Three conditioning regimens for high-risk neuroblastoma are discussed: busulfan-melphalan (BuMel), carboplatin-etoposide-melphalan (CEM), and treosulfan-melphalan (TreoMel). A randomized trial found BuMel had significantly better event-free and overall survival rates compared to CEM. TreoMel showed low toxicity in small studies but requires more research. Targeted radionuclide therapies with 131I-MIBG or anti-GD2 antibody are also being investigated.
2. • High-risk neuroblastoma (HR-NBL) is defined as
• Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit), any MYC
status*
or
• L2, M or Ms neuroblastoma with MYC amplification, any age
• Management :
• Induction chemotherapy
• local treatment (surgery and radiotherapy)
• High-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR)
• Maintenance treatment
3. • First high‐dose regimen used in the treatment of neuroblastoma was
single‐agent high‐dose melphalan
Progressed to various combinations of other agents, including
• HD carboplatin etoposide melphalan (CEM) and total body irradiation (TBI)
• MEC and HD melphalan
• TMT (Treosulfan, Melphalan, and Thiotepa)
• COG regimen - CEM (HD carboplatin- etoposide-melphalan )
• Bu Mel (Blusulfan melphalan )
• Treo Mel (Treosulfan, Melphalan)
4.
5. • High Dose Melphalan
• 5 yr EFS 38% vs 27%
no melphalan group
[Matthay KK, J Clin Oncol 2009]
6. • Matthay et al. published the long-term results
of patients treated with CEM+TBI followed by ASCR
and reported 5 year-EFS and OS rates of 30%
and 19%, respectively.
• In the COG A3973 study, CEM was selected as the standard of care in the attempt to find an optimal regimen
substituting for the TBI-containing once employed in the CCG 3891 protocol
7. • ENSG conducted a large, multinational cooperative randomized study (the
HR‐NBL1 trial)/SIOPEN randomized trial (R1) comparing the COG regimen of
carboplatin, etoposide, and melphalan (CEM) with the busulfan and melphalan
(BuMel) regimen
• Of 1,577 patients with HR-NBL, 563 were randomly assigned in a 1:1 ratio to either
Bu-Mel or CEM following rapid induction therapy with COJEC
• The trial was stopped because a pre-specified interim analysis showed:
• 49% EFS rate with Bu-Mel vs 33% for CEM (p< 0.001).[Ladenstein R, Lancet Oncol 2017]
• 3-year OS was 60% with Bu-Mel vs 48% for CEM (p=0.003)
• Five-year EFS and overall survival rates were 45% vs 33%, and 54% vs 41%, respectively in
BuMel VS CEM
• Rate of relapse or progression was significantly lower in the Bu-Mel group (47% vs 60%; p<
0.001).
8. • In addition to improved survival rates, patients in the busulfan and
melphalan group
• fewer severe life-threatening toxicities (4% vs 10%)
• fewer grade 3–4 adverse events, such as poor general condition (26 vs 38%),
• Infection (19 vs 27%),
• stomatitis (49 vs 59%).
• Veno-occlusive disease, however, was more common with Bu MEL
than with CEM (22 vs 9%).
Ladenstein et al. lancet oncology 2017
9. • A multivariate analysis confirmed that the improved EFS was associated with Bu-
Mel regimen.
• The toxicity was acceptable for both conditioning regimens.
• While the frequency of grade 3-4 infection, fever and renal toxicity was higher in
the CEM arm, the rate of sinusoidal occlusive syndrome (SOS), which was
reversible, was higher in the Bu-Mel arm
• The rate of acute toxic death was 3% for Bu-Mel and 5% for CEM, and severe
toxicity was not significantly different in the 2 arms.
• Therefore, HD Bu-Mel has now become the standard HD regimen in the SIOPEN
HR strategy
18. Ladenstein R., Pötschger U., Pearson A.D.J., Brock P., Luksch R., Castel V., Yaniv I., Papadakis V., Laureys G., Malis J., et al. Busulfan and melphalan versus carboplatin, etoposide, and
melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): An international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–514.
doi: 10.1016/S1470-2045(17)30070-0. [PubMed] [CrossRef] [Google Scholar] [Ref list]
10. • 49% EFS rate with Bu-
Mel vs 33% for CEM
(p<0.001).
• 3-year OS was 60% with
Bu-Mel vs 48% for CEM
(p=0.003)
• Five-year EFS and
overall survival rates
were 45% vs 33%, and
54% vs 41%,
respectively in BuMel
VS CEM
• Rate of relapse or
progression was
significantly lower in the
Bu-Mel group (47% vs
60%; p< 0.001).
12. • Toxicity of a treosulfan, melphalan, and thiotepa
(TMT) regimen evaluated in 17 children with
recurrent or refractory neuroblastoma who
underwent ASCT
• Reported nonhematologic toxicities
• All 17 patients had grade 4 leukopenia and neutropenia,
and 13 (76%) had fever.
• Reversible grade 3 nonhematologic toxicities
• Mucositis (n = 15; 88%) with total parenteral nutrition
(n = 15; 88%) and diarrhea (n = 5; 29%).
• Grade 1 to 3 hypertransaminitis (45%)
• 3 patients developed veno-occlusive disease (18%),
• No neurologic, cardiac, or dermatologic toxicities were
observed.
3‐year
EFS 56% vs EFS 28%
13. • Very few studies using Treo mel vs blu mel in neuroblastoma large study comparing treo
mel vs Bu Mel is lacking.
• However a small study done in between 2001-2007 used TREO instead of oral BU in M-
CHT before auto-HSCT in 10 patients aged from 8 months to 21 year (median age: 4.5
year).
• NBL n= 7 children (5 in CR1, 1 in CR2, 1 in PR) and ES/PNET n= 3 children (2 in CR1,1 in PR).
• TREO was given in total dose of 36 gm2 (12 g/m2/day ) i.v. for 3 consecutive days) and
melphalan 140 mg/[m2] i.v. in one dose
Choma, M., et al. "Treosulfan plus melphalan as megachemotherapy for autologous haematopoietic stem cell transplantation in children and young adults with high-risk or relapsed
neuroblastoma and Ewing/PNET." Bone Marrow Transplantation, vol. 43, no. S1, Mar. 2009, p. S155.
Treosulphan - melphalan in Neuroblastoma
14. Treo melphalan in Neuroblastoma
• None of the patient experienced organ toxicities greater then II WHO or live-threatening infection.
• 5/10 children relapsed (3 with NBL-2 in CR 1 and 1 in CR 2, 2 with ES/PNET--1 in CR1, 1 in PR) at median time of 13
months from auto-HSCT (range 6-24 months) and 4 of them subsequently died of disease progression.
• 6/10 patients are alive, including 5 in CCR (4 with NBL and 1 ES/PNET) since auto-HSCT with median observation
time of 49 months (range 14-76 months)
• Conclusions
• 1. M-CHT with TREO and MEL for auto-HSCT in patients with NBL and ES/PNET and high risk of
BU-related complications demonstrates low organ toxicity.
• 2. Results of auto-HSCT after M- CHT consisted of TREO and MEL in children with NBL and
ES/PNET seems to be comparable with those achieved with BU , need prospective high no of
cohort for validation
15.
16. Tandem Transplant in Neuroblastoma
• Three-year EFS was 61.6% (95% CI, 54.3%-68.9%) vs 48.4% (95% CI, 41.0%-
55.7%) in the single transplant group (1-sided log-rank P=.006).
• The most common significant toxicities following tandem vs single transplant
were mucosal (11.7% vs 15.4%) and infectious (17.9% vs 18.3%).
• Patients aged 30 years or younger with high-risk neuroblastoma, tandem
transplant resulted in a significantly better EFS than single transplant.
• However, because of the low randomization rate, the findings may not be
representative of all patients with high-risk neuroblastoma.
17.
18. Targeted radionuclides as part of high‐dose
therapy
• Targeted radioisotope therapy using anti‐GD2 antibody or MIBG
• [131I] MIBG has been widely shown in European and US studies to elicit a 30–
40% response rate for refractory and relapsed neuroblastoma
• COG pilot study ANBL09P1 is testing the administration of 18mCi/kg
[131I]MIBG as the last cycle of induction prior to first stem‐cell infusion in
newly diagnosed patients, followed by BuMel conditioning prior to second
autologous HCT.
19. High‐dose conditioning regimens in high risk Neuroblastoma
Conditioning
regimens
Single agent
Melphalan
CEM +TBI MEC and HD
melphalan
Melphalan + Thiotepa TMT
(Treosulfan,
Melphalan, and
Thiotepa)
COG regimen -
CEM (HD
carboplatin-
etoposide-
melphalan )
Bu - Mel
(Blusulfan
melphalan )
Treo-Mel
(Treosulfan,
Melphalan)
[131I] MIBG anti‐GD2
antibody
Dosing 180mg/m2 2 Cycles
400 mg/m2 thiotepa &
140 mg/m2 melphalan
N= 41
ORR
CR
5 yr EFS 41.5 ± 7.7%
5-year EFS
of MYCN-
amplified high-
risk
neuroblastoma
60.9 ± 10.2%
5 yr OS 56.1 ± 7.8%
Non
hematological
S/E ( Grade3/4)
Mucositis-84%
Diarrhoea—20%
Hematological
s/e ( Grade3/4)
Deaths 3/50 , 2 infection, 1- AKI
20. • Two cycles of thiotepa and melphalan at a 1-week interval.
• 8Thiotepa (age≥2years,200mg/m2/day; age<2years,8mg/kg/day)was
infused intravenously over 24 hours on days −12,−11,−5, and−4, and
melphalan (age≥2years,70mg/m2/day; age<2 years, 1.5 mg/kg/day) was
infused intravenously over1 hour on days−12,−11,−5,and−4.
• If creatinine clearance(Ccr) was<100ml/min/1.73m2 in patients
aged≥2years,the dosage was principally adjusted before and during HDC
using the following formula:
• given dose(mg/m2)=(Ccr/100)×200mg/m2/day(thiotepa)or70mg/m2/day
(melphalan).
• If a patient’s Ccr was under 50ml/min/1.73m2, we disregarded this
regimen
Editor's Notes
treosulfan (10 g/m2/day for 3 days), melphalan (70 mg/m2/day for 2 days), and thiotepa (2 × 5 mg/kg body weight [BW] for 1 day).
