Case Report: Successful Treatment With Anti-C5 Monoclonal Antibody in a Japanese Adolescent Who Developed Thrombotic Microangiopathy After Autologous Bone Marrow Transplantation for Malignant Lymphoma

Abstract

Background
Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of bone marrow transplantation (BMT). Recently, abnormalities in the complement system have been identified in the pathogenesis of TA-TMA, and there are series of reports stating that anti-C5 monoclonal antibody (eculizumab) is effective in patients with high levels of the membrane attack complex (C5b-9).

Case Presentation
A 12-year-old boy underwent autologous BMT after receiving high-dose chemotherapy for malignant lymphoma. The patient was engrafted on day 19 after transplantation; however, hemolytic anemia and non-immune thrombocytopenia persisted, and haptoglobin decreased on day 46. Moreover, on day 83, the patient developed pulmonary hemorrhage, hypertension, severe proteinuria, hematuria, and acute kidney injury (AKI). Pulmonary bleeding stopped with daily platelet transfusion and hemostatic agents, but reappeared on day 100. Based on the presence of destruction of red blood cells, elevated lactate dehydrogenase levels, negative direct and indirect Coombs tests, normal ADAMTS13 levels, hemolytic anemia, non-immune thrombocytopenia, and AKI, the patient was diagnosed with systemic TA-TMA and we initiated plasma exchange (PE) and continuous hemodialysis for AKI. High C5b-9 levels were identified at the start of the series of PE, therefore we decided to administer eculizumab. After three courses of eculizumab, no pulmonary hemorrhage was observed, and anemia, thrombocytopenia, renal dysfunction, hematuria, and proteinuria all tended to improve. Three years after transplantation, the patient is alive and does not require eculizumab.

Discussion
Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage C5 and the formation of C5b-9. In this case, TA-TMA could not be controlled with PE alone. We therefore decided to use eculizumab relatively early based on the high C5b-9 level and could resolve the momentum of TA-TMA.

Conclusion
In previous reports, TA-TMA typically occurred in early post-allogeneic BMT of patients with lymphoma or in post-autologous BMT of patients with neuroblastoma and was treated with eculizumab. We here reported that eculizumab could be successful treatment for TA-TMA in post-autologous BMT of patient with lymphoma.

Full text

CASE REPORT
published: 04 July 2022
doi: 10.3389/fped.2022.908183
Frontiers in Pediatrics | www.frontiersin.org 1July 2022 | Volume 10 | Article 908183
Edited by:
Toshihiro Sawai,
Shiga University of Medical
Science, Japan
Reviewed by:
Sarah E. Sartain,
Baylor College of Medicine,
United States
Nabanita Bhunia,
Nationwide Children’s Hospital,
United States
*Correspondence:
Tamaki Morohashi
morohashi.tamaki@nihon-u.ac.jp
Specialty section:
This article was submitted to
Pediatric Nephrology,
a section of the journal
Frontiers in Pediatrics
Received: 30 March 2022
Accepted: 06 June 2022
Published: 04 July 2022
Citation:
Shimizu S, Morohashi T, Kanezawa K,
Yagasaki H, Takahashi S and Morioka I
(2022) Case Report: Successful
Treatment With Anti-C5 Monoclonal
Antibody in a Japanese Adolescent
Who Developed Thrombotic
Microangiopathy After Autologous
Bone Marrow Transplantation for
Malignant Lymphoma.
Front. Pediatr. 10:908183.
doi: 10.3389/fped.2022.908183
Case Report: Successful Treatment
With Anti-C5 Monoclonal Antibody in
a Japanese Adolescent Who
Developed Thrombotic
Microangiopathy After Autologous
Bone Marrow Transplantation for
Malignant Lymphoma
Shoichi Shimizu 1, Tamaki Morohashi 1
*, Koji Kanezawa 1, Hiroshi Yagasaki1,
Shori Takahashi 2and Ichiro Morioka 1
1Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan, 2Itabashi Central Medical
Center, Tokyo, Japan
Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious
complication of bone marrow transplantation (BMT). Recently, abnormalities in the
complement system have been identified in the pathogenesis of TA-TMA, and there are
series of reports stating that anti-C5 monoclonal antibody (eculizumab) is effective in
patients with high levels of the membrane attack complex (C5b-9).
Case Presentation: A 12-year-old boy underwent autologous BMT after receiving
high-dose chemotherapy for malignant lymphoma. The patient was engrafted on day
19 after transplantation; however, hemolytic anemia and non-immune thrombocytopenia
persisted, and haptoglobin decreased on day 46. Moreover, on day 83, the patient
developed pulmonary hemorrhage, hypertension, severe proteinuria, hematuria, and
acute kidney injury (AKI). Pulmonary bleeding stopped with daily platelet transfusion
and hemostatic agents, but reappeared on day 100. Based on the presence of
destruction of red blood cells, elevated lactate dehydrogenase levels, negative direct
and indirect Coombs tests, normal ADAMTS13 levels, hemolytic anemia, non-immune
thrombocytopenia, and AKI, the patient was diagnosed with systemic TA-TMA and
we initiated plasma exchange (PE) and continuous hemodialysis for AKI. High C5b-9
levels were identified at the start of the series of PE, therefore we decided to administer
eculizumab. After three courses of eculizumab, no pulmonary hemorrhage was observed,
and anemia, thrombocytopenia, renal dysfunction, hematuria, and proteinuria all tended
to improve. Three years after transplantation, the patient is alive and does not
require eculizumab.
Discussion: Eculizumab is a humanized monoclonal antibody that binds complement
protein C5, preventing cleavage C5 and the formation of C5b-9. In this case, TA-TMA

Shimizu et al. Case Report: Eculizumab for TA-TMA After BMT
could not be controlled with PE alone. We therefore decided to use eculizumab relatively
early based on the high C5b-9 level and could resolve the momentum of TA-TMA.
Conclusion: In previous reports, TA-TMA typically occurred in early post-allogeneic
BMT of patients with lymphoma or in post-autologous BMT of patients with
neuroblastoma and was treated with eculizumab. We here reported that eculizumab
could be successful treatment for TA-TMA in post-autologous BMT of patient
with lymphoma.
Keywords: transplant-associated thrombotic microangiopathy (TA-TMA), anti-C5 monoclonal antibody
(eculizumab), membrane attack complex (C5b-9), acute kidney injury (AKI), graft-versus-host disease (GVHD)
INTRODUCTION
Transplant-associated thrombotic microangiopathy (TA-TMA)
is an increasingly recognized complication of bone marrow
transplantation (BMT) with high rates of morbidity and
mortality. TA-TMA is characterized by microangiopathic
hemolytic anemia, consumptive thrombocytopenia, and organ
damage due to microcirculatory failure (1) and is associated with
approximately 10–25% of allogeneic transplants (2).
The clinical findings of TA-TMA include rapid progression
of anemia, fragmentation of red blood cells, delayed platelet
recovery, transfusion refractoriness, elevated serum lactate
dehydrogenase (LDH) levels, and acute renal failure. Disease
onset often occurs after leukocyte engraftment and up to 100 days
after transplantation (3).
Although the pathophysiology of TA-TMA is not fully
understood, it is ultimately caused by vascular endothelial cell
damage in multiple organs, including the kidney, lung, intestine,
and central nervous system (4). The causes of TA-TMA include
intense chemotherapy and total body irradiation during pre-
transplant treatment, administration of calcineurin inhibitors for
graft-versus-host disease (GVHD) prophylaxis, complications of
severe GVHD, and post-transplant infections (5,6).
TA-TMA is a poor prognostic complication of BMT, and even
if the patient survives, irreversible damage to the renal tissue may
occur, leading to chronic kidney disease (CKD) in some cases (7).
There is currently no standard of care for TA-TMA, and
mortality is high, despite the use of plasma exchange (PE).
Eculizumab, an anti-C5 monoclonal antibody, inhibits the
formation of the terminal membrane attack complex (C5b-9)
and TMA progression (8,9). Eculizumab is commonly used as
a treatment for paroxysmal nocturnal hemoglobinuria (PNH)
and atypical hemolytic uremic syndrome (HUS), and there are a
series of reports that were also effective in patients with TA-TMA
which has similar presentation and pathophysiology to atypical
HUS (10–12).
Previous reports have shown that TA-TMA usually occurred
in early post-allogeneic BMT of patients with lymphoma or
in post-autologous BMT of patients with neuroblastoma, and
the therapeutic effects of eculizumab have been recognized in
these pathological conditions (11,13). However, there are few
reports of the use of eculizumab for TA-TMA that occurs
in post-autologous BMT of patient with lymphoma. Herein,
we report the case of a 12-year-old boy who underwent
autologous BMT after high-dose chemotherapy for primary
gastric lymphoma and developed TA-TMA that was successfully
treated with eculizumab.
CASE DESCRIPTION
A 12-year-old patient underwent autologous BMT after high-
dose chemotherapy included etoposide, carboplatin, and
cyclophosphamide for malignant lymphoma. The patient was
engrafted on day 19 after transplantation; however, anemia and
non-immune thrombocytopenia persisted. Additionally, the
bone marrow findings on day 31 showed hypoplastic marrow,
and haptoglobin levels suggestive of the presence of hemolytic
anemia decreased to 15 mg/dL on day 46. He had hypertension
due to intravascular overflow and needed a calcium blocker.
Bloody sputum and respiratory distress appeared on day 83,
and chest computed tomography showed diffuse pulmonary
hemorrhage and bilateral pleural effusions. Although pulmonary
bleeding stopped with platelet transfusion and hemostatic agents,
it reappeared on day 100. Furthermore, the patient developed
hypertension, severe proteinuria, and hematuria. Laboratory
tests showed anemia associated with fragmented red blood cells
and elevated LDH levels consistent with hemolytic anemia,
negative direct and indirect Coombs tests, normal ADAMTS13
levels, and non-immune thrombocytopenia. Acute kidney
injury (AKI) was defined as elevated creatinine (Cr) levels and
decreased urine output (Table 1).
The patient was finally diagnosed as having systemic TA-
TMA based on the diagnostic criteria of Jodele et al. (9),
and we initiated daily PE along with continuous hemodialysis
for AKI. Despite a decrease in Cr and an upward trend in
platelet level, pulmonary hemorrhage could not be controlled,
leading to temporary endotracheal intubation and artificial
respiration management to secure the airway and positive
pressure ventilation. However, the therapeutic effect of PE
on TA-TMA was limited. Because of the high C5b-9 levels
(213.9 ng/ml, normal 85.5 ±21.1 ng/ml) at the beginning of
PE, we decided to stop PE and to administer eculizumab.
Eculizumab was administered once per week for a total
of three doses. We prescribed eculizumab after receiving
approval for its off-label use in the hospital. We also obtained
full informed consent from the patient and his parents,
and the patient was administered a meningococcal vaccine
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Shimizu et al. Case Report: Eculizumab for TA-TMA After BMT
TABLE 1 | Blood and urine test findings at the time of the second pulmonary hemorrhage (Parentheses indicate normal values).
Blood
WBC 3,400 (3,300∼8,600) /µLT-Bil 3.47 (0.4∼1.5) mg/dL
Neu 81.0 % D-Bil 0.84 (0.05∼0.4) mg/dL
Mono 6.0 % AST 39 (13∼30) IU/L
Lymph 13.0 % ALT 55 (10∼42) IU/L
RBC 2.15 ×106(4.35∼5.55 ×106)/µL LDH 883 (124∼222) IU/L
Hb 6.2 (13.7∼16.8) g/dL BUN 47.1 (8∼20) mg/dL
Ht 19.2 (40.7∼50.1) % Cr 1.21 mg/dL
Plt 3.2 ×104(15.8∼34.8 ×104)/µLNa 146 (138∼145) mmol/L
Ret 45 (4∼20) ‰K 3.3 (3.6∼4.8) mmol/L
Cl 112 (101∼108) mmol/L
CRP 0.40 (<0.2) mg/dL
TP 5.9 (6.6∼8.1) g/dL
Alb 3.5 (4.1∼5.1) g/dL
Cr-eGFR 63.9 (>90) mL/min/ 1.73m2
Blood Urine
PT ratio 1.01 (0.9∼1.1) pH 6.5 (5.0∼7.0)
APTT 39.9 (27∼45) sec SG 1.023 (1.005∼1.02)
Fib 293 (150∼400) mg/dL Protein (4+)
AT-3 80 (70∼130) % Sugar (1+)
FDP 12.0 (<5) µg/dL OB (3+)
D-dimer 5.4 (<5) µg/dL URO (±)
Bil (-)
Cystatin C 1.08 (0.58∼0.98) mg/L Ket (-)
Renin 0.6 (0.2∼3.9) ng/mL/hr RBC 50∼99 /HPF
Aldosterone 10.0 (<173) pg/mL
NAG 48.6 (<5) IU/L
CH50 50.5 (30∼45) U/mL β2MG 10048 (5∼300) µg/L
Haptoglobin <10 (19∼170) mg/dL
ADAMTS13 92 (50∼150) % U-TP/Cre 23.05 (<0.2) g/ gCr
direct coombs (-)
indirect coombs (-)
Blood and urine showed fragmented red blood cells, elevated LDH and creatinine levels, negative direct and indirect Coombs tests, normal ADAMTS13 levels, hemolytic anemia, and
non-immune thrombocytopenia.
WBC, white blood cell; Neu, neutrophils; Mono, monocyte; Lymph, lymphocytes; RBC, red blood cell; Hb, hemoglobin; Ht, hematocrit; Plt, blood platelet; Ret, reticulocytes; pH, pounds
hydrogenii; PaCO2, alveolar carbon dioxide tension; PaO2, partial pressure of arterial oxygen; HCO3−, bicarbonate ion; BE, base excess; T-Bil, total bilirubin; D-Bil, direct bilirubin; AST,
aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; BUN, urea nitrogen; Cr, creatinine; Na, sodium; K, potassium; Cl, chloride; CRP, C-reactive
protein; TP, total protein; Ab, albumin; Cr-eGFR, creatinine-estimated glomerular filtration rate; PT, prothrombin time; APTT, activated partial thromboplastin time; Fib, fibrinogen; AT-3,
antithrombin; FDP, fibrin degradation product; CH50, 50% hemolytic unit of complement; ADAMSTS13, a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13;
SG, specific gravity; OB, occult blood; URO, urobilinogen; UTP/Cr, Urinary protein-creatinine ratio; Bil, bilirubin; Ket, ketone; NAG, N-acetylglucosaminidase; β2MG, β2 -microglobulin;
U-TP/Cre, urine protein-to-creatinine ratio. The bold indicates out of normal range.
with eculizumab. The patient was also given cefozopran
hydrochloride as antimicrobial prophylaxis adequate to cover
meningococcal infection.
Jodele et al. proposed an algorithm for effective administration
of eculizumab to patients with TMA using CH50 levels and
serum levels of eculizumab (14). When steady CH50 suppression
is achieved and hematologic TMA parameters and plasma
sC5b-9 normalize, eculizumab should be advanced to a
maintenance schedule. Then, if TMA remains controlled after
3 to 4 maintenance doses, eculizumab may be discontinued.
In this case, after three courses of eculizumab, no pulmonary
hemorrhage was observed, and hemolysis, thrombocytopenia,
renal dysfunction, hematuria, and proteinuria tended to
improve. Thereafter, the complement levels normalized,
and regular eculizumab infusion was not necessary. Two
months later, the patient became transfusion independent
(Figure 1).
Ten months after TA-TMA onset, renal biopsy was performed
to evaluate the long-term prognosis of the kidney. The
estimated glomerular filtration rate (eGFR) of Cr was 119.7
mL/min/1.73 m2 at the time of the biopsy. Changes in the
basement membrane of the glomeruli were minimal, mesangial
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Shimizu et al. Case Report: Eculizumab for TA-TMA After BMT
FIGURE 1 | Post-transplant clinical course. Platelet count, serum creatinine level, urine protein-creatinine ratio, haptoglobin, and complement titers are also shown to
illustrate changes in transplant-associated thrombotic microangiopathy disease status. BMT, Bone marrow transplantation; Plt, blood platelet; Cr, creatinine;
U-TP/Cre, urine protein-to-creatinine ratio; CH50, 50% hemolytic unit of complement; C5b-9, membrane attack complex; HDF, hemodiafiltration; RCC-LR, red cell
concentrates-leukocytes reduced; PC, platelet concentrate; Ca, calcium.
proliferation was partial, and fibrosis was only observed in
10% of the entire tissue. There were only two sclerotic
glomeruli, out of 18 (Figure 2). The immunofluorescence
antibody method showed focal and segmental staining of
IgM and fibrinogen, which was consistent with TMA, and
there were no obvious abnormal electron microscopic findings.
The membranoproliferative glomerulonephritis-like changes in
glomeruli, global glomerular sclerosis, arterial fibrous thickening,
tubular atrophy, and interstitial fibrosis that were observed
during the chronic repair phase of TMA were absent. From
these findings, we presume that the damage to the renal tissue
caused by TMA was resolved early and the tissue repair was
good. Three years have passed since the onset of TA-TMA, and
the current eGFR of Cr is 142 mL/min/1.73 m2, maintaining a
normal level.
DISCUSSION
Currently, no effective treatment for TA-TMA has been
established. Treatment of comorbidities and reduction or
discontinuation of calcineurin inhibitors cannot be deemed as a
positive treatment for progressive TMA.
PE is effective in diseases such as acquired thrombotic
thrombocytopenic purpura, in which ADAMTS13 activity is
severely reduced. Additionally, it has been reported to be
effective against TA-TMA (15). However, in TA-TMA, the
effect of PE is poor in terms of both survival and renal
function (16). In particular, diffuse alveolar hemorrhage has
been reported to be a potentially fatal complication that
occurs at a high rate in patients with TA-TMA (17). Further,
high proteinuria and high C5b-9 levels, as in this case, are
poor prognostic factors for TA-TMA (1) and require more
aggressive treatment.
Eculizumab is a humanized monoclonal antibody to
complement protein C5 that can prevent tissue damage by
inhibiting the formation of C5b-9 as a treatment for PNH and
atypical hemolytic uremic syndrome (18). The mechanism
of action against TA-TMA is thought to prevent tissue
damage by inhibiting the production of C5b-9. In Japan,
eculizumab is not approved for the treatment of TA-TMA;
nevertheless, other investigators have recently reported that
eculizumab is useful for the treatment of TA-TMA (8,9).
Jodele et al. reported that 18 patients with TA-TMA with
high proteinuria and high C5b-9 levels were managed with
eculizumab and 11 without, and the 1-year survival rates
were 56 and 9%, respectively (13). Atypical hemolytic uremic
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Shimizu et al. Case Report: Eculizumab for TA-TMA After BMT
FIGURE 2 | Pathological findings (optical microscopy). (A,B) Two different glomeruli at 400x of PAS. (C) Glomerulus at 400x of PAM. (D) Kidney tissue at 20x of
MASSON. The changes in the basement membrane of the hoof were minimal, mesangial proliferation was partial, and fibrosis was observed in only 10% of the cases.
No membranoproliferative glomerulonephritis-like findings were observed in the chronic phase of impaired TMA, and there were only two sclerotic glomeruli (arrow) out
of 18. PAS, periodic acid Schiff stain; PAM, periodic acid-methenamine-silver stain; MASSON, masson trichrome stain.
syndrome (aHUS) is caused by uncontrolled activation of the
alternative complement pathway, which results in TMA. In the
treatment of aHUS with TMA, there was a difference in the
recovery of eGFR between patients who received eculizumab
within 1 week after the onset and those who received it
after 1 week (14); the mean eGFR change from baseline at
1 year was significantly higher in patients treated for ≤7
days than in those treated for >7 days. This indicates that
eculizumab has been shown to be more effective in TMA when
started early.
The significance of eculizumab in this case is as follows. First,
C5b-9 levels were measured in early stage of TMA, immediately
before PE, and used for eculizumab induction, which allowed
the affected child to survive without complications. Renal
function was reversible particularly, and renal biopsy
revealed very little irreversible tissue damage. The patient’s
renal function remained normal even after several years.
Second, eculizumab was administered only thrice, making
it less expensive. Additionally, it is very interesting that
this patient required to take eculizumab only three times,
because most of the published literature shows that a
prolonged eculizumab course should be needed. Shorter
courses of eculizumab may be possible if the drug is started
early and the drug monitoring is appropriately performed.
Finally, several years have passed since the onset of TA-TMA
without relapse.
In Japan, there was a case report which stated that eculizumab
was useful for TA-TMA, and the rationale for its use is the
same as in other countries with high C5b-9 levels (19). In
addition, it has been proposed that proteinuria plus C5b-9
can be used as a diagnostic criterion for TA-TMA in other
countries (9).
In this case, complement (C) 4d in the renal tissue, especially
the glomeruli and renal tubules, was not studied. In patients
with TA-TMA, C4d deposition in the renal tissue may reflect
complement activity, and therefore, if evaluated, could have been
used to assess disease activity at the time of renal biopsy.
CONCLUSION
Autologous stem cell transplantation with high-dose
chemotherapy in patients with neuroblastoma has been
reported to be a high risk for TA-TMA (20). Herein we
reported a case of TA-TMA after autologous stem cell
transplantation in a patient with lymphoma and successful
treatment with eculizumab. The use of eculizumab improved
the condition of TA-TMA and showed functional and
pathological reversibility in the kidney. It could be valuable
to use eculizumab in the early phase of TA-TMA using C5b-9
levels as one of the rationales, unless other life-saving measures
are available.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding author/s.
AUTHOR CONTRIBUTIONS
SS carried out the assessment and the management of the
patient, literature search, and drafted the manuscript. TM
Frontiers in Pediatrics | www.frontiersin.org 5July 2022 | Volume 10 | Article 908183

Shimizu et al. Case Report: Eculizumab for TA-TMA After BMT
evaluated histopathological features, contributed histological
part, and supported drafting of manuscript. HY supported
the evaluation and management of the patient and drafting
of manuscripts. KK contributed to the management of the
patient. ST and IM reviewed and revised the manuscript for
important intellectual content. All authors read and approved the
final manuscript.
ACKNOWLEDGMENTS
We would like to express our gratitude to Dr. Hiroshi Moritake,
Dr. Hideaki Imamura, and Dr. Hiroshi Takemori, Department of
Pediatrics, Division of Developmental Urology and Reproductive
Medicine, Faculty of Medicine, University of Miyazaki, for
measuring C5b-9.
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Frontiers in Pediatrics | www.frontiersin.org 6July 2022 | Volume 10 | Article 908183