RESULTS
From 1996 to 2014, 198 patients with high-risk NB underwent HD CT followed by ASCT at a median age of 4.16 years (0.35 – 23.67) at GianninaGaslini Institute in Genoa (Italy); 28 (14.1 %) of these were treated, after induction or salvage therapy and further chemotherapy, with additional Th-131I-MIBG closely followed by HD-MAT BuMel and ASCT as part of consolidation treatment, and were therefore deemed eligible for this retrospective study. Twenty-four patients (85.7 %) were newly diagnosed (all but one stage 4) with refractory disease after induction therapy, and 4 (14.3%) were enrolled after relapse (2 stage 4, 1 stage 4s and 1 stage 2), which occurred after a median time from diagnosis of 68 months (range 27 – 84).
At the end of induction therapy, all 28 patients showed residual MIBG-avid disease: 12 showed partial response (42.86 %) and 16 poor response (57.14 %) (Table 1 ); 7 patients (25%) received an additional course of HD-MAT with Thiotepa followed by ASCT.
High-dose BU-Mel and autologous stem cell transplantation and acute toxicities
The conditioning regimen with Busulfan and Melphalan was started a median of 17 days (IQR 14 – 25) after Th-131I-MIBG; the median dose of autologous CD34+ cells grafted was 4.6 x 106/kg (2.9 – 10).
In all patients, neutrophil and platelet engraftment occurred a median of 14 days (11 – 29) and 30 days (13 – 80), respectively, after ASCT. Oral mucositis was the main toxicity observed after Th-131I-MIBG and HD-BuMel, occurring in all patients (28, 100%): high-grade (3 - 4) in 22 (78.6%) and low-grade (1 - 2) in 6 (21.4%). Gastrointestinal involvement occurred in 6 patients (21.4%): grade 4 in 2 (7.1%) and grade ≤ 2 in 4 (14.3%). No pulmonary toxicity was observed, while renal involvement was observed in 1 (grade 2). Hepatic toxicity was observed in 20 patients (71.4%): grade 1 - 2 in 17 (60.7 %) and grade 3 – 4 in 3 (10.7 %). Two patients developed VOD/SOS(7.1%), which resolved completely after treatment with defibrotide. Only one patient developed sepsis (Gram-) and no deep mycosis was observed.
Treatment after Th-131MIBG and HD BU-Mel
All patients completed the therapeutic protocol with 6 courses of oral isotretinoin. Eleven patients (39.3%) received immunotherapy with anti-GD2 antibody.
Disease response, relapse, survival and late toxicities
After Th-131I-MIBG and HD-MAT BuMel, 10 patients (35.7%) obtained a good response (CR, VGPR), 11 (39.3%) and 7 (25%) obtained partial and poor responses, respectively. In summary, 19 (67.8%, p <0.05) patients improved their disease status after Th-131MIBG and HD BU-Mel (Table 2 ).
Twenty patients suffered relapse after the end of treatments (71.4%) at a median time of 3.2 years (0.2 – 13.2) after ASCT (17 out of 24 newly diagnosed, 3 out of 4 relapsed) in metastatic sites in 13 (46.4%), in primary site in 3 (10.7%) and combined (primary + metastatic) in 4 (14.3%).
Hypothyroidism requiring hormone replacement therapy occurred after a median of 11.5 months after ASCT (5.1 – 16.8) in 9 patients (31.1 %), without significant differences of induction therapy, median dose of Th131-I-MIBG, thyroid blockade treatment or age on ASCT from patients who did not develop thyroid failure; two patients developed benign thyroid nodules, while no secondary malignancies were diagnosed.
Over a median follow-up of 15.9 years (IQR 1stq 7.0 – 3rd q 16.9) after Th-131I-MIBG and HD-MAT BuMel, 15 patients (53.6%) died of disease progression. Of the 13 (46.4%) surviving patients, 4 (14.3%) were disease-free and 9 (32.1%) had stable residual disease(Table 3) . No toxic deaths occurred.
The 3-year and 5-year rates of overall survival (OS) probability were 53% (CI 0.33 – 0.69) and 41% (CI 0.22 – 0.59) respectively(Figure 2) and the 3-year and 5-year rates of cumulative risk of relapse were 64% (CI 0.47 - 0.81) and 73% (CI 0.55 – 0.88), respectively (Figure 3) . In terms of OS and CRR, no differences were observed between the entire cohort and the 24 newly diagnosed patients (3-year and 5-year OS probability 54% [CI 0.32 – 0.71] and 39% [CI 0.20 – 0.58], respectively; 3-year and 5-year CRR 67% [CI 0.48 – 0.84] and 72% [CI 0.53 – 0.88], respectively).
On Cox multivariate analysis, MYCN amplification emerged as the only risk factor significantly associated with OS (HR 3.58; p 0.041), while the other variables considered were not significantly associated with outcome. In particular,123I-MIBG score (< 3 versus ≥ 3) and disease response before Th-131I-MIBG were not associated with outcome (Table 4) .