Int J Hematol (2013) 98:719–722 DOI 10.1007/s12185-013-1455-0
CASE REPORT
Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia Minoru Kojima • Shinichiro Machida • Ai Sato • Mitsuki Miyamoto • Makiko Moriuchi Yoshiaki Ohbayashi • Kiyoshi Ando
•
Received: 25 February 2013 / Revised: 18 September 2013 / Accepted: 16 October 2013 / Published online: 26 October 2013 Ó The Japanese Society of Hematology 2013
Abstract A 64-year-old woman developed pure red cell aplasia (PRCA) 4 years after thymectomy for thymoma. During anti-thymocyte globulin treatment, the patient developed cytomegalovirus pneumonia and was thus unable to continue immunosuppressive therapy and became transfusion dependent. Deferasirox was started for treatment with iron overload when serum ferritin increased to [1000 ng/mL. Seven months after initiation of deferasirox treatment, serum ferritin level decreased the normal range and the patient has remained transfusion independent thereafter. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months. Hypotheses have been raised regarding the improvement of hematopoiesis by deferasirox treatment, but the mechanism whereby this might be achieved remains unclear. Deferasirox treatment may be clinically beneficial both by reducing iron overload and by improving hematopoiesis in patients with PRCA. Keywords Pure red cell aplasia Deferasirox Iron chelation Iron overload
M. Kojima (&) S. Machida A. Sato M. Miyamoto M. Moriuchi K. Ando Division of Hematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1143, Japan e-mail: [email protected] M. Kojima S. Machida M. Moriuchi Y. Ohbayashi Division of Internal Medicine, Hadano Red Cross Hospital, Hadano, Japan
Introduction Pure red cell aplasia (PRCA) is characterized by normocytic anemia associated with reticulocytopenia in peripheral blood and severe erythroid hypoplasia in an otherwise normal bone marrow. PRCA can manifest as either a congenital or an acquired disease. Primary PRCA is treated as an immunologically mediated disease. The major objective in the treatment of PRCA is to induce remission and promote recovery of erythropoiesis, thus reducing the need for transfusions and avoiding the complications of transfusion-associated problems. The therapeutic plan typically consists of the sequential use of various immunosuppressive strategies, such as corticosteroids, cyclophosphamide, cyclosporine A (CyA), anti-thymocyte globulin (ATG), splenectomy, and plasma apheresis, until complete remission (CR) is achieved. Recent studies have also described the efficacies of the anti-CD20 monoclonal antibody, rituximab [1, 2], and the anti-CD52 monoclonal antibody, alemtuzumab [3, 4], to induce remission in patients with therapy-resistant PRCA. Deferasirox is an oral iron chelator used for the management of transfusional iron overload [5, 6]. Several case reports and small studies of patients with myelodysplastic syndrome (MDS) and aplastic anemia (AA) have reported that iron chelation therapy (ICT) with deferasirox resulted in improvements in hematologic parameters and transfusion requirements [7–13] by mechanisms that remain unclear. However, no previous study has described hematologic improvement in response to deferasirox in patients with PRCA. The present report describes a case of a patient with transfusion-dependent PRCA and iron overload who was successfully treated with deferasirox, resulting in reduced serum ferritin, hematological improvement, and remission.
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Fig. 1 Clinical course of the PRCA patient
Case report A 64-year-old Japanese woman who underwent thymectomy for thymoma 4 years prior was diagnosed with lower hemoglobin of 5.0 g/dL, received four units of red cell concentrates (RCC) in local doctor and admitted to Hadano Red Cross Hospital due to anemia. Physical examination findings were non-specific. Laboratory examination at the first visit to our hospital showed normocytic anemia with a hemoglobin level of 7.9 g/dL and a hematocrit of 23.2 %, low reticulocyte count of 4 %, mild leukocytopenia, a leukocyte count of 3400/ll with normal differentials, and a normal platelet count. Blood chemistry was normal, except for a decreased serum total protein. Examination of a bone marrow aspiration specimen showed normal granulocytopoiesis and megakaryocytopoiesis with the absence of an erythroid component (M/E ratio of 86.4). Bone marrow presented normal morphology without MDS-related changes. The marrow karyotype was a normal female type. Based on these data, a diagnosis of PRCA was made. The patient required more than 4U/month of RCC transfusion and underwent treatment with ATG and CyA. Twenty-two days after initiation of treatment, the patient developed dyspnea and fever, and chest X-ray showed bilateral interstitial lung disease. Serum cytomegalovirus (CMV) antigenemia was positive, consistent with a diagnosis of CMV pneumonia. CyA was immediately stopped, and ganciclovir and steroid pulse treatment were started, but the patient’s respiratory condition deteriorated rapidly, and she was intubated for initiation of mechanical ventilation. She gradually recovered and was successfully extubated 29 days later. She temporarily achieved
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transfusion-free status, but became transfusion-dependent again on day 137 after ATG therapy. Since CMV antigenemia had been positive, she did not receive immunosuppressive therapy and was only supported by RCC transfusions. She was transfusion dependent but her organ damages were not observed. Deferasirox was started when serum ferritin increased to 1240 ng/mL, serum iron increased to 202 lg/dL and unsaturated iron-binding capacity decreased to 1 lg/dL and transferrin saturation was 100 %. The starting dose of deferasirox was 1000 mg/ day, but she needed dose reduction after developing grade 3 diarrhea. She could continue 500 mg/day of deferasirox. Serum ferritin level decreased to 1000 ng/mL, and she was no longer RCC transfusion-dependent at 7 months after initiation of deferasirox treatment. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months (Fig. 1).
Discussion In the present report, the patient was diagnosed with PRCA on the basis of anemia, low number of reticulocytes in the peripheral blood (PB) and low number of erythroblasts in the bone marrow (BM). This patient developed PRCA 4 years after thymectomy, and immunosuppressive therapy (IST) with ATG and CyA was effective. However, she had to terminate IST due to onset of CMV pneumonia, and PRCA subsequently recurred. Unexpectedly, deferasirox was effective in terms of iron chelation and also in terms of promoting erythropoiesis in this patient, and she was
Deferasirox treatment improved PRCA
ultimately able to attain CR without IST. This is the first report to describe the successful treatment of PRCA with deferasirox. The pathophysiology of PRCA is not well understood but likely involves several distinct pathways that can lead to the clinical syndrome. Theories as to the etiology of the disease have included a humoral factor suppressing the erythroid lineage, antibodies against erythropoietin, cellmediated suppression (including T cells, large granular lymphocytes, and natural killer cells), and direct toxic effects of viruses or drugs on erythroid precursors [14]. Studies of patients with PRCA have frequently found abnormal karyotypes; T-cell receptor gene rearrangement analyses have documented the presence of clonal cell populations [15]. Since IST was effective in the case, an immunological mechanism was likely involved in the pathophysiology of this case. A recent in vitro study showed that deferasirox is a potent inhibitor of nuclear factor kappa light-chain enhancer of activated B cells (NFjB). Since exposure to deferoxamine or deferiprone has no effect on NF-jB activity, this effect is not simply related to a decrease in iron levels, but rather, seems to be a specific effect of deferasirox [16]. Therefore, the effect of deferasirox on PRCA in this case may be mediated by the suppression of autoreactive B or T cells through inhibition of NF-jB by deferasirox. The second possible mechanism to explain the effect of deferasirox in this case is the stimulation of erythropoiesis. There are some reports of patients with lower risk myelodysplasia syndrome (MDS) that experienced an improvement of hematopoiesis while receiving ICT [7– 10, 12]. Similar observations were made in patients with AA [11] and in those with Diamond-Blackfan anemia [13], but not in patients with PRCA. Although the underlying mechanism is unclear, there are some hypotheses. It is reported that iron chelators promote iron release from storage sites, facilitating its use by hematopoietic tissue; furthermore, the reduction of iron stores seems to upregulate erythropoietin, resulting in an increase in hemoglobin [17]. In patients with MDS, treatment with deferasirox significantly reduces reactive oxygen species, membrane lipid peroxidation and the labile iron pool and concomitantly increases glutathione in RBCs. Deferasirox also increases glutathione in platelets and neutrophils and decreases the labile iron pool in platelets [18]. Guariglia et al. [12] described a rapid improvement in erythroid and platelet counts after starting ICT, even when serum ferritin levels were still high, which suggests that deferasirox may have a direct effect on the activity of neoplastic cells. This observation is reminiscent of the rapid improvement in cardiac function that can be achieved with intensive chelation therapy in patients with beta-thalassemia major and heart failure.
721
These observations suggest that the level of oxidative stress (rather than the level of tissue iron accumulation) is directly responsible for organ dysfunction, and we speculate that the hematopoietic system in the present patient was particularly sensitive to oxidative stress. Taher et al. [13] reported a case of patient with Diamond-Blackfan anemia who achieved transfusion independence after treatment with deferasirox, but Diamond-Blackfan anemia is a special subtype of PRCA, so it was not equal to the response mechanism of ICT between Diamond-Blackfan anemia and this case. Attributable mechanisms of such a response may be drug or disease specific [19]. Iron redistribution to the hematopoietic tissue, suppression of increased erythroblast apoptosis, and a decline in mitochondrial damage secondary to erythroblast iron deposition (as evident by decreased erythroblast membrane iron) have all been postulated [20–22]. Surgical resection is the primary mode of treatment for thymoma-associated PRCA and results in alleviation of anemia. Further, thymectomy has been reported to result in occasional improvement of PRCA [23]. Surgical resection of thymoma is recommended as the initial treatment of thymoma-associated PRCA and is associated with a hematological response rate of 25–38 % [23, 24]. However, in a more recent report of 13 patients who underwent thymectomy, thymectomy did not produce normalization of erythropoiesis in all cases [25]. Therefore, the effectiveness of thymectomy in PRCA is unclear. In the present case, PRCA occurred 4 years after thymectomy. Hirokawa et al. [26] studied 36 patients who underwent surgical resection of thymoma and reported that 16 of those patients developed PRCA at a median of 80 months after thymectomy. The mechanism and difference between PRCA that develops pre-thymectomy versus PRCA that develops post-thymectomy is unclear. Masuda et al. [27] described a case of a patient with thymomaassociated PRCA and clonal T-cell expansion in both the thymoma and circulating blood. On the other hand, Fujishima et al. [28] described a patient with clonal T-cell expansions in the blood but not in the thymoma. Thus, the mechanism may be different for each case and may be influenced by cytotoxic T cells, and the role of thymoma in providing an environment for clonal expansions of pathogenic T cells may be different among individuals. In conclusion, deferasirox treatment may be clinically beneficial in terms of reducing iron overload and in improving hematopoiesis in patients with PRCA. Further long-term studies in larger patient populations are needed to clarify the effect and safety of deferasirox-mediated restoration of hematopoiesis in patients with PRCA. Conflict of interest funding to disclose.
The authors have no conflicts of interests or
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References 1. Zecca M, De Stefano P, Nobili B, Locatelli F. Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia. Blood. 2001;97(12):3995–7. 2. Dungarwalla M, Marsh JC, Tooze JA, Lucas G, Ouwehand W, Pettengell R, Dearden CE, Gordon Smith EC, Elebute MO. Lack of clinical efficacy of rituximab in the treatment of autoimmune neutropenia and pure red cell aplasia: implications for their pathophysiology. Ann Hematol. 2007;86(3):191–7. 3. Willis F, Marsh JC, Bevan DH, Killick SB, Lucas G, Griffiths R, Ouwehand W, Hale G, Waldmann H, Gordon-Smith EC. The effect of treatment with Campath-1H in patients with autoimmune cytopenias. Br J Haematol. 2001;114(4):891–8. 4. Au WY, Lam CC, Chim CS, Pang AW, Kwong YL. Alemtuzumab induced complete remission of therapy-resistant pure red cell aplasia. Leuk Res. 2005;29(10):1213–5. 5. Cappellini MD, Porter J, El-Beshlawy A, Li CK, Seymour JF, Elalfy M, Gattermann N, Giraudier S, Lee JW, Chan LL, Lin KH, Rose C, Taher A, Thein SL, Viprakasit V, Habr D, Domokos G, Roubert B, Kattamis A. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. EPIC Study Investigators. Haematologica. 2010;95(4):557–66. 6. Miyazawa K, Ohyashiki K, Urabe A, Hata T, Nakao S, Ozawa K, Ishikawa T, Kato J, Tatsumi Y, Mori H, Kondo M, Taniguchi J, Tanii H, Rojkjaer L, Omine M. A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a phase I study in Japan. Int J Hematol. 2008;88(1):73–81. 7. Messa E, Cilloni D, Messa F, Arruga F, Roetto A, Saglio G. Deferasirox treatment improved the hemoglobin level and decreased transfusion requirements in four patients with the myelodysplastic syndrome and primary myelofibrosis. Acta Haematol. 2008;120(2):70–4. 8. Capalbo S, Spinosa G, Franzese MG, Palumbo G. Early deferasirox treatment in a patient with myelodysplastic syndrome results in a long-term reduction in transfusion requirements. Acta Haematol. 2009;121(1):19–20. 9. Oliva EN, Ronco F, Marino A, Alati C, Pratico` G, Nobile F. Iron chelation therapy associated with improvement of hematopoiesis in transfusion-dependent patients. Transfusion. 2010;50(7): 1568–70. 10. Okabe H, Suzuki T, Omori T, Mori M, Uehara E, Hatano K, Ueda M, Matsuyama T, Toshima M, Qzaki K, Nagai T, Muroi K, Ozawa K. Hematopoietic recovery after administration of deferasirox for transfusional iron overload in a case of myelodysplastic syndrome. Rinsho Ketsueki. 2009;50(11):1626–9. 11. Lee SE, Yahng SA, Cho BS, Eom KS, Kim YJ, Lee S, Min CK, Kim HJ, Cho SG, Kim DW, Min WS, Park CW, Lee JW. Improvement in hematopoiesis after iron chelation therapy with deferasirox in patients with aplastic anemia. Acta Haematol. 2012;129(2):72–7. 12. Guariglia R, Martorelli MC, Villani O, Pietrantuono G, Mansueto G, Daˆ€TMAuria F, Grieco V, Bianchino G, Lerose R, Bochicchio GB, Musto P. Positive effects on hematopoiesis in patients with myelodysplastic syndrome receiving deferasirox as oral iron chelation therapy: a brief review. Leuk Res. 2011;35(5):566–70.
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M. Kojima et al. 13. Taher AT, Musallam KM, Koussa S, Inati A. Transfusion independence in Diamond-Blackfan anemia after deferasirox therapy. Ann Hematol. 2009;88(12):1263–4. 14. Fisch P, Handgretinger R, Schaefer HE. Pure red cell aplasia. Br J Haematol. 2000;111(4):1010–22. 15. Lacy MQ, Kurtin PJ, Tefferi A. Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities. Blood. 1996;87(7):3000–6. 16. Messa E, Carturan S, Maffe` C, Pautasso M, Bracco E, Roetto A, Messa F, Arruga F, Defilippi I, Rosso V, Zanone C, Rotolo A, Greco E, Pellegrino RM, Alberti D, Saglio G, Cilloni D. Deferasirox is a powerful NF-kappaB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging. Haematologica. 2010;95(8):1308–16. 17. Vreugdenhil G, Smeets M, Feelders RA, Van Eijk HG. Iron chelators may enhance erythropoiesis by increasing iron delivery to haematopoietic tissue and erythropoietin response in ironloading anaemia. Acta Haematol. 1993;89:57–60. 18. Ghoti H, Fibach E, Merkel D, Perez-Avraham G, Grisariu S, Rachmilewitz EA. Changes in parameters of oxidative stress and free iron biomarkers during treatment with deferasirox in ironoverloaded patients with myelodysplastic syndromes. Haematologica. 2010;95(8):1433–4. 19. Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100(13):4272–90. 20. Louache F, Testa U, Pelicci P, Thomopoulos P, Titeux M, Rochant H. Regulation of transferrin receptors in human hematopoietic cell lines. J Biol Chem. 1984;259(18):11576–82. 21. Kontoghiorghes GJ, May A. Uptake and intracellular distribution of iron from transferrin and chelators in erythroid cells. Biol Met. 1990;3(3–4):183–7. 22. Taoka K, Kumano K, Nakamura F, Hosoi M, Goyama S, Imai Y, Hangaishi A, Kurokawa M. The effect of iron overload and chelation on erythroid differentiation. Int J Hematol. 2012;95(2): 149–59. 23. Zeok JV, Todd EP, Dillon M, DeSimone P, Utley JR. The role of thymectomy in red cell aplasia. Ann Thorac Surg. 1979;28(3): 257–60. 24. Masaoka A, Hashimoto T, Shibata K, Yamakawa Y, Nakamae K, Iizuka M. Thymomas associated with pure red cell aplasia. Histologic and follow-up studies. Cancer. 1989;64(9):1872–8. 25. Thompson CA, Steensma DP. Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience. Br J Haematol. 2006;135(3):405–7. 26. Hirokawa M, Sawada K, Fujishima N, Nakao S, Urabe A, Dan K, Fujisawa S, Yonemura Y, Kawano F, Omine M, Ozawa K. Longterm response and outcome following immunosuppressive therapy in thymoma-associated pure red cell aplasia: a nationwide cohort study in Japan by the PRCA collaborative study group. PRCA Collaborative Study Group. Haematologica. 2008;93(1): 27–33. 27. Masuda M, Arai Y, Okamura T, Mizoguchi H. Pure red cell aplasia with thymoma: evidence of T-cell clonal disorder. Am J Hematol. 1997;54(4):324–8. 28. Fujishima N, Hirokawa M, Fujishima M, Wada C, Toyoshima I, Watanabe S, Sawada K. Oligoclonal T cell expansion in blood but not in the thymus from a patient with thymoma-associated pure red cell aplasia. Haematologica. 2006;91(12 Suppl):ECR47.
CASE REPORT
Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia Minoru Kojima • Shinichiro Machida • Ai Sato • Mitsuki Miyamoto • Makiko Moriuchi Yoshiaki Ohbayashi • Kiyoshi Ando
•
Received: 25 February 2013 / Revised: 18 September 2013 / Accepted: 16 October 2013 / Published online: 26 October 2013 Ó The Japanese Society of Hematology 2013
Abstract A 64-year-old woman developed pure red cell aplasia (PRCA) 4 years after thymectomy for thymoma. During anti-thymocyte globulin treatment, the patient developed cytomegalovirus pneumonia and was thus unable to continue immunosuppressive therapy and became transfusion dependent. Deferasirox was started for treatment with iron overload when serum ferritin increased to [1000 ng/mL. Seven months after initiation of deferasirox treatment, serum ferritin level decreased the normal range and the patient has remained transfusion independent thereafter. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months. Hypotheses have been raised regarding the improvement of hematopoiesis by deferasirox treatment, but the mechanism whereby this might be achieved remains unclear. Deferasirox treatment may be clinically beneficial both by reducing iron overload and by improving hematopoiesis in patients with PRCA. Keywords Pure red cell aplasia Deferasirox Iron chelation Iron overload
M. Kojima (&) S. Machida A. Sato M. Miyamoto M. Moriuchi K. Ando Division of Hematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1143, Japan e-mail: [email protected] M. Kojima S. Machida M. Moriuchi Y. Ohbayashi Division of Internal Medicine, Hadano Red Cross Hospital, Hadano, Japan
Introduction Pure red cell aplasia (PRCA) is characterized by normocytic anemia associated with reticulocytopenia in peripheral blood and severe erythroid hypoplasia in an otherwise normal bone marrow. PRCA can manifest as either a congenital or an acquired disease. Primary PRCA is treated as an immunologically mediated disease. The major objective in the treatment of PRCA is to induce remission and promote recovery of erythropoiesis, thus reducing the need for transfusions and avoiding the complications of transfusion-associated problems. The therapeutic plan typically consists of the sequential use of various immunosuppressive strategies, such as corticosteroids, cyclophosphamide, cyclosporine A (CyA), anti-thymocyte globulin (ATG), splenectomy, and plasma apheresis, until complete remission (CR) is achieved. Recent studies have also described the efficacies of the anti-CD20 monoclonal antibody, rituximab [1, 2], and the anti-CD52 monoclonal antibody, alemtuzumab [3, 4], to induce remission in patients with therapy-resistant PRCA. Deferasirox is an oral iron chelator used for the management of transfusional iron overload [5, 6]. Several case reports and small studies of patients with myelodysplastic syndrome (MDS) and aplastic anemia (AA) have reported that iron chelation therapy (ICT) with deferasirox resulted in improvements in hematologic parameters and transfusion requirements [7–13] by mechanisms that remain unclear. However, no previous study has described hematologic improvement in response to deferasirox in patients with PRCA. The present report describes a case of a patient with transfusion-dependent PRCA and iron overload who was successfully treated with deferasirox, resulting in reduced serum ferritin, hematological improvement, and remission.
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Fig. 1 Clinical course of the PRCA patient
Case report A 64-year-old Japanese woman who underwent thymectomy for thymoma 4 years prior was diagnosed with lower hemoglobin of 5.0 g/dL, received four units of red cell concentrates (RCC) in local doctor and admitted to Hadano Red Cross Hospital due to anemia. Physical examination findings were non-specific. Laboratory examination at the first visit to our hospital showed normocytic anemia with a hemoglobin level of 7.9 g/dL and a hematocrit of 23.2 %, low reticulocyte count of 4 %, mild leukocytopenia, a leukocyte count of 3400/ll with normal differentials, and a normal platelet count. Blood chemistry was normal, except for a decreased serum total protein. Examination of a bone marrow aspiration specimen showed normal granulocytopoiesis and megakaryocytopoiesis with the absence of an erythroid component (M/E ratio of 86.4). Bone marrow presented normal morphology without MDS-related changes. The marrow karyotype was a normal female type. Based on these data, a diagnosis of PRCA was made. The patient required more than 4U/month of RCC transfusion and underwent treatment with ATG and CyA. Twenty-two days after initiation of treatment, the patient developed dyspnea and fever, and chest X-ray showed bilateral interstitial lung disease. Serum cytomegalovirus (CMV) antigenemia was positive, consistent with a diagnosis of CMV pneumonia. CyA was immediately stopped, and ganciclovir and steroid pulse treatment were started, but the patient’s respiratory condition deteriorated rapidly, and she was intubated for initiation of mechanical ventilation. She gradually recovered and was successfully extubated 29 days later. She temporarily achieved
123
transfusion-free status, but became transfusion-dependent again on day 137 after ATG therapy. Since CMV antigenemia had been positive, she did not receive immunosuppressive therapy and was only supported by RCC transfusions. She was transfusion dependent but her organ damages were not observed. Deferasirox was started when serum ferritin increased to 1240 ng/mL, serum iron increased to 202 lg/dL and unsaturated iron-binding capacity decreased to 1 lg/dL and transferrin saturation was 100 %. The starting dose of deferasirox was 1000 mg/ day, but she needed dose reduction after developing grade 3 diarrhea. She could continue 500 mg/day of deferasirox. Serum ferritin level decreased to 1000 ng/mL, and she was no longer RCC transfusion-dependent at 7 months after initiation of deferasirox treatment. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months (Fig. 1).
Discussion In the present report, the patient was diagnosed with PRCA on the basis of anemia, low number of reticulocytes in the peripheral blood (PB) and low number of erythroblasts in the bone marrow (BM). This patient developed PRCA 4 years after thymectomy, and immunosuppressive therapy (IST) with ATG and CyA was effective. However, she had to terminate IST due to onset of CMV pneumonia, and PRCA subsequently recurred. Unexpectedly, deferasirox was effective in terms of iron chelation and also in terms of promoting erythropoiesis in this patient, and she was
Deferasirox treatment improved PRCA
ultimately able to attain CR without IST. This is the first report to describe the successful treatment of PRCA with deferasirox. The pathophysiology of PRCA is not well understood but likely involves several distinct pathways that can lead to the clinical syndrome. Theories as to the etiology of the disease have included a humoral factor suppressing the erythroid lineage, antibodies against erythropoietin, cellmediated suppression (including T cells, large granular lymphocytes, and natural killer cells), and direct toxic effects of viruses or drugs on erythroid precursors [14]. Studies of patients with PRCA have frequently found abnormal karyotypes; T-cell receptor gene rearrangement analyses have documented the presence of clonal cell populations [15]. Since IST was effective in the case, an immunological mechanism was likely involved in the pathophysiology of this case. A recent in vitro study showed that deferasirox is a potent inhibitor of nuclear factor kappa light-chain enhancer of activated B cells (NFjB). Since exposure to deferoxamine or deferiprone has no effect on NF-jB activity, this effect is not simply related to a decrease in iron levels, but rather, seems to be a specific effect of deferasirox [16]. Therefore, the effect of deferasirox on PRCA in this case may be mediated by the suppression of autoreactive B or T cells through inhibition of NF-jB by deferasirox. The second possible mechanism to explain the effect of deferasirox in this case is the stimulation of erythropoiesis. There are some reports of patients with lower risk myelodysplasia syndrome (MDS) that experienced an improvement of hematopoiesis while receiving ICT [7– 10, 12]. Similar observations were made in patients with AA [11] and in those with Diamond-Blackfan anemia [13], but not in patients with PRCA. Although the underlying mechanism is unclear, there are some hypotheses. It is reported that iron chelators promote iron release from storage sites, facilitating its use by hematopoietic tissue; furthermore, the reduction of iron stores seems to upregulate erythropoietin, resulting in an increase in hemoglobin [17]. In patients with MDS, treatment with deferasirox significantly reduces reactive oxygen species, membrane lipid peroxidation and the labile iron pool and concomitantly increases glutathione in RBCs. Deferasirox also increases glutathione in platelets and neutrophils and decreases the labile iron pool in platelets [18]. Guariglia et al. [12] described a rapid improvement in erythroid and platelet counts after starting ICT, even when serum ferritin levels were still high, which suggests that deferasirox may have a direct effect on the activity of neoplastic cells. This observation is reminiscent of the rapid improvement in cardiac function that can be achieved with intensive chelation therapy in patients with beta-thalassemia major and heart failure.
721
These observations suggest that the level of oxidative stress (rather than the level of tissue iron accumulation) is directly responsible for organ dysfunction, and we speculate that the hematopoietic system in the present patient was particularly sensitive to oxidative stress. Taher et al. [13] reported a case of patient with Diamond-Blackfan anemia who achieved transfusion independence after treatment with deferasirox, but Diamond-Blackfan anemia is a special subtype of PRCA, so it was not equal to the response mechanism of ICT between Diamond-Blackfan anemia and this case. Attributable mechanisms of such a response may be drug or disease specific [19]. Iron redistribution to the hematopoietic tissue, suppression of increased erythroblast apoptosis, and a decline in mitochondrial damage secondary to erythroblast iron deposition (as evident by decreased erythroblast membrane iron) have all been postulated [20–22]. Surgical resection is the primary mode of treatment for thymoma-associated PRCA and results in alleviation of anemia. Further, thymectomy has been reported to result in occasional improvement of PRCA [23]. Surgical resection of thymoma is recommended as the initial treatment of thymoma-associated PRCA and is associated with a hematological response rate of 25–38 % [23, 24]. However, in a more recent report of 13 patients who underwent thymectomy, thymectomy did not produce normalization of erythropoiesis in all cases [25]. Therefore, the effectiveness of thymectomy in PRCA is unclear. In the present case, PRCA occurred 4 years after thymectomy. Hirokawa et al. [26] studied 36 patients who underwent surgical resection of thymoma and reported that 16 of those patients developed PRCA at a median of 80 months after thymectomy. The mechanism and difference between PRCA that develops pre-thymectomy versus PRCA that develops post-thymectomy is unclear. Masuda et al. [27] described a case of a patient with thymomaassociated PRCA and clonal T-cell expansion in both the thymoma and circulating blood. On the other hand, Fujishima et al. [28] described a patient with clonal T-cell expansions in the blood but not in the thymoma. Thus, the mechanism may be different for each case and may be influenced by cytotoxic T cells, and the role of thymoma in providing an environment for clonal expansions of pathogenic T cells may be different among individuals. In conclusion, deferasirox treatment may be clinically beneficial in terms of reducing iron overload and in improving hematopoiesis in patients with PRCA. Further long-term studies in larger patient populations are needed to clarify the effect and safety of deferasirox-mediated restoration of hematopoiesis in patients with PRCA. Conflict of interest funding to disclose.
The authors have no conflicts of interests or
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