Blood Cells, Molecules and Diseases 54 (2015) 281–283
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Short Communication
Cyclosporine dependent pure red cell aplasia: A case presentation Karam Al-Issa a, Valeria Visconte a, Heesun J. Rogers b, Vikas Dembla c, Alan E. Lichtin d, Ramon V. Tiu a,d,⁎ a
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Department of Laboratory Medicine, Cleveland Clinic, OH, USA c Overton Brooks VA Medical Center, Shreveport, LA, USA d Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA b
a r t i c l e
i n f o
Article history: Submitted 26 September 2014 Accepted 15 November 2014 Available online 25 November 2014 (Communicated by M. Narla, DSc, 13 November 2014) Keywords: Pure red cell aplasia Cyclosporine Anemia Discontinuation
© 2014 Elsevier Inc. All rights reserved.
To the Editor Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by a selective decrease or absence of erythrocytes and their progenitors in the peripheral blood and bone marrow (BM) [1]. It can be either idiopathic or secondary, occurring in association with other diseases (systemic lupus erythematous, infections, pregnancy, lymphoproliferative disorders, nutritional deficiencies, medications). Idiopathic PRCA is usually treated with immunosuppressive therapies (IST) including cyclosporine (CsA). Single agent CsA can result in response rates of 46% [2]. However, the optimal duration of treatment and whether there is a need to taper treatment or the best taper schedule are not clear. Further, relapse can occur even in patients who achieved complete remission (CR). In a related disease like severe aplastic anemia (SAA), some patients successfully treated with horse anti-thymocyte globulin (hATG) + CsA are CsA dependent and can have significant disease relapse if CsA is discontinued abruptly. Here, we describe a patient with PRCA who successfully achieved CR after 12 weeks of CsA therapy but developed worsening anemia after ⁎ Corresponding author at: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Fax: +1 216 636 2498. E-mail address: [email protected] (R.V. Tiu).
http://dx.doi.org/10.1016/j.bcmd.2014.11.013 1079-9796/© 2014 Elsevier Inc. All rights reserved.
CsA tapering and had improvement in blood counts after CsA dose was increased. A 63-year-old Caucasian male, with a past medical history of symptomatic cold agglutinin disease successfully treated with 1 cycle of rituximab (375 mg/m2 IV weekly × 4) in 2003. He was doing well and had normal counts until 2012 when he experienced significant weakness after recovering from a sinus infection. He was found to have severe anemia with hemoglobin (Hgb) of 5.6 g/dL. He was admitted in the hospital and received 4 units of red blood cells (RBCs) which raised his Hgb to 9.0 g/dL. He was given a presumptive diagnosis of cold agglutinin disease and was started on prednisone (60 mg PO once daily) with no response. He also received rituximab (375 mg/m2 IV weekly × 4) without achieving any response and remained RBC transfusion dependent. He underwent a BM biopsy which showed 80% cellularity with granulocytic hyperplasia, markedly reduced erythroid maturation, no significant dysplasia, no increased BM blasts, and reticulin fibrosis (Fig. 1). No giant pronormoblasts, lymphoid aggregates or infections were noted. Metaphase cytogenetics and FISH analysis using probes for myelodyplastic syndrome (MDS) were unremarkable. Additional laboratory results showed normal serum folate, vitamin B12, LDH, uric acid and TSH levels. His remote hepatitis panel, PNH flow cytometry, Parvovirus B19 IgM and IgG, and HIV 1&2 testing were unremarkable. As expected, serum iron and ferritin levels were elevated due to numerous transfusions. He denied fever, chills, night sweats, weight loss, blood clots, joint pain, photosensitivity, rash, hematuria, hematemesis, and
282
K. Al-Issa et al. / Blood Cells, Molecules and Diseases 54 (2015) 281–283
Fig. 1. Bone marrow morphology of the case presentation. (A–C) Bone marrow (BM) aspirate (A) and core biopsy (C) show 80% cellularity and predominantly granulocytic and megakaryocytic maturation and reduced erythroid cells. No increase in the percentage of blasts and no sign of dysplasia. Reticulin stain (B) demonstrates mild to moderate increase in reticulin fibers (grade 1–2) in the core biopsy. (D) Peripheral blood smear shows normocytic anemia.
melena. His past medical history was significant for bladder cancer treated by surgical excision without chemotherapy, kidney stones that were removed surgically, umbilical hernia, and sleep apnea managed with continuous positive airway pressure. His social, family, and exposure history were all unremarkable. His medications included daily intake of folic acid (1 mg), prednisone (20 mg), and aspirin (325 mg). The vital signs and physical examination findings were unremarkable. A diagnosis of idiopathic PRCA was made. He was started on CsA 175 mg PO BID. The patient achieved a slow but steady improvement in Hgb levels (14.2 g/dL) 10 months after starting CsA, and was able to keep the same Hgb level for 6 months. Fourteen months since starting CsA, slow taper of CsA was started but resulted in a precipitous decline
Fig. 2. Complete blood cell count in the case presentation. Line graph illustrates hemoglobin (Hgb), white blood cells (WBCs), platelet (PLT) counts and absolute reticulocytes (RETIC) pre- and post-cyclosporine treatment. Quadrants show the different time points. Data are expressed as: Hgb (g/dL), WBCs (×109/L), PLT (×107/L), and RETIC (108/μL).
in Hgb levels. A reduction in his CsA levels down to 100 mg PO BID resulted in a decline in Hgb levels down to 9.5 g/dL. The dose of CsA was escalated back to 175 mg PO BID which resulted in restoration of a normal Hgb. Attempts at reducing CsA dose resulted in a decline in Hgb and only salvaged by CsA dose readjustment back to 175 mg PO BID (Fig. 2). The pathogenesis of PRCA is poorly understood. However, idiopathic PRCA is thought to be mediated by autoimmune mechanisms, due to dysregulated B- and T-cell or even NK cell activities [3]. A study showed that gamma delta T-cells (γδ T-cells) are increased in some patients with PRCA and that the reduction in the number of γδ T-cells coincided with a significant improvement of anemia after IST. Additional data supporting the role of γδ T-cells in PRCA is the selective inhibition of colony forming unit-erythroid (CFU-E) and burst forming uniterythroid (BFU-E) cell populations by γδ T-cells while sparing CFUGM in-vitro [4]. The role of immune cells in the pathogenesis of some patients with PRCA and clinical responses to various IS agents that tied into the reduction of specific immune cell populations in PRCA serves as the basis for the use of IST such as CsA in PRCA. CsA works by inhibiting the phosphatase activity of calcineurin through formation of a complex with cyclophilin, blocking nuclear translocation, and activating the NFAT transcription factors. Its ability to block the activation of c-Jun-N terminal kinase and p38 signaling pathways, which are triggered by antigen recognition, can also explain its high specificity as an inhibitor of T cell activation [5–7]. CsA is one of the most commonly used first-line therapy for PRCA [6]. It is also a commonly used IS agent in other BM failure syndromes (BMFS) resembling PRCA such as AA, hypocellular MDS and T cell large granular lymphocyte leukemia. The efficacy and safety of CsA in BMFS are most established in severe AA mainly with hATG use. The incidence of CsA dependent response was assessed in 42 children with AA finding that 18% of patients who responded were CsA dependent. The study identified that relapse rate (RR) was highly
K. Al-Issa et al. / Blood Cells, Molecules and Diseases 54 (2015) 281–283
associated with rapid discontinuation of CsA (60%) compared to 7.6% in the slow taper group [8]. Studies evaluating CsA dependency in less common BMFS like PRCA are limited. A study in Japan which included 185 PRCA patients (73 primary and 112 secondary PRCA) showed that discontinuation of CsA maintenance therapy was strongly correlated with PRCA relapse (P b 0.001). Indeed, of 14 patients whose CsA was discontinued, 12 patients (86%) relapsed after a median of 3 months (range, 1.5–40), while only 3 of 27 patients (11%) relapsed during CsA-containing maintenance therapy [5]. Such observations have not been reported in the Caucasian population. Furthermore, our study is instructive in that a slow CsA taper will be ideal given the high RR after CsA discontinuation. Dose adjustments of CsA at the first observation of declining Hgb can lead to full restoration of Hgb levels and may prevent a full blown relapse of PRCA mediated anemia and transfusion dependence. In summary, the ideal treatment plan for PRCA is still not clear, and CsA therapy can lead to CR. Disease relapse can occur with discontinuation of CsA and is best characterized as CsA dependent patients and may be obviated by slow taper of CsA. Authorship contributions KA-I collected clinical information and wrote the manuscript. VV edited the manuscript. HJR provided images and edited the manuscript. VD gave insights to the manuscript. AEL edited the manuscript. RVT conceived the study, supervised the clinical data collection, and wrote the manuscript. All authors approved the final version of the manuscript. Acknowledgments We thank the Cleveland Clinic Seed Support (RVT).
283
References [1] K. Fukushima, T. Sato, S. Mitsuhashi, T. Gono, K. Kaneko, M. Yazaki, M. Mastuda, S. Ikeda, Pure red cell aplasia developing after treatment of pleural recurrence of thymoma, successfully treated with cyclosporin A but not with tacrolimus, Intern. Med. 45 (2006) 485–486. [2] J. Marsh, H. Schrezenmeier, P. Marin, O. Ilhan, P. Ljungman, S. McCann, G. Socie, A. Tichelli, J. Passweg, J. Hows, A. Raghavachar, A. Locasciulli, A. Bacigalupo, Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party, Blood 93 (1999) 2191–2195. [3] P. Fisch, R. Handgretinger, H.E. Schaefer, Pure red cell aplasia, Br. J. Haematol. 111 (2000) 1010–1022. [4] M. Liu, T. Liu, W.T. Meng, H.L. Zhu, X. Cui, Role of gamma delta T cells in pathogenesis of acquired pure red cell aplastic anemia, Zhongguo Shi Yan Xue Ye Xue Za Zhi 15 (2007) 142–146. [5] K. Sawada, M. Hirokawa, N. Fujishima, M. Teramura, M. Bessho, K. Dan, H. Tsurumi, S. Nakao, A. Urabe, M. Omine, K. Ozawa, PRCA Collaborative Study Group, Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA collaborative study group, Haematologica 92 (2007) 1021–1028. [6] K. Sawada, N. Fujishima, M. Hirokawa, Acquired pure red cell aplasia: updated review of treatment, Br. J. Haematol. 142 (2008) 505–514. [7] S. Matsuda, S. Koyasu, Mechanisms of action of cyclosporine, Immunopharmacology 47 (2000) 119–125. [8] P. Saracco, P. Quarello, A.P. Iori, M. Zecca, D. Longoni, J. Svahn, S. Varotto, G.C. Del Vecchio, C. Dufour, U. Ramenghi, A. Bacigalupo, A. Locasciulli, Bone Marrow Failure Study Group of the AIEOP (Italian Association of Paediatric Haematology Oncology), Cyclosporin A response and dependence in children with acquired aplastic anaemia: a multicentre retrospective study with long-term observation follow-up, Br. J. Haematol. 140 (2008) 197–205.
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd
Short Communication
Cyclosporine dependent pure red cell aplasia: A case presentation Karam Al-Issa a, Valeria Visconte a, Heesun J. Rogers b, Vikas Dembla c, Alan E. Lichtin d, Ramon V. Tiu a,d,⁎ a
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Department of Laboratory Medicine, Cleveland Clinic, OH, USA c Overton Brooks VA Medical Center, Shreveport, LA, USA d Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA b
a r t i c l e
i n f o
Article history: Submitted 26 September 2014 Accepted 15 November 2014 Available online 25 November 2014 (Communicated by M. Narla, DSc, 13 November 2014) Keywords: Pure red cell aplasia Cyclosporine Anemia Discontinuation
© 2014 Elsevier Inc. All rights reserved.
To the Editor Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by a selective decrease or absence of erythrocytes and their progenitors in the peripheral blood and bone marrow (BM) [1]. It can be either idiopathic or secondary, occurring in association with other diseases (systemic lupus erythematous, infections, pregnancy, lymphoproliferative disorders, nutritional deficiencies, medications). Idiopathic PRCA is usually treated with immunosuppressive therapies (IST) including cyclosporine (CsA). Single agent CsA can result in response rates of 46% [2]. However, the optimal duration of treatment and whether there is a need to taper treatment or the best taper schedule are not clear. Further, relapse can occur even in patients who achieved complete remission (CR). In a related disease like severe aplastic anemia (SAA), some patients successfully treated with horse anti-thymocyte globulin (hATG) + CsA are CsA dependent and can have significant disease relapse if CsA is discontinued abruptly. Here, we describe a patient with PRCA who successfully achieved CR after 12 weeks of CsA therapy but developed worsening anemia after ⁎ Corresponding author at: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Fax: +1 216 636 2498. E-mail address: [email protected] (R.V. Tiu).
http://dx.doi.org/10.1016/j.bcmd.2014.11.013 1079-9796/© 2014 Elsevier Inc. All rights reserved.
CsA tapering and had improvement in blood counts after CsA dose was increased. A 63-year-old Caucasian male, with a past medical history of symptomatic cold agglutinin disease successfully treated with 1 cycle of rituximab (375 mg/m2 IV weekly × 4) in 2003. He was doing well and had normal counts until 2012 when he experienced significant weakness after recovering from a sinus infection. He was found to have severe anemia with hemoglobin (Hgb) of 5.6 g/dL. He was admitted in the hospital and received 4 units of red blood cells (RBCs) which raised his Hgb to 9.0 g/dL. He was given a presumptive diagnosis of cold agglutinin disease and was started on prednisone (60 mg PO once daily) with no response. He also received rituximab (375 mg/m2 IV weekly × 4) without achieving any response and remained RBC transfusion dependent. He underwent a BM biopsy which showed 80% cellularity with granulocytic hyperplasia, markedly reduced erythroid maturation, no significant dysplasia, no increased BM blasts, and reticulin fibrosis (Fig. 1). No giant pronormoblasts, lymphoid aggregates or infections were noted. Metaphase cytogenetics and FISH analysis using probes for myelodyplastic syndrome (MDS) were unremarkable. Additional laboratory results showed normal serum folate, vitamin B12, LDH, uric acid and TSH levels. His remote hepatitis panel, PNH flow cytometry, Parvovirus B19 IgM and IgG, and HIV 1&2 testing were unremarkable. As expected, serum iron and ferritin levels were elevated due to numerous transfusions. He denied fever, chills, night sweats, weight loss, blood clots, joint pain, photosensitivity, rash, hematuria, hematemesis, and
282
K. Al-Issa et al. / Blood Cells, Molecules and Diseases 54 (2015) 281–283
Fig. 1. Bone marrow morphology of the case presentation. (A–C) Bone marrow (BM) aspirate (A) and core biopsy (C) show 80% cellularity and predominantly granulocytic and megakaryocytic maturation and reduced erythroid cells. No increase in the percentage of blasts and no sign of dysplasia. Reticulin stain (B) demonstrates mild to moderate increase in reticulin fibers (grade 1–2) in the core biopsy. (D) Peripheral blood smear shows normocytic anemia.
melena. His past medical history was significant for bladder cancer treated by surgical excision without chemotherapy, kidney stones that were removed surgically, umbilical hernia, and sleep apnea managed with continuous positive airway pressure. His social, family, and exposure history were all unremarkable. His medications included daily intake of folic acid (1 mg), prednisone (20 mg), and aspirin (325 mg). The vital signs and physical examination findings were unremarkable. A diagnosis of idiopathic PRCA was made. He was started on CsA 175 mg PO BID. The patient achieved a slow but steady improvement in Hgb levels (14.2 g/dL) 10 months after starting CsA, and was able to keep the same Hgb level for 6 months. Fourteen months since starting CsA, slow taper of CsA was started but resulted in a precipitous decline
Fig. 2. Complete blood cell count in the case presentation. Line graph illustrates hemoglobin (Hgb), white blood cells (WBCs), platelet (PLT) counts and absolute reticulocytes (RETIC) pre- and post-cyclosporine treatment. Quadrants show the different time points. Data are expressed as: Hgb (g/dL), WBCs (×109/L), PLT (×107/L), and RETIC (108/μL).
in Hgb levels. A reduction in his CsA levels down to 100 mg PO BID resulted in a decline in Hgb levels down to 9.5 g/dL. The dose of CsA was escalated back to 175 mg PO BID which resulted in restoration of a normal Hgb. Attempts at reducing CsA dose resulted in a decline in Hgb and only salvaged by CsA dose readjustment back to 175 mg PO BID (Fig. 2). The pathogenesis of PRCA is poorly understood. However, idiopathic PRCA is thought to be mediated by autoimmune mechanisms, due to dysregulated B- and T-cell or even NK cell activities [3]. A study showed that gamma delta T-cells (γδ T-cells) are increased in some patients with PRCA and that the reduction in the number of γδ T-cells coincided with a significant improvement of anemia after IST. Additional data supporting the role of γδ T-cells in PRCA is the selective inhibition of colony forming unit-erythroid (CFU-E) and burst forming uniterythroid (BFU-E) cell populations by γδ T-cells while sparing CFUGM in-vitro [4]. The role of immune cells in the pathogenesis of some patients with PRCA and clinical responses to various IS agents that tied into the reduction of specific immune cell populations in PRCA serves as the basis for the use of IST such as CsA in PRCA. CsA works by inhibiting the phosphatase activity of calcineurin through formation of a complex with cyclophilin, blocking nuclear translocation, and activating the NFAT transcription factors. Its ability to block the activation of c-Jun-N terminal kinase and p38 signaling pathways, which are triggered by antigen recognition, can also explain its high specificity as an inhibitor of T cell activation [5–7]. CsA is one of the most commonly used first-line therapy for PRCA [6]. It is also a commonly used IS agent in other BM failure syndromes (BMFS) resembling PRCA such as AA, hypocellular MDS and T cell large granular lymphocyte leukemia. The efficacy and safety of CsA in BMFS are most established in severe AA mainly with hATG use. The incidence of CsA dependent response was assessed in 42 children with AA finding that 18% of patients who responded were CsA dependent. The study identified that relapse rate (RR) was highly
K. Al-Issa et al. / Blood Cells, Molecules and Diseases 54 (2015) 281–283
associated with rapid discontinuation of CsA (60%) compared to 7.6% in the slow taper group [8]. Studies evaluating CsA dependency in less common BMFS like PRCA are limited. A study in Japan which included 185 PRCA patients (73 primary and 112 secondary PRCA) showed that discontinuation of CsA maintenance therapy was strongly correlated with PRCA relapse (P b 0.001). Indeed, of 14 patients whose CsA was discontinued, 12 patients (86%) relapsed after a median of 3 months (range, 1.5–40), while only 3 of 27 patients (11%) relapsed during CsA-containing maintenance therapy [5]. Such observations have not been reported in the Caucasian population. Furthermore, our study is instructive in that a slow CsA taper will be ideal given the high RR after CsA discontinuation. Dose adjustments of CsA at the first observation of declining Hgb can lead to full restoration of Hgb levels and may prevent a full blown relapse of PRCA mediated anemia and transfusion dependence. In summary, the ideal treatment plan for PRCA is still not clear, and CsA therapy can lead to CR. Disease relapse can occur with discontinuation of CsA and is best characterized as CsA dependent patients and may be obviated by slow taper of CsA. Authorship contributions KA-I collected clinical information and wrote the manuscript. VV edited the manuscript. HJR provided images and edited the manuscript. VD gave insights to the manuscript. AEL edited the manuscript. RVT conceived the study, supervised the clinical data collection, and wrote the manuscript. All authors approved the final version of the manuscript. Acknowledgments We thank the Cleveland Clinic Seed Support (RVT).
283
References [1] K. Fukushima, T. Sato, S. Mitsuhashi, T. Gono, K. Kaneko, M. Yazaki, M. Mastuda, S. Ikeda, Pure red cell aplasia developing after treatment of pleural recurrence of thymoma, successfully treated with cyclosporin A but not with tacrolimus, Intern. Med. 45 (2006) 485–486. [2] J. Marsh, H. Schrezenmeier, P. Marin, O. Ilhan, P. Ljungman, S. McCann, G. Socie, A. Tichelli, J. Passweg, J. Hows, A. Raghavachar, A. Locasciulli, A. Bacigalupo, Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party, Blood 93 (1999) 2191–2195. [3] P. Fisch, R. Handgretinger, H.E. Schaefer, Pure red cell aplasia, Br. J. Haematol. 111 (2000) 1010–1022. [4] M. Liu, T. Liu, W.T. Meng, H.L. Zhu, X. Cui, Role of gamma delta T cells in pathogenesis of acquired pure red cell aplastic anemia, Zhongguo Shi Yan Xue Ye Xue Za Zhi 15 (2007) 142–146. [5] K. Sawada, M. Hirokawa, N. Fujishima, M. Teramura, M. Bessho, K. Dan, H. Tsurumi, S. Nakao, A. Urabe, M. Omine, K. Ozawa, PRCA Collaborative Study Group, Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA collaborative study group, Haematologica 92 (2007) 1021–1028. [6] K. Sawada, N. Fujishima, M. Hirokawa, Acquired pure red cell aplasia: updated review of treatment, Br. J. Haematol. 142 (2008) 505–514. [7] S. Matsuda, S. Koyasu, Mechanisms of action of cyclosporine, Immunopharmacology 47 (2000) 119–125. [8] P. Saracco, P. Quarello, A.P. Iori, M. Zecca, D. Longoni, J. Svahn, S. Varotto, G.C. Del Vecchio, C. Dufour, U. Ramenghi, A. Bacigalupo, A. Locasciulli, Bone Marrow Failure Study Group of the AIEOP (Italian Association of Paediatric Haematology Oncology), Cyclosporin A response and dependence in children with acquired aplastic anaemia: a multicentre retrospective study with long-term observation follow-up, Br. J. Haematol. 140 (2008) 197–205.
