Successful treatment of refractory metastatic neuroblastoma with panobinostat in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine therapy
Soheila Zareifar, Nader Shakibazad, Omid Reza Zekavat, Mohammadreza Bordbar and Mahdi Shahriari
1 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2 Pediatric Hematology and Oncology, Bushehr University of Medical Sciences, Bushehr, Iran
Abstract
Introduction: Neuroblastoma commonly required multimodal therapy containing surgery, chemotherapy, radiotherapy, and immunotherapy.
Case report: In our case, who had refractory metastatic neuroblastoma, we use histone deacetylase inhibitor (pano- binostat) in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine (MIBG) therapy.
Management and outcome: This approach leads to successfully treat the patient. MIBG scan and bone marrow examination after therapy revealed no evidence of tumor. Now, she underwent autologous transplantation six months ago and free of tumor.
Conclusion: Panobinostat can cause apoptosis induction in refractory metastatic neuroblastoma in combination with MIBG therapy and chemotherapy.
Introduction
Neuroblastoma is the most common extracranial solid tumor in childhood. The prevalence is about one case per 7000 live births.1,2 About 37% are diagnosed as infants, and 90% are younger than five years at diag- nosis, with a median age at diagnosis of 19 months.1
Neuroblastoma usually needs multimodal therapy including surgery, chemotherapy, radiotherapy, and immunotherapy. The role of each is determined by clin- ical and molecular characteristics determined at diag- noses such as age, stage, and biological features.3
Patients with metastatic, recurrent neuroblastoma are treated as patients with newly diagnosed high-risk neuroblastoma.4 Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include topotecan in combination with cyclophosphamide or etoposide,5 irinotecan and temo- zolomide,6 ifosfamide, carboplatin, and etoposide.7 In addition, 131I-metaiodobenzylguanidine therapy,8,9 oxaliplatin and doxorubicin could be used.10 The experimental targeted therapy and immunotherapy that recently used in refractory/relapsed neuroblastoma include anaplastic lymphoma kinase inhibitors,11,12 his- tone deacetylase inhibitors,9,13,14 anti-GD2 monoclonal antibody,15 and isotretinoin therapy.14
Therefore, the aim of the study is to treat the meta- static refractory neuroblastoma with panobinostat as histone deacetylase inhibitors in combination with chemotherapy and iodine-131-meta-iodobenzylguani- dine therapy.
Case presentation
A nine-year-old girl, known case of high-risk neuro- blastoma since four years ago, initially presented with fever, bone pain, weight loss, and abdominal pain for two weeks prior to admission. In the workup, an abdominal mass, irregularly shaped measuring about 100 × 110 × 180 mm in the retroperitoneal region near the aortic bifurcation without calcification was detected confirmed by abdominopelvic MRI. Mass biopsy was done and immunohistochemistry (IHC) positive mar- kers included CD56, Chromogranin A, Synaptophysin and Neuron-specific enolase (NSE), and negative mar- kers included cytokeratin, vimentin, CD99, CD45, desmin, and S100. According to these IHC findings and morphology, undifferentiated neuroblastoma was diagnosed. She was evaluated for metastasis that revealed bone marrow involvement by neuroblastoma cells. In addition, the whole body bone scan (TC99m- MDP) revealed multiple bone metastasis of spine both Sacroiliac (SI) joints, both shaft and distal of a femur, both tibia and fibula (Figure 1).
She received chemotherapy every 10 days for undif- ferentiated high-risk neuroblastoma stage 4 according to The International Neuroblastoma Staging System (INSS) with chemotherapeutic agents including vincris- tine, carboplatin/cisplatin, etoposide, and cyclophos- phamide. Iodine-123-metaiodobenzylguanidine (123-I- MIBG) revealed increased uptake in the upper and mid abdomen. Due to poor response to chemotherapy after four courses, the chemotherapy protocol was changed to ICE (ifosfamide, carboplatin, and etopo- side). She was also referred for surgery; exploratory laparotomy and partial resection were done. Pathology specimen showed undifferentiated neuro- blastoma with lymph node involvement, 10% necrosis and 3 per 10 high power fields mitosis were seen. Genetic study of the mass showed MYCN amplification.
She received six courses of ICE protocol and evaluation was done. The lesions in the whole body bone scan regressed, but SI joints and acetabulum lesions still remained. Bone marrow revealed no evi- dence of metastasis. 123-I-MIBG was normal. In abdominopelvic MRI, the abdominal mass com- pletely disappeared.
Consequently, due to the lesion in the bone scan, her chemotherapy was changed to topotecan salvage chemotherapy. After four courses of chemotherapy, treated with topotecan, unfortunately, bone lesions were not resolved. Finally, we decided to treat the patient with panobinostat in combination with 131-I- MIBG therapy. Because there were few studies on the use of panobinostat in the treatment of neuroblastoma, the probable dose-limiting toxicities were discussed carefully for her parents and written informed consent was taken from them.
After 131-I-MIBG therapy, she received six courses of panobinostat plus etoposide and doxorubicin (every 21 days). Her last weight, height, and body surface area were 19 kg, 123 cm, and 0.81/m2, respectively.
The dose of panobinostat was 10 mg orally three times/week (Monday, Wednesday, and Friday) days 1, 3, 5, 8, 10, 12 for two weeks and then one week off. Additionally, in each course, she received etoposide 100 mg/m2 intravenous infusion for 2 hours on days 1 to 3 and doxorubicin 30 mg/m2 intravenous infusion for 4 hours on day 1 of each course. The dose and time of panobinostat administration were planned based on PANORAMA 2 study,16 which is done on adults. Therefore, we used 50% of that dose in our studied patient. Additionally, in the study of Paul J. Wood et al. that was performed in pediatric patients with solid tumor, panobinostat was used as 10 mg dose which was well tolerated by pediatric patients.17 We used etoposide and doxorubicin as the concomitant chemotherapy regimen in order to prevent multidrug resistance. Additionally, the study of Guan Wang et al. on neuroblastoma cells revealed that panobino- stat increases the cytotoxic effects of doxorubicin or etoposide on high-risk neuroblastoma cells.13 They clo- sely observed the aspect of echocardiography (ECG) changes and other complications. ECG before and after treatment revealed normal heart function with left ventricular ejection fraction about 61%. Her QTc interval before starting panobinostat was 0.41 s and was 0.42 s during and after treatment which was in normal range. She had vomited after each course without diar- rhea that improved with an antiemetic. Mild to moder- ate myelosuppression was observed during treatment but there is no need to hold the panobinostat. She totally received 180 mg/m2 doxorubicin and it was felt dexrazoxane was not necessary. She also had two-time admission due to febrile neutropenia in the hospital that was successfully managed with antibiotics, G-CSF, and supportive care. No cardiac or serious complications regarding panobinostat were observed during treatment. Fortunately, bone lesions have been resolved after 131-I-MIBG therapy and six courses of panobinostat plus chemotherapy (Figure 2). She was under close follow-up and had no residual disease until six months after receiving full course of panobino- stat. Then, she underwent autologous stem cell transplantation. Now she is on four months post- transplantation and free of disease. She is under regular follow-up and under treatment with isotretinoin. To give a more concise view of the patient’s course through multiple therapies, a timeline of chart to show her pro- gress over time was summarized in Figure 3.
Discussion
Altering the transcription of genes involved in cell cycle checking, differentiation or apoptosis through deregu- lated acetylation of histones acts as a main role in the pathogenesis of solid tumors and hematologic malignancies.18
Blockage of histone deacetylase is considered as a potential therapeutic strategy in the treatment of hema- tological and solid tumor malignancies. This drug can induce hyperacetylation of lysine residues on both histone and non-histone targets in malignant cells.19 Panobinostat therapy augmented histone acetylation, diminished cell proliferation, and survival, and inhib- ited cell cycle development at G2/M with a simultan- eous decrease in S phase, and caused apoptosis of malignant cells.20 In a study by Guan Wang et al.,13 it was showed that panobinostat has a synergistic effect to enhance the cytotoxicity of DNA damaging drugs including cisplatin, doxorubicin, or etoposide on neuro- blastoma cells. The histone deacetylases are known to interact with N-MYC and control numerous cellular processes via epigenetic modulation, including differentiation.21
Therefore, panobinostat in combination with chemotherapy and I-131-MIBG therapy can be a good choice for refractory metastatic neuroblastoma.
Our patient was the only child of the family and she did not have a good response to previous chemother- apy regimens; inevitably, after a full description of the side effects of the drug for a family, we start panobino- stat for her. After three courses of chemotherapy, a whole body bone scan revealed regression of bone lesion, which was completely resolved after the sixth course of panobinostat. Fortunately, the results were satisfactory without serious complications with the men- tioned dose. However, in order to be able to recommend this drug definitely for relapsed or refractory neuroblast- oma, more clinical studies should be conducted on more patients. Of course, we had a good experience in our patient. Our problem with this drug is that it was not easily accessible.
Conclusion
The combination of panobinostat, doxorubicin, and etoposide plus MIBG therapy can be a good choice for refractory metastatic neuroblastoma. However, a study on a larger population is needed.