversity. Blood 2009; 113: more remarkable was the drop in her absolute lymphocyte 6511–6521. count (ALC) from 18 Â 103/ml at the beginning of treatment to 4 Harrington WJ, Minnich V, Hollingsworth JW, Moore CV. Demons- 3 tration of a thrombocytopenic factor in the blood of patients with 5.5 Â 10 /ml over the first 6 months on eltrombopag. The thrombocytopenic purpura. J Lab Clin Med 1951; 38: 1–10. absolute neutrophil count (ANC) for patient 1 remained stable. 5 Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, For patient 2, the change was owing to platelet response to Buzby JS et al. Immune thrombocytopenic purpura (ITP) plasma eltrombopag; he had no significant change in his other counts, and purified ITP monoclonal autoantibodies inhibit megakaryo- including ANC, ALC and HGB over the month of treatment. cytopoiesis in vitro. Blood 2003; 102: 887–895. Two points make these results with eltrombopag therapy in 6 Nurden AT, Viallard J-F, Nurden P. New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic patients with CLL important. First, in a large number of cases of purpura. Lancet 2009; 373: 1562–1569. CLL-associated ITP, response to traditional treatment is transient 7 Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L et al. and multiple treatment courses with different agents are needed Effect of eltrombopag on platelet counts and bleeding during to control ITP. Both patients responded relatively quickly to treatment of chronic idiopathic thrombocytopenic purpura: a eltrombopag. One patient has had a durable response with randomised, double-blind, placebo-controlled trial. Lancet 2009; continued treatment; the other was taken off treatment and has 373: 641–648. 8 Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, not been retreated. Second, currently available therapeutic Senecal FM et al. Efficacy of romiplostim in patients with chronic option for secondary ITP is immunosuppression. In CLL, in immune thrombocytopenic purpura: a double-blind randomised which the disease itself impairs the immune system and controlled trial. Lancet 2008; 371: 395–403.

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