Bone Marrow Transplantation (2014) 49, 1116–1118 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Recovery from life-threatening transplantation-associated thrombotic microangiopathy using eculizumab in a patient with very severe aplastic anemia Bone Marrow Transplantation (2014) 49, 1116–1118; doi:10.1038/ bmt.2014.97; published online 12 May 2014
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic SCT (HSCT). Particularly, prognosis of the TA-TMA with multiorgan impairment is poor because there is no definitive therapy.1–3 The pathogenesis of TA-TMA remains undetermined; however, Jodele et al.4 reported that dysregulation of the complement system may be involved in the pathogenesis of TA-TMA. Eculizumab, a humanized moAb against the complement component C5 that prevents tissue damage by blocking the formation of the membrane attack complex, has been successful in the treatment of paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome (aHUS).5,6 Thus, if uncontrolled activation of the complement system has an important role in the development of TA-TMA, eculizmab could be a targeted therapy for TA-TMA. We report the case of a 9-year-old male who was diagnosed with SAA. The patient underwent transplantation with HLAidentical BM cells from the sibling after treatment with fludarabine, CY and antithymocyte globulin (ATG). CsA was administered as a prophylaxis for acute GVHD. Recovery of WBC after HSCT was poor due to mixed chimerism. Next, the patient received DLI twice (on days 22 and 45). On day 54, the patient had acute GVHD (skin: stage 1; gut: stage 1). Despite treatment with methylprednisolone (mPSL) in addition to CsA, gut symptoms (for example, abdominal pain and melena) worsened with proteinlosing enteropathy on day 80. Pathological findings of the duodenal mucosal membrane biopsied by intestinal endoscopy were consistent with those for GVHD (stage 4, grade III). Efficacy of administration of 2.5 mg/kg ATG on day 112, infliximab from day 161 or tacrolimus instead of CsA from day 189 was limited for gut GVHD. Therefore, from day 237, the patient received mPSL (1 mg/kg) and infliximab (every 3 weeks) as treatment for GVHD. On day 303 after transplantation, the patient developed posterior reversible encephalopathy syndrome and subsequently developed respiratory distress with massive pleural effusion and pulmonary edema accompanied by systemic fluid retention, including subcutaneous effusion and pericardial effusion (Figure 1, left panel). Work-up examinations revealed no involvement of infectious agents such as CMV, fungi or Pneumocystis jiroveci. The counts of RBC, reticulocytes and platelets, and Hb levels were 1.81 × 109/L, 0.26 × 109/L, and 27 × 109/L, and 6.7 g/dL, respectively. Serum levels of lactate dehydrogenase (LDH) were 948 IU/L. Haptoglobin levels were below the limit of detection. Fragmented red cells were noted on the blood smear. On the basis of all findings, we diagnosed the patient with TA-TMA on day 305. Intensive supportive therapy (that is, mechanical ventilation, albumin replacement and diuretics) was initiated for respiratory distress in the intensive care unit; however, neuropsychiatric symptoms and hemolysis remained severe. Frequent blood transfusions were required, whereas the patient’s Hb level abruptly fell to 4.2 g/dL (Figure 2). Serum levels of LDH, fibrin
degradation product (FDP), blood urea nitrogen and creatinine were 1635 IU/L, 25.5 ng/mL, 70 mg/dL and 0.29 mg/dL, respectively. Furthermore, serum levels of direct bilirubin increased to 2.2 mg/dL, suggesting the development of TA-TMA with multiorgan impairment on day 315. On the basis of a case report that showed a dramatic resolution of symptoms associated with TA-TMA after eculizumab administration,7 we administered eculizumab according to the dose for aHUS (600 mg weekly as an initial dose based on the patient’s body weight).6 Two doses of eculizumab improved the serum levels of LDH, FDP and Hb (Figure 2). However, serum levels of LDH rebounded before the third eculizumab administration (Figure 2). Therefore, we increased the next three doses of eculizumab to 900 mg every week. The patient tolerated eculizumab therapy without any side effects. After the fourth eculizmab administration, oxygen inhalation was stopped, and chest computed tomography (day 344) revealed the improvement of pleural effusion and pulmonary edema, whereas pericardial effusion persisted (Figure 1, right panel). Similarly, four doses of eculizumab were required to resolve neuropsychiatric symptoms completely. Notably, protein-losing enteropathy improved with no decrease in serum levels of albumin. We decreased the dose of the sixth eculizumab administration to 600 mg, and then from the seventh eculizumab administration to the last (fourteenth) administration, eculizumab was administered every 2 weeks. Eculizumab administration was stopped after confirming that the patient’s peripheral blood cell counts and serum levels of LDH were within the age-controlled normal range (WBC: 5.4 × 109/L; Hb: 12.6 g/dL; platelet: 248 × 109/L; LDH: 296 IU/L). It has been 2 months since the last eculizumab administration and the patient is now doing well with no sign of relapse of TA-TMA. In this patient, complement components (C3, C4 and factor H) and CH50 activity were within normal ranges before eculizumab administration. A decrease in ADAMTS13 activity was not identified. Expression levels of complement factor H (CFH), CFHrelated 1 and 3 proteins were detected and anti-CFH antibody was not identified in the patient’s plasma by western blotting. Typical deletions in the CFH-related genes 3 and 1 observed in patients with aHUS8 or TA-TMA4 were not identified by multiplex ligationdependent probe amplification. In our investigation, we failed to show the finding that the dysregulation of the complement system was associated with the development of TA-TMA in this patient. It remains undetermined what dose or duration of eculizumab therapy is required for TA-TMA resolution. We administered eculizumab with 600 mg as the initial dose according to recommendations for children with aHUS because the patient’s weight was 23 kg.6 However, we should have increased the dose to 900 mg, suggesting that a much higher dose of eculizumab may be required for the treatment of TA-TMA compared with the dose required for the treatment of aHUS. After four doses of eculizumab every week, the hematological parameters associated with TA-TMA began to improve with other complications, including neuropsychiatric symptoms and respiratory distress.
Letter to the Editor
1117 Chest CT: Day 316 befor eculizumab
Chest CT: Day 344 after four doses of eculizumab
Figure 1. Chest computed tomography. Left panel: chest computed tomography examined on day 316 after HSCT revealed massive pleural effusion and pulmonary edema accompanied by systemic fluid retention, including subcutaneous effusion and pericardial effusion. Right panel: on day 344 after HSCT (after four doses of eculizumab administration), pleural effusion and pulmonary edema were resolved, whereas pericaridial effusion persisted. PRES (day 303)
Normal values (9 years old male) Hb: 11.5-15.5 g/dL Platelet: 150-400 x 109/L LDH: 175-320 IU/L
TA-TMA Diag. ---> Severe (day 305) (day 315)
Neuropsychiatric symptoms
Hb (g/dl)
Hb 15 ICU
10
Hb 5 1
PLT (x 10*9/L)
PLT
0 300
2
3
4
5
6
7
8
9
10
11
12
13
14
Eculizumab 600 mg 900 mg
200
Haptoglobin 10> mg/dl
PLT
133 mg/dl
100 0 2000
LDH
LDH (IU/l)
1600 1200 800
LDH
400
500
493
486
479
472
465
458
451
444
437
430
423
416
409
402
395
388
381
374
367
360
353
346
339
332
325
318
311
304
297
290
283
276
269
262
0 Days (after BMT)
Figure 2.
Clinical and biological responses to eculizumab therapy in a patient with TA-TMA after BMT.
In total, 14 doses were required for the normalization of the laboratory data associated with TA-TMA. Further studies will need to clarify the role of the complement system in the pathogenesis of TA-TMA and establish the treatment strategy of eculizumab therapy for TA-TMA.
M Okano, N Sakata, S Ueda and T Takemura Department of Pediatrics, Kinki University Faculty of Medicine, Osaka, Japan E-mail: [email protected] REFERENCES
CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank Yoko Yoshida, MD (Department of Blood Transfusion, Nara Medical University) for estimating the expression of CFH, CHFR-1, -3 and anti-CFH antibody.
© 2014 Macmillan Publishers Limited
1 Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 571–575. 2 Nakamae H, Yamane T, Hasegawa T, Nakamae M, Terada Y, Hagihara K et al. Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. Am J Hematol 2006; 81: 525–531.
Bone Marrow Transplantation (2014) 1116 – 1118
Letter to the Editor
1118 3 Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs 2009; 69: 183–198. 4 Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA et al. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood 2013; 122: 2003–2007. 5 Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. New Engl J Med 2004; 350: 552–559.
Bone Marrow Transplantation (2014) 1116 – 1118
6 Schmidtko J, Peine S, El-Housseini Y, Pascual M, Meier P. Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis 2013; 61: 289–299. 7 Peffault de Latour R, Xhaard A, Fremeaux-Bacchi V, Coppo P, Fischer AM, Helley D et al. Successful use of eculizumab in a patient with post-transplant thrombotic microangiopathy. Br J Haematol 2013; 161: 279–280. 8 Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 2010; 115: 379–387.
© 2014 Macmillan Publishers Limited
LETTER TO THE EDITOR
Recovery from life-threatening transplantation-associated thrombotic microangiopathy using eculizumab in a patient with very severe aplastic anemia Bone Marrow Transplantation (2014) 49, 1116–1118; doi:10.1038/ bmt.2014.97; published online 12 May 2014
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic SCT (HSCT). Particularly, prognosis of the TA-TMA with multiorgan impairment is poor because there is no definitive therapy.1–3 The pathogenesis of TA-TMA remains undetermined; however, Jodele et al.4 reported that dysregulation of the complement system may be involved in the pathogenesis of TA-TMA. Eculizumab, a humanized moAb against the complement component C5 that prevents tissue damage by blocking the formation of the membrane attack complex, has been successful in the treatment of paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome (aHUS).5,6 Thus, if uncontrolled activation of the complement system has an important role in the development of TA-TMA, eculizmab could be a targeted therapy for TA-TMA. We report the case of a 9-year-old male who was diagnosed with SAA. The patient underwent transplantation with HLAidentical BM cells from the sibling after treatment with fludarabine, CY and antithymocyte globulin (ATG). CsA was administered as a prophylaxis for acute GVHD. Recovery of WBC after HSCT was poor due to mixed chimerism. Next, the patient received DLI twice (on days 22 and 45). On day 54, the patient had acute GVHD (skin: stage 1; gut: stage 1). Despite treatment with methylprednisolone (mPSL) in addition to CsA, gut symptoms (for example, abdominal pain and melena) worsened with proteinlosing enteropathy on day 80. Pathological findings of the duodenal mucosal membrane biopsied by intestinal endoscopy were consistent with those for GVHD (stage 4, grade III). Efficacy of administration of 2.5 mg/kg ATG on day 112, infliximab from day 161 or tacrolimus instead of CsA from day 189 was limited for gut GVHD. Therefore, from day 237, the patient received mPSL (1 mg/kg) and infliximab (every 3 weeks) as treatment for GVHD. On day 303 after transplantation, the patient developed posterior reversible encephalopathy syndrome and subsequently developed respiratory distress with massive pleural effusion and pulmonary edema accompanied by systemic fluid retention, including subcutaneous effusion and pericardial effusion (Figure 1, left panel). Work-up examinations revealed no involvement of infectious agents such as CMV, fungi or Pneumocystis jiroveci. The counts of RBC, reticulocytes and platelets, and Hb levels were 1.81 × 109/L, 0.26 × 109/L, and 27 × 109/L, and 6.7 g/dL, respectively. Serum levels of lactate dehydrogenase (LDH) were 948 IU/L. Haptoglobin levels were below the limit of detection. Fragmented red cells were noted on the blood smear. On the basis of all findings, we diagnosed the patient with TA-TMA on day 305. Intensive supportive therapy (that is, mechanical ventilation, albumin replacement and diuretics) was initiated for respiratory distress in the intensive care unit; however, neuropsychiatric symptoms and hemolysis remained severe. Frequent blood transfusions were required, whereas the patient’s Hb level abruptly fell to 4.2 g/dL (Figure 2). Serum levels of LDH, fibrin
degradation product (FDP), blood urea nitrogen and creatinine were 1635 IU/L, 25.5 ng/mL, 70 mg/dL and 0.29 mg/dL, respectively. Furthermore, serum levels of direct bilirubin increased to 2.2 mg/dL, suggesting the development of TA-TMA with multiorgan impairment on day 315. On the basis of a case report that showed a dramatic resolution of symptoms associated with TA-TMA after eculizumab administration,7 we administered eculizumab according to the dose for aHUS (600 mg weekly as an initial dose based on the patient’s body weight).6 Two doses of eculizumab improved the serum levels of LDH, FDP and Hb (Figure 2). However, serum levels of LDH rebounded before the third eculizumab administration (Figure 2). Therefore, we increased the next three doses of eculizumab to 900 mg every week. The patient tolerated eculizumab therapy without any side effects. After the fourth eculizmab administration, oxygen inhalation was stopped, and chest computed tomography (day 344) revealed the improvement of pleural effusion and pulmonary edema, whereas pericardial effusion persisted (Figure 1, right panel). Similarly, four doses of eculizumab were required to resolve neuropsychiatric symptoms completely. Notably, protein-losing enteropathy improved with no decrease in serum levels of albumin. We decreased the dose of the sixth eculizumab administration to 600 mg, and then from the seventh eculizumab administration to the last (fourteenth) administration, eculizumab was administered every 2 weeks. Eculizumab administration was stopped after confirming that the patient’s peripheral blood cell counts and serum levels of LDH were within the age-controlled normal range (WBC: 5.4 × 109/L; Hb: 12.6 g/dL; platelet: 248 × 109/L; LDH: 296 IU/L). It has been 2 months since the last eculizumab administration and the patient is now doing well with no sign of relapse of TA-TMA. In this patient, complement components (C3, C4 and factor H) and CH50 activity were within normal ranges before eculizumab administration. A decrease in ADAMTS13 activity was not identified. Expression levels of complement factor H (CFH), CFHrelated 1 and 3 proteins were detected and anti-CFH antibody was not identified in the patient’s plasma by western blotting. Typical deletions in the CFH-related genes 3 and 1 observed in patients with aHUS8 or TA-TMA4 were not identified by multiplex ligationdependent probe amplification. In our investigation, we failed to show the finding that the dysregulation of the complement system was associated with the development of TA-TMA in this patient. It remains undetermined what dose or duration of eculizumab therapy is required for TA-TMA resolution. We administered eculizumab with 600 mg as the initial dose according to recommendations for children with aHUS because the patient’s weight was 23 kg.6 However, we should have increased the dose to 900 mg, suggesting that a much higher dose of eculizumab may be required for the treatment of TA-TMA compared with the dose required for the treatment of aHUS. After four doses of eculizumab every week, the hematological parameters associated with TA-TMA began to improve with other complications, including neuropsychiatric symptoms and respiratory distress.
Letter to the Editor
1117 Chest CT: Day 316 befor eculizumab
Chest CT: Day 344 after four doses of eculizumab
Figure 1. Chest computed tomography. Left panel: chest computed tomography examined on day 316 after HSCT revealed massive pleural effusion and pulmonary edema accompanied by systemic fluid retention, including subcutaneous effusion and pericardial effusion. Right panel: on day 344 after HSCT (after four doses of eculizumab administration), pleural effusion and pulmonary edema were resolved, whereas pericaridial effusion persisted. PRES (day 303)
Normal values (9 years old male) Hb: 11.5-15.5 g/dL Platelet: 150-400 x 109/L LDH: 175-320 IU/L
TA-TMA Diag. ---> Severe (day 305) (day 315)
Neuropsychiatric symptoms
Hb (g/dl)
Hb 15 ICU
10
Hb 5 1
PLT (x 10*9/L)
PLT
0 300
2
3
4
5
6
7
8
9
10
11
12
13
14
Eculizumab 600 mg 900 mg
200
Haptoglobin 10> mg/dl
PLT
133 mg/dl
100 0 2000
LDH
LDH (IU/l)
1600 1200 800
LDH
400
500
493
486
479
472
465
458
451
444
437
430
423
416
409
402
395
388
381
374
367
360
353
346
339
332
325
318
311
304
297
290
283
276
269
262
0 Days (after BMT)
Figure 2.
Clinical and biological responses to eculizumab therapy in a patient with TA-TMA after BMT.
In total, 14 doses were required for the normalization of the laboratory data associated with TA-TMA. Further studies will need to clarify the role of the complement system in the pathogenesis of TA-TMA and establish the treatment strategy of eculizumab therapy for TA-TMA.
M Okano, N Sakata, S Ueda and T Takemura Department of Pediatrics, Kinki University Faculty of Medicine, Osaka, Japan E-mail: [email protected] REFERENCES
CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank Yoko Yoshida, MD (Department of Blood Transfusion, Nara Medical University) for estimating the expression of CFH, CHFR-1, -3 and anti-CFH antibody.
© 2014 Macmillan Publishers Limited
1 Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 571–575. 2 Nakamae H, Yamane T, Hasegawa T, Nakamae M, Terada Y, Hagihara K et al. Risk factor analysis for thrombotic microangiopathy after reduced-intensity or myeloablative allogeneic hematopoietic stem cell transplantation. Am J Hematol 2006; 81: 525–531.
Bone Marrow Transplantation (2014) 1116 – 1118
Letter to the Editor
1118 3 Choi CM, Schmaier AH, Snell MR, Lazarus HM. Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. Drugs 2009; 69: 183–198. 4 Jodele S, Licht C, Goebel J, Dixon BP, Zhang K, Sivakumaran TA et al. Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy. Blood 2013; 122: 2003–2007. 5 Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. New Engl J Med 2004; 350: 552–559.
Bone Marrow Transplantation (2014) 1116 – 1118
6 Schmidtko J, Peine S, El-Housseini Y, Pascual M, Meier P. Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis 2013; 61: 289–299. 7 Peffault de Latour R, Xhaard A, Fremeaux-Bacchi V, Coppo P, Fischer AM, Helley D et al. Successful use of eculizumab in a patient with post-transplant thrombotic microangiopathy. Br J Haematol 2013; 161: 279–280. 8 Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 2010; 115: 379–387.
© 2014 Macmillan Publishers Limited
