Tandem transplant offers significant advantages when combined with immunotherapy

Treatment / Research
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I was reading through the submissions to ANR and found this talk:

A Phase 3 randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG) study (#90)

Julie R Park 1 , Susan G Kreissman 2 , Wendy B London 3 , Arlene Naranjo 4 , Susan L Cohn 5 , Michael D Hogarty 6 , Sheena C Teeney 4 , Daphne Haas-Kogan 3 , Peter J Shaw 7 , John Doski 8 , James Geiger 9 , Sandra W Gorges 10 , Gheetika Khanna 11 , Stephan Voss 3 , John M Maris 6 , Lisa Diller 3 , Stephan Grupp 6
University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
Duke University, Durnham, North Carolina, USA
Dana-Farber/Boston Children’s Cancer and Blood Disorder Center, Harvard Medical School, Boston, MA, USA
Children’s Oncology Group, University of Florida, Gainesville, Florida, USA
University of Chicago, Chicago, Illinois, USA
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
The Children’s Hospital at Westmead, Sydney, Australia
University of Texas Health Center at San Antonio, San Antonio, Texas, USA
C.S. Mott Children’s Hospital, Ann Arbor, Michigan, USA
University of California, Davis, Sacromento, California, USA
Washington University School of Medicine, St. Louis, Missouri, USA
Background: ASCT improves event-free survival (EFS) for HR-NB. Pilot studies suggest that intensification of myeloablative therapy using tandem ASCT further improves outcome for HR-NB. We conducted a multicenter RCT comparing tandem vs. single consolidation in patients with HR-NB.

Methods: Between 11/2007 and 2/2012, 652 eligible patients (pts) with newly diagnosed HR-NB received induction therapy: 6 cycles of chemotherapy including initial 2 cycles of dose-intensive cyclophosphamide/topotecan followed by PBSC collection. Randomization occurred at end induction to single ASCT with carboplatin-etoposide-melphalan (CEM) or tandem ASCT with thiotepa–cyclophosphamide ASCT followed by a modified CEM (TC:CEM). HR pts with non-MYCN amplified Stage 3 (age>18mos) or Stage 4 (age 12-18 mos) tumors were non-randomly assigned to single ASCT (CEM). EFS and overall survival (OS) were analyzed as intent-to-treat.

Results: Median age at study entry was 3.1 yrs, 88% (n=574 pts) had Stage 4 disease and 38.2% (n=249 tumors) had MYCN amplification. A total of 355 pts were randomized (CEM n=179 pts; TC:CEM n=176 pts) and 27 patients were non-randomly assigned to CEM. Of randomized pts, 249 patients received post-consolidation immunotherapy on COG trials. Treatment-related mortality was 2.6% (Induction n=7 [1%]; Consolidation n=10 [2.8%; n=8 CEM, n=2 TC:CEM]). Rates of severe mucosal, infectious or liver toxicities were similar between arms. 3-year EFS and OS from diagnosis were 51.1±2.0% and 68.2±1.9%, respectively. EFS and OS for randomized cohort are noted in the Table.

Cohorts	N	3-yr EFS +/- SE (%)	2-sided p-value	3-yr OS +/- SE (%)	2-sided p-value

CEM	179	48.8 ± 4.0		69.0 ± 3.6
TC:CEM	176	61.8 ± 4.1	0.0082	73.8 ± 3.7	0.2563

Immunotherapy

CEM	129	55.4 ± 4.6		75.7 ± 3.9
TC:CEM	120	73.7 ± 4.4	0.0009	86.3 ± 3.4	0.0158

Conclusions: Tandem myeloablative consolidation therapy improves survival probability in patients with high-risk neuroblastoma, especially in the setting in post-consolidative immunotherapy

source : Oral Presentation — ASN Events

The particular thing that sticks out to me is pushing up event free survival up to 73% after 3 years, which is way better than the 50 figure we are used to. I noticed some people on the forum (@teamjakemom) are having tandem transplants, so this should be some very good news.

I am still very unclear what this means for SIOPEN protocol treatment as the induction under COG is very different and drugs used during transplant under SIOPEN are different (BuMel etc.). I guess this is a good question for the panel at ANR.

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Carter will be starting carboplatin-etoposide-melphalan (CEM) on May 24th as part of his tandem BMT process. He had horrible mucositis and CDIFF but was doing great after 5 weeks! Great enough that they released us to the RMH for 2 weeks to await the next step! I am only able to focus on 1 part at a time so I have not even asked about immunotherapy or which drugs he will get. I do know that he is helping the COG in a study to ensure that tandem transplants are beneficial enough to become the standard. Cincinnati already does 2 automatically!

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My son gets to have Dr. Park as his doctor while he receives his tandem transplant. We just got back from our consultation in Seattle.

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Here is a video of Dr. Julie Park talking about the results

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Are tandem transplant usual in the US ? In Europe it’s always a single one.
I’m surprised to hear this doctor saying that chances of survival are proven to be higher with this protocol. Why do they still do single ones though ???

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The answer to this is “it is complicated”.

Kids are treated under different protocols. The majority of the kids in the US are treated under COG. The majority of children in Europe are treated under SIOPEN.

These protocols use different drugs and schedules during induction chemotherapy and different drugs during transplant.

SIOPEN used to use CEM (High-dose carboplatin, etoposide and melphalan) but found that BuMel (busulfan and melphalan) was more effective and less toxic in the context of the SIOPEN protocol.

http://www.siopen.org/siopen-studies/completed/mat

COG published the effectiveness of tandem transplants in the context of the COG protocol. COG still use CEM during transplant. The “tandem” transplant starts out with a " Thiotepa cyclophosphamide (TC)" transplant followed by CEM.

Interpreting the results in the context of COG is quite straight forward, but it is very hard to tell if the same results would also happen in the context for the SIOPEN protocol.

To answer these questions both SIOPEN and COG are going to start some new trials:

COG are trying to answer:

  • Can they use BuMel instead of CEM during transplants? (this will reduce the intensity of treatment)

SIOPEN are trying to answer:

  • Do they need to intensify transplant regime and introduce tandem transplants? (and add the equivalent of tandem transplants but for SIOPEN)

This research is going to take many years.

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Thanks a lot for all these answers! That’s very insturctive.

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Need to pick your brains, please - my son Marko was originally planned for the tandem transplant given his tumour’s unusual presentation ( completely resected low risk NB which mutated to HR metastatic NB, spread to bone and bone marrow). He’s had a very positive early response to COG chemo protocol (the original 10cm adrenal tumour disappeared after 3 cycles, one small spot remains in hip and one single cell was found in bilateral BM aspirates). Now they’re thinking only one transplant with Bu/Mel, followed by radiation to the primary site and Ch14.18 immunotherapy with retinoic acid. Apparently, they had 80% success rate so far with this protocol for HRNB. My concern us that the Royal Children’s in Melbourne is still treating a relatively small number of kids with HRNB compared to some overseas hospitals, so not sure if their 80% is truly statistically reliable… any thoughts? Should I be pushing for tandem?

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I have a question about Tandem Transplant protocol. Is it offered in Europe also? Under SIOPEN protocol as a Clinical Trial? What drugs were for each of the 2 cycles? Our Onco team is suggesting tandem transplant post induction phase (3 more cycles + surgery to go). We follow SIOPEN protocol and I am already worried :fearful: