High dose chemotherapy and autologous hematopoietic stem cell rescue for children with high risk neuroblastoma: Two case report
High dose chemoBthệnerhavpiyệnanTdruanugtoưlơonggoHusu..ế.
HIGH DOSE CHEMOTHERAPY AND AUTOLOGOUS
HEMATOPOIETIC STEM CELL RESCUE FOR CHILDREN
WITH HIGH RISK NEUROBLASTOMA: TWO CASE REPORT
Nguyen Thi Kim Hoa1, Tran Kiem Hao1, Chau Van Ha1, Phan Canh Duy2,
Dong Si Sang3, Phan Thi Thuy Hoa3, Ho Huu Thien4, Nguyen Thi My Linh1, Pham Nhu Hiep4
DOI: 10.38103/jcmhch.2020.62.16
ABSTRACT
Introduction: High-risk neuroblastoma is a childhood malignancy with a poor prognosis. Gradual
improvements in survival have correlated with therapeutic intensity, and the ability to harvest, process and
store autologous hematopoietic stem cells has allowed for dose intensification beyond marrow tolerance.
Case: We report two cases which were diagnosed high risk neuroblastoma. The first case had big
heterogeneous at his left adrenal gland with metastasis in bone marrow and his brain. The second case
with localised tumor at her right kidney and NMYC positive. Both cases were treated with SIOPEN protocol,
starting with 8 course RAPID COJECT. Patients had partial response and were collected stem cells. Then
they were primary tumor resection; receiving high dose chemotherapy with autologous- stem cell rescue,
radiation and retino acid treatment, respectively.
Conclusion: This is initially report of autologous stem cell transpant for high risk neuroblastoma. Even
only two patients, the results showed that stem cell transplant was safe and effective. We are continuing
to implement for more case with high risk neuroblastoma and will have better report with a bigger number.
I. INTRODUCTION
and early childhood, with the highest number of
cases diagnosed in the first month of life. Before
the development of comprehensive, multimodality
therapy, long term survival probabilities for high
risk neuroblastoma patient were less than 15% [2].
High dose chemotherpay with autologous stem
cell rescue has improved the outcomes for children
with high risk neuroblastoma [3,4]. Using busulfan
and melphalan (BuMel) as conditioning regime,
the International Society of Pediatric Oncology
Neuroblastoma HR NBL1 protocol reported 3 year
Neuroblastoma is the most common extracranial
solid tumor in children[1], accounting for 7% to 8%
of all childhood cancers. The prevalence is about 1
case per 7.000 live births. Neuroblastoma is slightly
more common in boys than in girls, with a male to
female ratio of 1.1 to 1. The peak incidence occurs
at 2 years of age, some studies show that 89% are
youngerthan5years, and98%ofcasesarediagnosed
in the first 10 years of life. The distribution of cases
by age clearly shows that this is a disease of infancy
Corresponding author: Nguyen Thi Kim Hoa
Email: kimhoa.fmi@gmail.com
Received: 8/5/2020; Revised: 17/5/2020
Accepted: 20/6/2020
1. Pediatric Center, Hue Central Hospital
2. Oncology Center, Hue Central Hospital
3. Blood and Transfusion Center, Hue Central Hospital
4. Department of Abdominal Emergency and Pediatric
Surgery, Hue Central Hospital
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EFS and OS of 49% and 60%, respectively[2].
and found out one heterogeneous tumor at his
Since 2016, Hue Pediatric Center has been starting retroperitoneum, measuring 8.6x5.1x4.9cm, with
to treat for children with solid tumor, and has been calcification inside. The tumor encased some
receiving many neuroblastoma patients, in which arteries at retroperitoneum, invased left kidney and
there are 60% high risk neuroblastoma. How to left adrenal gland. At his occipital area and sinciput
improve the survival rate for high risk neuroblastoma area, there were lesions measuring from 10-40 mm.
is a challenge for our team. With the great support He was done bilateral bone marrow biopsy and the
from Board Director of Hue Central Hospital, Hue result showed metastasis neuroblastoma.
Pediatric Center did autologous transplant sucessfully
Thesecondcase:5 year oldfemale was admittedto
for two high risk neuroblastoma cases, and hopefully Hue Pediatric Center due to She came to my hospital
we has been continuing to do more cases in order due to her abdominal distention. She was done CT
to build Hue Central Hospital as one of Vietnam’s scan whole body and found out one heterogeneous
leading medical center.
tumor at her right kidney measuring 7.9x8.3x8.9 cm
(Figure 1, Figure 2). This tumor compressed right
kidney and the right kidney had hydronephrosis. The
tumor also invased the liver and right adrenal gland.
II. CASE REPORT
2.1. Clinical features and imaging finding
The first case: 5 year old male was admitted She was done bilateral bone marrow biopsy and the
to Hue Pediatric Center due to fever and pain at result was negative. She was done needle biopsy with
his right knee. He was done CT scan whole body the result: neuroblastoma, NMYC: positive.
Figure 1: CT scan whole body of the first patient showed tumours at his abdomen and his brain (at initial time)
Figure 2: CT scan whole body of the second patient showed tumours at her abdomen (at initial time)
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2.2. Pathology results
situ hybridization for MYNC performed at St. Jude
was negative for amplification.
For the first case, we did needle biopsy the
primary tumor and the result showed neuroblastoma,
with synaptophysin, chromogranin: positive, LCA,
CK AE1/3, Vimemtin, CD 99: negative. The result
of bilateral bone marrow biopsy were reviewed in St
Jude Children’s Research Hospital. The result showed
that the mononuclear cells were subset positive for
vimentin, chromogranin A, synaptophysin, CD
99dim while negative for keratin AE1/3, EMA. CD
43, myogenin, MyoD1, CD42b. These finding were
consistent with metastatic neuroblastoma.
The result of second case:
The histologic sections showed a neuroblastic
tumor composed of sheets of malignant small round
cells with minimal interspersed fibrillary neuropil-
like material and large areas of tumor necrosis.
The tumor cells exhibitted brisk mitosis with
karyorrhexis in more than 4% of the tumor cells.
Immunohistochemically, the tumor cells showed
patchy positive staining for synaptophysin, whereas,
cytokeratine AE1/AE3, desmin, BCOR, and CD 99
are negative. The overall features were consistent
with a poorly differentiated neuroblastoma with an
unfavorable histopathology.
After remove the residual tumor, we sent the
sample to St Jude Children’s Research Hospital
in Memphis to review. The result showed:
microscopic examination of the slide showed a
large nerve fascicle attached to a small fragment
of the tumor with evidence of therapy effect. The
tumor was composed of Schwannian stroma with
scattered neuroblastic cells in different stages of
maturation along with ganglion cells and scattered
hemosiderin - laden macrophages. Fuorescence in
Fluorescence in situ hybridization testing
performed at St. Jude showed MYCN amplification.
2.3. Diagnosis and treatment and evaluation
Both cases were diagnosed high risk neuroblas-
toma and were treated with SIOPEN protocol for
high risk neuroblastoma. They were received 8
course of RAPID COJECT.
After 8 course chemotherapy, both patients had partial respones.
The first patient: the tumor at his adrenal gland shrank significantly, with the dimesion: 3.6x3.1x2.8 cm.
The lesion at his brain membrane at the right side of sinciput shrank, measuing: 39x10 mm (Figure 3,
Figure 4).
Figure 3: CT scan whole body of the first patient after treatment
The second patient: the tumor shrank very well, measuring 3.2x4x4.5 cm.
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Figure 4: CT scan whole body of the second patient after treatment
With the partial reponses, both patients were collected stem cells. The first patient had 4.11x 106 CD
34 cells, the second patient had 2.87x106 CD 34 cells. Then, both of them was removed than 80% original
tumors, and were ready for stem cell transplantation.
2.4. High dose chemotherapy and stem cell transplantation
Both patients were received conditioning regimen with Bul/Mel as the below:
Medicine
- 7
- 6
-5
-4
-3
-2
-1
0
Busulfan IV
xx
xxxx
xxxx
xxxx
xx
Melphalan IV
x
x
Hydration 3l/m2/d
Stem cell infusion
x
x
x
x
x
x
x
Mephalan dose: 140mg/m2/day, Busulfan dose: Then they were received radiation to primary tumor,
1mg/kg/day.
and took 13 cis retino acid. Now, both of them
During transplant, patient were received ursodiol are very healthy: the first patient has completed
300mg/m2/day (from D-8 to D+80 to prevent VOD; remission after 13 months, and the second patient has
Acyclovir 250mg/m2 every 8 hours from D-8 đến completed remission after 12 months..
D 100. Levofloxacine 10mg/kg x 2 times per day
(D-8 to D30; G-CSF since D+5 until Neutrophile >
0.5x109/l for two consecutive days, and radiation
blood products.
III. DISCUSSION
The diagnosis of high risk neuroblastoma for
both patients were clearly and based on their
After transplant, both patients appeared responses, they had indication to receive high
neutropenic fever, mucosa ulcer with grade I, II, dose chemotherapy and autologous stem cell
elevated CRP and PCT, and were treated with transplantation.[5] However, due to receiving
antibiotic and antifungal. The second case lasted many chemotherapy, their marrows were often
fever for 6 days due to Chromobacterium violaceum hypocellulary, so the amount of stem cell
infection. The first patient had neutrophile and collection were not high, only 4.11x 106 CD
platelet recovery on day 11 and day 25 respectively. 34 cells for the first case, and 2.87x106 CD 34
The second patient had neutrophile and platelet cells for the second case. This is a reason why
recovery on day 42 and day 45 respectively. Both nowadays, they prefer to collect stem cells earlier
patients were discharged on day 32 and day 72 if patients do not have bone marrow metastasis
respectively without any special side effects (kidney, or bone marrow clears after chemotherpy. [4,6]
interstitial pneumonitis and venoocclusive diseas). Regarding conditioning regimen, there are two
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regimens: Bul/Mel (busulfan and melphalan) and side effects, such as: renal effects, interstitial
CEM (carboplatin, etoposide and melphalan). pneumonitis and venooclusive disease.
[3,6,7] We chosed myeloablative therapy with
Bul/Mel followed by 13 cis retino-acid.[8,9] After
IV. CONCLUSION
transplant, the first patient recoveried faster than
Management high risk neuroblastoma is
the second patient. This could be explained due to very challenge and need combined many drugs.
the amount of CD 34 cell infusion. According to Autologous stem cell transplant plays an important
Fish and Ali: the number of CD34+ cells infused role in consolidation. This is the first two case
to a patient correlates with the likelihood of autologous stem cell transplant for high risk
successful engraftment. [4,10] The treatment was neuroblastoma. Both of them tolerated well and had
well tolerated. Mucositis was the main toxicity, no special side effects. Until now, they have one more
with grade I and II. Both of them had developed year survival since diagnosis. We continue to follow
neutropenia fever and without any special up and implement the new therapy to more patients.
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