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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

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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.
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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 (1012).
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 (3,3008,600) /µLT-Bil 3.47 (0.41.5) mg/dL
Neu 81.0 % D-Bil 0.84 (0.050.4) mg/dL
Mono 6.0 % AST 39 (1330) IU/L
Lymph 13.0 % ALT 55 (1042) IU/L
RBC 2.15 ×106(4.355.55 ×106)/µL LDH 883 (124222) IU/L
Hb 6.2 (13.716.8) g/dL BUN 47.1 (820) mg/dL
Ht 19.2 (40.750.1) % Cr 1.21 mg/dL
Plt 3.2 ×104(15.834.8 ×104)/µLNa 146 (138145) mmol/L
Ret 45 (420) K 3.3 (3.64.8) mmol/L
Cl 112 (101108) mmol/L
CRP 0.40 (<0.2) mg/dL
TP 5.9 (6.68.1) g/dL
Alb 3.5 (4.15.1) g/dL
Cr-eGFR 63.9 (>90) mL/min/ 1.73m2
Blood Urine
PT ratio 1.01 (0.91.1) pH 6.5 (5.07.0)
APTT 39.9 (2745) sec SG 1.023 (1.0051.02)
Fib 293 (150400) mg/dL Protein (4+)
AT-3 80 (70130) % Sugar (1+)
FDP 12.0 (<5) µg/dL OB (3+)
D-dimer 5.4 (<5) µg/dL URO (±)
Bil (-)
Cystatin C 1.08 (0.580.98) mg/L Ket (-)
Renin 0.6 (0.23.9) ng/mL/hr RBC 5099 /HPF
Aldosterone 10.0 (<173) pg/mL
NAG 48.6 (<5) IU/L
CH50 50.5 (3045) U/mL β2MG 10048 (5300) µg/L
Haptoglobin <10 (19170) mg/dL
ADAMTS13 92 (50150) % 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
Frontiers in Pediatrics | www.frontiersin.org 3July 2022 | Volume 10 | Article 908183
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
Frontiers in Pediatrics | www.frontiersin.org 4July 2022 | Volume 10 | Article 908183
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
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Article
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Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) and diffuse alveolar hemorrhage (DAH) are well recognized post-transplant complications that carry a high risk of mortality; however, the risk of DAH complicating the course of transplant patients with TA-TMA is not well understood. We conducted a ten-year retrospective study at our institution to determine the incidence of DAH in a cohort of pediatric patients with TA-TMA and described their presentation and outcomes. Additionally, autopsy slides, when available, were reviewed to assess for histological evidence of microvascular injury and alveolar hemorrhages. A total of 58 pediatric patients with TA-TMA were identified. Of these, 14 (24%) had DAH. Majority of DAH cases occurred within a week of TA-TMA diagnosis (n = 8, 57%, range 0-698 days). Mortality was 100% for patients with DAH and TA-TMA. Infections were found to be a significant risk factor for DAH in TA-TMA. Autopsy was performed in 11 of the 14 patients, and pulmonary slides were available for review in ten cases. 70% cases had pathological evidence of microvascular injury, concerning for pulmonary TA-TMA. We conclude that DAH is a potentially fatal complication in patients with TA-TMA and may be a result of pulmonary microangiopathy.
Article
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Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT. Method: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020. Results: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection. Conclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA.
Article
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Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial damage syndrome that is increasingly identified as a complication of both autologous and allogeneic hematopoietic cell transplantation (HCT) in children. If not promptly diagnosed and treated, TA-TMA can lead to significant morbidity (e.g., permanent renal injury) or mortality. However, as the recognition of the early stages of TA-TMA may be difficult, we propose a TA-TMA “triad” of hypertension, thrombocytopenia (or platelet transfusion refractoriness), and elevated lactate dehydrogenase (LDH). While not diagnostic, this triad should prompt further evaluation for TA-TMA. There is increased understanding of the risk factors for the development of TA-TMA, including those which are inherent (e.g., race, genetics), transplant approach-related (e.g., second HCT, use of HLA-mismatched donors), and related to post-transplant events (e.g., receipt of calcineurin inhibitors, development of graft-vs. -host-disease, or certain infections). This understanding should lead to enhanced screening for TA-TMA signs and symptoms in high-risk patients. The pathophysiology of TA-TMA is complex, resulting from a cycle of activation of endothelial cells to produce a pro-coagulant state, along with activation of antigen-presenting cells and lymphocytes, as well as activation of the complement cascade and microthrombi formation. This has led to the formulation of a “Three-Hit Hypothesis” in which patients with either an underlying predisposition to complement activation or pre-existing endothelial injury (Hit 1) undergo a toxic conditioning regimen causing endothelial injury (Hit 2), and then additional insults are triggered by medications, alloreactivity, infections, and/or antibodies (Hit 3). Understanding this cycle of injury permits the development of a specific TA-TMA treatment algorithm designed to treat both the triggers and the drivers of the endothelial injury. Finally, several intriguing approaches to TA-TMA prophylaxis have been identified. Future work on the development of a single diagnostic test with high specificity and sensitivity, and the development of a robust risk-scoring system, will further improve the management of this serious post-transplant complication.
Article
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Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplant (HSCT) that causes severe multi-organ injury. The kidneys are almost universally affected. There is no proven therapy, but therapeutic plasma exchange (TPE) is commonly used to treat TA-TMA at Texas Children's Hospital (TCH). To date, there have been no studies assessing the long-term efficacy of TPE in preventing the development of chronic kidney disease (CKD) in TA-TMA patients. In this study, we retrospectively analyzed the incidence of CKD in TA-TMA pediatric patients treated with TPE to determine if this treatment modality improves renal morbidity. We reviewed records between January 2007 and June 2017 of pediatric HSCT patients diagnosed with TA-TMA, identified through an internal database maintained at TCH. To be included, patients must have completed a course of TPE per the TPE in TA-TMA institutional protocol at TCH. CKD was defined as kidney damage for at least three months and stratified into stages 1-5 according to estimated glomerular filtration rate (eGFR). Stage 4 and 5 were considered "severe CKD". In the ten-year timeframe, fifteen patients with TA-TMA completed a course of TPE per our institutional protocol and were subsequently followed for a median of 963 days. Fourteen patients developed CKD, and five out of these fourteen patients developed severe CKD. The cumulative incidence of severe CKD development was 33% (95% CI: 11 - 57%). Six patients required dialysis and two patients received a renal transplant. Five patients received eculizumab in addition to TPE. In our patients, a TPE course of at least seven weeks (and up to 25 weeks) was not effective in the prevention of CKD. Our data indicate a need for alternative therapeutic measures to prevent the development of CKD in TA-TMA patients.
Article
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Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant that can result in multi-organ failure (MOF). Patients undergoing high-dose chemotherapy with autologous stem cell transplant (aHCT) for neuroblastoma require good organ function to receive post-transplant radiation and immunotherapy. We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens. Sixty patients underwent aHCT using high-dose chemotherapy: 41 patients received carboplatin/etoposide/melphalan (CEM), 13 patients busulfan/melphalan (Bu/Mel) and six patients received tandem transplant (cyclophosphamide/thiotepa and CEM). TA-TMA with MOF was diagnosed in 13 patients (21.7%) at a median of 18 days after aHCT. TA-TMA occurred in 12 patients receiving CEM and in 1 after cyclophosphamide/thiotepa. There were no incidences of TA-TMA after Bu/Mel regimen. Six of 13 patients with TA-TMA and MOF received terminal complement blocker eculizumab for therapy. They all recovered organ function and received planned post-transplant therapy. Out of seven patients who did not get eculizumab, two died from TA-TMA complications and four progressed to ESRD. We conclude that the CEM regimen is associated with a high incidence of clinically significant TA-TMA after aHCT and eculizumab can be safe and effective treatment option to remediate TA-TMA associated MOF.
Article
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Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplant (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity (CH50), and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined inter-individual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n=18) to patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n=11). In the PK analysis, we found significant inter-patient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, were significant determinants of eculizumab clearance and disease response. Sixty one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared to untreated patients (56% versus 9%, p=0.003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinurina. Our eculizumab dosing algorithm, including pre-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
Article
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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare entity with no standard of care and high mortality, despite the use of plasma exchange. Using specific search terms, all cases having TA-TMA treated with eculizumab and indexed in MEDLINE (English language only) by November 2014 were reviewed. A total of 26 cases, 53% men, had a median age of 33 years (range 2-61). Transplant-associated thrombotic microangiopathy occurred after stem-cell transplant (35%) or solid-organ transplant (65%), frequently associated with the use of cyclosporine or tacrolimus (96%). A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) level was always >10%. After TA-TMA diagnosis, the following drug adjustments were made: discontinuation of cyclosporine or tacrolimus in 45%, dose reduction in another 27%, continuation of the drugs in 23%, and switch from cyclosporine to tacrolimus in remaining 5%. Plasma exchange was performed in ∼43%. The median interval between transplant and initiation of eculizumab was 63 days (range 11-512). A median of 5.5 doses (range 2-21) of eculizumab was utilized with 92% response occurring after a median of 2 doses (range 1-18). At a median follow-up of 52 weeks (range 3-113), the survivors (92%) were doing well. Within the limits of this retrospective analysis, our study demonstrates that eculizumab use may result in high response rate and 1-year survival in patients with TA-TMA refractory to discontinuation of calcineurin inhibitor and plasma exchange. © The Author(s) 2015.
Article
Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience of 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab. We demonstrate significant improvement in 1y post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with same high-risk TA-TMA features that had 1y post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive eculizumab therapy course using PK/PD guided dosing, requiring a median of 11 doses of eculizumab (IQR 7-20). Therapy was discontinued due to resolution of TA-TMA at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of therapy were less likely to respond to treatment (OR =0.15, p-value 0.0014), and required more doses of eculizumab [r = 0.43, p-value = 0.0004]. Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9, p=0.0015), and had lower 1y survival (44% vs 78%, p=0.01). Over 70% of survivors had proteinuria on long term follow up. The best GFR recovery in survivors was a median 20% lower (IQR 7.3-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for high risk TA-TMA, but some patients with severe disease lack a complete response, prompting us to propose early intervention strategies and search for additional targetable endothelial injury pathways.
Article
Background TA‐TMA is a described complication of aHCT in children with neuroblastoma. Outcomes are poor with mortality rates approaching 60%. Described late effects in survivors include chronic kidney disease and persistent pulmonary hypertension. Case We report a case of a 2‐year‐old with neuroblastoma who developed severe TA‐TMA 35 days after high dose chemotherapy and autologous stem cell rescue. He presented with respiratory failure, pericardial and pleural effusions, hemolysis, hypertension, and mild altered mental status. He was mechanically ventilated for 3 weeks and after sedation was lifted, he was minimally responsive. He was treated with eculizumab with resolution of hemolysis, kidney injury and polyserositis. Initially he was more responsive; however, after almost a year of intensive therapy he remained nonverbal and had persistent irritability and behavioral changes. He had an extensive negative evaluation. On day +345, he presented with severe, refractory epilepsy. Three years after TA‐TMA, he continues to have severe neurologic disabilities. Conclusions To our knowledge, persistent neurologic toxicity has not been reported in TA‐TMA. However, deficits and seizures are reported in other TMAs, particularly in children with atypical HUS who present with significant neurologic changes at diagnosis. Our patient's persistent neurologic disability despite eculizumab response in all other involved organs may reflect irreversible damage. This case describes a new long‐term sequela of TA‐TMA and highlights the need for further studies to understand both acute and long‐term neurologic complications of this disease.
Article
Objective To evaluate response rates and survival in adults with transplant‐associated thrombotic microangiopathy (TA‐TMA) after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with eculizumab (ECU). Methods Patients were identified retrospectively and data collected through HSCT and pharmacy databases. Results Ten patients with TA‐TMA after allogeneic HSCT were treated with ECU between 2013 and 2016. TA‐TMA was diagnosed at a median of 93 days post‐HSCT. Organ‐specific injury was documented in all ten patients at time of TA‐TMA diagnosis, the most common being renal dysfunction (90%). Acute GVHD (70%) and active infection (80%) were common at time of diagnosis. The median time to ECU initiation from TA‐TMA diagnosis was 4 days. Seven patients received ECU as first‐line therapy in combination with other treatment modalities, while three patients were treated with ECU as second‐line therapy. ECU was well tolerated with the exception of one case of severe skin rash leading to discontinuation. ECU achieved an overall hematologic response rate of 70% and an overall survival rate of 60%. One patient achieved a complete response with corresponding organ recovery. Conclusion Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival. This article is protected by copyright. All rights reserved.