Correspondence to:
Kang-Hsi Wu MD
Department of Pediatrics, Chung Shan Medical University Hospital,
Taichung, Taiwan.
Address: No.110, Sec. 1, Jianguo N. Rd., South Dist., Taichung City 402
Tel: 886-4-4-24739595#; Fax: 886-4-22032798;
Email: cshy1903@gmail.com
Running head: Haploidentical PBSCT with PTCy for relapsed neuroblastoma
Keywords: Neuroblastoma, Haploidentical, Post-transplant
Cyclophosphamide
The text word count: 900
The number of figures: 2
Neuroblastoma (NB) is the most common extra-cranial solid tumor of
childhood.1 High dose chemotherapy (HDCT) with
autologous hematopoietic stem cell transplantation (Auto-HSCT) rescue as
consolidation therapy has improved outcomes.2 However,
the relapse rate of high-risk NB in children over one year of age is
still high. Despite recent advances, children with relapsed and
refractory NB have a poor long-term survival.3 Some
reports highlight a graft-versus-tumor (GvT) effect with adopted
allogeneic hematopoietic stem cell transplantation (Allo-HSCT)
approaches. Haploidentical hematopoietic stem cell transplantation
(Haplo-HSCT) is a feasible option in high-risk malignancy capable of
inducing long-term remission due to GvT effect. Relapsed NB after
Auto-HSCT treated with Haplo-HSCT with
post-transplant
cyclophosphamide (PTCy) have not been reported.
We reported a 4 years-old male who was admitted due to persistent fever
for two weeks. Severe pain in the bilateral thighs was told. After
admission, the laboratory data were within normal range, except elevated
serum lactate dehydrogenase level of 1269 IU/L (normal range:
180-240IU/L) and urinary vanillylmandelic acid (VMA) level of
76.58mg/day (normal range for children: 1-3 mg/day). The abdominal
magnetic resonance imaging revealed an 8.6 × 8.9 cm ill-defined mass
arising from the left adrenal gland. The nearby tissue and great vessels
were involved. Bone scan showed multiple bone metastasis. The bone
marrow biopsy revealed invasion of NB cells that were positive for
neuron-specific enolase and synaptophysin. NB stage IV with bone and
bone marrow metastasis was confirmed. Then, he received neoadjuvant
chemotherapy, which included four courses of
CDV
(cyclophosphamide, dactinomycin, and vincristine) and two courses of
CiE
(cisplatin and etoposide). After completing neoadjuvant chemotherapy, he
received grossly total surgical resection of residual tumor only because
of great vessels embracing by the residual tumor. Subsequently, he
received autologous peripheral blood stem cell transplantation (PBSCT)
as consolidation therapy. The conditioning regimen consisted of
carboplatin,
etoposide, and melphalan. After blood cell recovery, this patient
received local radiotherapy and six months of oral 13-cis-retinoic acid
for maintenance therapy. Following
positron
emission
tomography-computed
tomography (PET-CT) scan after treatment revealed no evidence of active
tumor.
Ten months after completing maintenance treatment, some enlarged masses
on the right neck and submandibular area were noted. Computed tomography
of head and neck revealed local tumor recurrence (Fig 1). The biopsy
confirmed relapsed NB. This patient received salvage chemotherapy with
TOTEM
(Topotecan, Temozolomide)4 alternative to ICE
(ifosfamide, carboplatin, and etoposide)5. After the
six cycles of salvage chemotherapy, haploidentical PBST with PTCy from
his father was performed. Fludarabine (90 mg/m2) plus
total body irradiation (12 Gy) was used for conditioning
regimen6. Cyclophosphamide (50 mg/kg/day) was given on
days 3 and 4 after haploidentical PBSCT. Intravenous cyclosporine
3mg/kg/day every 12 hours and mycophenolate mofetil (MMF) 15mg/kg three
times per day were started on day five after transplantation. Neutrophil
engraftment was found on day 13. He completed haploidentical PBSCT with
PTCy smoothly. Only graft-versus-host disease grade (GVHD) I in skin and
cytomegalovirus reactivation were encountered. MMF was stopping on day
35, and cyclosporine was discontinued within six months after
transplantation. When preparing this manuscript (52 months after
haploidentical PBSCT), the PET-CT scan confirmed no evidence of active
tumor and normalized urine VMA levels. He is doing well and has good
quality of life. The clinical course and treatment are summarized in Fig
2.
The outcome of relapsed NB remains dismal. Mody et al. reported that
objective responses (complete or partial) were seen in 22 (41.5%) of 53
children with refractory or relapsed NB treated with irinotecan,
temozolomide, and dinutuximab, and GM-CSF.7 However,
dinutuximab is not available in many places and very expensive. Because
of inferior outcomes in relapsed NB, more feasible treatment is urgently
needed. Haplo-HSCT is expected to treat relapsed and refractory NB.
Illhardt et al. reported that event-free survival and overall survival
at five years were 19% and 23%, respectively, in refractory or
relapsed NB receiving Haplo-HSCT with T and B cells ex vitro depleted by
CliniMACS device. No transplantation-related mortality was
observed.8 This study indicates that Haplo-HSCT is a
feasible treatment and can induce long-term remission in some refractory
or relapsed NB. However, T cell ex vitro by the device is also not
available in many places. In contrast, Haplo-HSCT with PTCy is feasible
and safe in many hospitals.
Immunotherapy with anti-GD2 Antibody has documented effective treatment
for NB.7,9 Besides, some basic studies have found that
immunotherapy is one of the good ways to cure NB.10Therefore, immunotherapy for NB is expecting.11 PTCy
regimen developed by Luznet al. al was adapted to overcome graft failure
and severe GVHD after haplo-HSCT.12 Haplo-HSCT with
PTCy has been reported a valid treatment in advanced Hodgkin
lymphoma.13 These findings indicate that the GvT
effect after Haplo-HSCT with PTCy may be practical and cure some types
of malignancies. In addition to the GvT effect, the high dose
cyclophosphamide after Haplo-HSCT also kills the undetectable residual
NB tumor cells. Therefore, we speculate that Haplo-HSCT with PTCy may be
effective in treating relapsed and refractory NB.
In the present patient, he is the first case with relapsed NB after
Auto-HSCT and has been found tumor-free survival 52 months after
Haplo-HSCT with PTCy. We expect the GvT effect of Haplo-HSCT with PTCy,
which effectively treats advanced Hodgkin lymphoma, may also be valid to
treat relapsed NB. Because of available donors, fast donation,
feasibility, and safety in Haplo-HSCT with PTCy, more and more patients
will receive this treatment. Further studies are warranted to confirm
the effect of Haplo-HSCT with PTCy in relapsed NB.
CONFLICT OF
INTEREST
The authors declare no conflict of interest
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