LTI infusion for for CH 14.18 immunotherapy

(Sam Saffron) #1

In the past few years SIOPEN have been running a trial for the effects of Long Term Infusion for immunotherapy using CH 14.18.

The researchers’ analysis of pain assessment scores and use of intravenous morphine indicated that long-term infusion of ch14.18/CHO was associated with reduced pain, compared with data previously reported for children treated with short-term infusion. The patients also had lower frequencies of grade 3 or higher adverse events in the long-term infusion group vs the short-term infusion group, except for equal frequencies in vomiting.

“In our study, by changing the method of antibody delivery from short-term infusion to long-term infusion, we observed an impressive reduction of on-target [pain] and off-target [inflammation] side effects, while maintaining effective drug levels over the entire treatment period, as assessed in a variety of bioassays, demonstrating the immune-modulatory effect of ch14.18/CHO and its potency to mediate destruction of neuroblastoma cells constantly over a period of 6 months,”

So it looks like LTI

  • Increases the amount of time you are in hospital from 5 to 10 days per immunotherapy cycle

  • Reduces pain

  • Is just as effective as STI (short term infusion)

Does anyone who participated in the trial have any stories for us? How painful is immunotherapy under STI? Is this something I should explore?

(Nick) #2

LTI allows the patient (child) to go home with the antibody infusion in a Baxter pump worn in a very small shoulder bag, so hospital stay will be at least no longer, and hopefully shorter than STI. The slower rate of the infusion may reduce pain - particularly in later rounds no morphine may be required (oral pain medication such as Neurontin may suffice). There is no evidence in any large scale Phase III trial that LTI is as effective as STI. And this is also ch14.18/CHO, rather than ch14.18/SP2/0 as used in COG studies. The results appear similar, but this is where clinicians who normally school parents in the criticality of robust scientific evidence blur their own boundaries somewhat. Those two antibodies have never, and likely will never be compared in a randomized trial. Equally LTI vs. STI is not being compared in a randomized fashion either. And GM-CSF is not given at all in the SIOPEN

(Sam Saffron) #3

I just finished attending the ANR parents day and information day.

One of the talks was by Holger Lode who is in charge of the LTI trials.

Under SIOPEN both LTI and STI are using the same drug, ch14.18/CHO. The main focus around the LTI trial is to look at reducing toxicity while maintaining efficacy.

A huge reason this may become very important is the recent discontinuation of GM-CSF and Interleukin 2 under SIOPEN. When reviewing the SIOPEN data recently the board found that adding cytokines (IL2/GM-CSF) to immunotherapy did not improve outcomes. The result of this recent finding is that SIOPEN discontinued the cytokine test arm.

However, the data had a reasonable flaw. In particular, adding cytokines to immunotherapy is so painful that a much larger group of patients simply stopped immunotherapy prior to finishing the course. The graphs were looking at ALL the patients even the ones that did not complete immunotherapy. Personally, I am surprised that in such a setting outcomes were so close.

So the big question still remains. Does adding cytokines improve outcomes on cohorts that complete the full immunotherapy course?

SIOPEN are going to test this hypothesis with an LTI trial. Since is it significantly less painful, adding cytokines becomes feasible without introducing the same huge levels of pain.

So, I guess, the big promise of LTI, beyond reduced pain is that there is a possibility that they can administer cytokines in a much less painful setting.

Beyond the question of pain there are some other concerns with LTI that need lots of attention.

Not every parent is comfortable taking their child home with a pump. What if something goes wrong? What if you are 50km from the hospital? What if the complications of sending kids home with a pump are deemed too high and you are stuck for 2 weeks in hospital every immunotherapy round for 6 months with a mostly fine kid. That is gruelling psychologically.

(Alexey) #4

Hi @sam,

We just spoke with our doctor and he said that under the SIOPEN protocol there is a still an option with IL2, but with the different dose and update about dropping the IL2 arm in the study was about the old treatment approach. So we confused now, because we thought that IL2 arm was completely dropped from the protocol, but seems its not.

I watched the video from the recent NB conference and I couldn’t find that there is another IL2 option which is currently in the protocol…

Do you know anything else about this topic? Have you spoke about the immunotherapy with your doctor?


(Sam Saffron) #5

Cytokines are a very loaded subject and the recent discontinuation by SIOPEN is very loaded. COG still treat with GM-CSF and IL-2, all the mouse studies show that using cytokines make a measurable difference. Yet, the SIOPEN study showed no actual improvement. (Note: this discrepancy is particularly strange in my hospital where people are treated under both COG and SIOPEN some get cytokines and some not)

Toby Trahair our national deputy for SIOPEN confirmed the discontinuation of GM-CSF and IL-2 with us, we are now undergoing CH 14:18 treatment without cytokines. Just about to finish the first week and even without cytokines it is a rough ride. Perhaps ask your oncologist to confirm with your SIOPEN deputy? It is possible something changed in the past few weeks.

My understanding is that LTI will have an arm that tests IL-2, this is to test the theory that it actually helps but is too toxic to apply to STI.

Are you going to be treated with a long-term infusion? If so, it is probably applicable (though my understanding is that LTI is only given to refractory/relapse cases)

(Alexey) #6

Thanks, @sam ! I will clarify with our doctor.

(Sam Saffron) #7

Let me know what you find out! :slight_smile:

(Alexey) #8

Our doctor showed us the following picture:

I think this is related to the following section here:

R4 randomisation: R4 was activated in April 2014. The SIOPEN long term infusion (LTI) ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time of the same total ch14.18/CHO antibody dose of 100mg/m² to 10 days of continuous infusion in relapsed /refractory patients. Hence the HRNBL1.7/SIOPEN study committee wishes to implement this more favourable immunotherapy dosing schedule for the time till the induction question R3 is answered and the HRNBL1.7/SIOPEN trial may be closed. Considering the high R2 dropout rate of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106 IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial.

(Tomica Tomek) #9

Hello for everybody. I just want to inform you that we are participating LTI infusion since Monday 05. December. Prof Lode is our doctor here in Greifswald. Germany. Thay gave us Ch14.18/cho without IL - 2. I hope everythink would be good after immunoterapy.

(Sam Saffron) #10

How is your son handling the LTI? How long did you spend in the hospital for round 1? Did they send you home with a pump?

(Tomica Tomek) #11

Dear Sam
During 1 cycle of Lti my son was in hospital 15 days. We had complication because thay found water around heart. Now is everything Ok and we are planing to be in Greifswald on 09.01.2017 on second cycles of Lti. Doctors said that second cycles shold be much easier than the first.


We are currently on round 2 of LTI with il2


One note - the pump is a Baxter elastomeric pump. No moving parts. You simply check it every day to ensure it’s infusing. Once you follow the rules we have found it reasonably reliable.

(Tomica Tomek) #14

Hello! I didn’t been in this forum for a three months. Now we are in Griefswald on 5 th cycle od Lti ch14.18. Our boy is ok and we are preparing for finish immunoterapy. Dinumaxitab beta Aperion got positive opinion of EMA before few days (8.5.2017). and now become legal medicine for all HR neuroblastomas in all EU. This is wonderfull news for all children who need that medicament