Incorporation of high-dose 131I-metaiodobenzylguanidine treatment into tandem high-dose chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma: results of the SMC NB-2009 study

Ji Won Lee, Sanghoon Lee, Hee Won Cho, Youngeun Ma, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Eun Joo Cho, Suk-Koo Lee, Do Hoon Lim, Ji Won Lee, Sanghoon Lee, Hee Won Cho, Youngeun Ma, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Eun Joo Cho, Suk-Koo Lee, Do Hoon Lim

Abstract

Background: In our previous SMC NB-2004 study of patients with high-risk neuroblastomas, which incorporated total-body irradiation (TBI) with second high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), the survival rate was encouraging; however, short- and long-term toxicities were significant. In the present SMC NB-2009 study, only TBI was replaced with 131I-meta-iodobenzylguanidine (MIBG) treatment in order to reduce toxicities.

Methods: From January 2009 to December 2013, 54 consecutive patients were assigned to receive tandem HDCT/auto-SCT after nine cycles of induction chemotherapy. The CEC (carboplatin + etoposide + cyclophosphamide) regimen and the TM (thiotepa + melphalan) regimen with (for metastatic MIBG avid tumors) or without (for localized or MIBG non-avid tumors) 131I-MIBG treatment (18 or 12 mCi/kg) were used for tandem HDCT/auto-SCT. Local radiotherapy, differentiation therapy with 13-cis-retinoic acid, and immunotherapy with interleukin-2 were administered after tandem HDCT/auto-SCT.

Results: Fifty-two patients underwent the first HDCT/auto-SCT and 47 patients completed tandem HDCT/auto-SCT. There was no significant immediate toxicity during the 131I-MIBG infusion. Acute toxicities during the tandem HDCT/auto-SCT were less severe in the NB-2009 study than in the NB-2004 study. Late effects such as growth hormone deficiency, cataracts, and glomerulopathy evaluated at 3 years after the second HDCT/auto-SCT were also less significant in the NB-2009 study than in NB-2004 study. There was no difference in the 5-year event-free survival (EFS) between the two studies (67.5 ± 6.7% versus 58.3 ± 6.9%, P = 0.340).

Conclusions: Incorporation of high-dose 131I-MIBG treatment into tandem HDCT/auto-SCT could reduce short- and long-term toxicities associated with TBI, without jeopardizing the survival rate.

Trial registration: ClinicalTrials.gov NCT03061656.

Keywords: Autologous stem cell transplantation; High-dose 131I-MIBG; High-dose chemotherapy; Neuroblastoma.

Figures

Fig. 1
Fig. 1
Treatment flow. Treatment flow of the patients is illustrated. CT chemotherapy, HDCT1 first high-dose chemotherapy, HDCT2 second HDCT, TBI total-body irradiation, TRM treatment-related mortality, Tx treatment, VOD hepatic veno-occlusive disease, ICH intracranial hemorrhage
Fig. 2
Fig. 2
Survival rates. The 5-year OS and EFS rates after diagnosis were 72.4 ± 6.4% and 58.3 ± 6.9%, respectively (a). There was no difference in EFS between the NB-2004 and NB-2009 studies (b). There was no difference in EFS between the TM-TBI regimen in the NB-2004 study and 12 mCi/kg of 131I-MIBG-TM in the NB-2009 study (c). EFS of patients in CR or VGPR at the first HDCT/auto-SCT was higher than in those patients with PR or worse (d)
Fig. 3
Fig. 3
Long-term sequelae after tandem HDCT. Vertical growth retardation (a) and poor weight gain (b) was less significant in the NB-2009 study compared to the NB-2004 study. Body mass index was not different between the two studies (c). There was no difference in full-scale intelligence quotient (FSIQ) between the NB-2004 and NB-2009 studies (d)

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