Big antibody news

The “third generation” humanized anti-GD2 antibody with protein fusion of IL2 to the antibody has completed Phase I and II clinical trials for melanoma and neuroblastoma, and is now ready for use in Phase III clinical trials. The license for hu14.18-IL2 was just acquired by a small biotech in Vienna called Apeiron. The license was acquired from Merck.

Apeiron’s press release:

Apeiron Licenses Phase II/III Anticancer Ab-IL2 Fusion Protein from Merck KGaA

Long-term follow up of children with and without ch14.18/CHO in German trials NB90 and NB97

It has been a very long wait to finally see this graph. The Germans reported on this at ANR 2008 in Japan, and again at ANR 2010 in Stockholm.  See Graph A in Figure 2. “Follow-up analysis of the patient cohort indicated that immunotherapy with ch14.18 [no cytokines] may prevent late relapses.” Remember this group reported in 2004 “analysis failed to demonstrate an advantage of antibody treatment” –

http://jco.ascopubs.org/content/22/17/3549.long

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The statement about late relapses is a little puzzling to me. Graph A shows that “events” (which are usually relapses) occurred up until 10 years in both the ch14.18 and maintenance groups. Only the “no consolidation” group had later events.

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The authors concluded:”Today, the most effective way of antibody based maintenance therapy seems to be a combination immunotherapy with MAB ch14.18, cytokines, and retinoic acid. But these results need confirmation by at least another randomized trial. Further, metronomic low dose oral chemotherapy consolidation was found as effective as MAB ch14.18 consolidation in this retrospective analysis and, therefore, also warrants further evaluation. Prospective clinical trials must demonstrate if the concept of low dose metronomic chemotherapy is feasible and effective after ASCT and in combination with immunotherapy.”

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Since the early results did not show a benefit of ch14.18 without cytokines, and yet the COG trial showed 20% advantage in early results, it could be argued that there might be a big difference in survival between oral metronomic chemotherapy and ch14.18 with cytokines.

http://www.biomedcentral.com/content/pdf/1471-2407-11-21.pdf

Germans report on outcomes of relapsed NB patients who received three different regimens

Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials.

Simon, T., Berthold, F., Borkhardt, A., Kremens, B., De Carolis, B. and Hero, B. (2011), Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials. Pediatric Blood & Cancer, 56: 578–583. doi: 10.1002/pbc.22693

This is an important publication and was presented at ANR 2010. Few groups have tackled relapsed NB in any systematic way. Wendy London’s abstract presented at ASCO 2010 and ANR 2010 on survival after relapse suggests that some relapsed NB children are salvageable, and the Germans and Swedes are advancing understanding in treating relapse. This same approach looking at more aggressive measures for relapsed leukemia kids is how relapse protocols were developed to treat relapsed leukemias.

Drs John Maris and Yael Mosse awarded patent for ALK mutation link to diagnosis, prognosis, and treatment of neuroblastoma

Summary of patent:

CHK1 suspected to be a promising target in NB — inhibitors are being tested in adults

‎”CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P < 0.0001) and high-risk (P = 0.03) tumors.”

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in n

www.pnas.org

Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved December 17, 2010 (received for review August 23, 2010)

Protein May Be Key to New Treatment in a Childhood Cancer — PHILADELPHIA, Feb. 7, 2011 /PRNewswire-

The neuroblastoma oral papers (OP2) presented on Friday October 22, 2010 at SIOP in Boston covered a range of topics including prognostic factors, targets, and stem cell contamination. This report will focus on the presentation on prognostic significance of segmental alterations in neuroblastoma tumors.

Accumulation of segmental alterations determines progression in neuroblastoma (O024)

Neuroblastoma tumor biology has long been an intense subject of study because of the heterogeneous nature of this disease. Looking at macro, micro, and genetic features reveals the differences in tumors, and why some children with neuroblastoma survive without treatment and others do poorly with the most intense treatments conceived. Now that technology is accessible to analyze genetic profiles, more precise risk can be assigned, and appropriate treatment given. Further, this analysis allows for understanding the evolution of tumor genetics as relapse and progression occurs.

Gudrun Schleiermacher from France presented on a study of numerical and segmental chromosome alterations in neuroblastoma tumors. This subject was a matter of interest at ANR in Stockholm as well, and this abstract was also presented at ASCO in June.[1]  This topic has been the subject of many abstracts at recent meetings, and several recent publications confirm the importance of this work [2-6].

Prior publication in 2009 from this French group included  a comprehensive overview of the genetic alterations of neuroblastoma and clinical significance. A series of 493 neuroblastoma samples was investigated by array-based comparative genomic hybridization and the analysis identified several types of profiles:

Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.[2]

Caren and collegues (Sweden) also concurred that these studies have:

implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment. [5]

Schleiermacher and colleagues analyzed 394 neuroblastoma tumors with array-based comparative genomic hybridization and linked the results to clinical data for outcomes. The tumor samples included all risk groups, and analysis was performed again in the event of relapse to discover changes in the tumor profile. The study confirmed that neuroblastoma tumors are characterized by two distinct genetic profiles — either numerical or segmental chromosome alterations.

Tumors were first divided into five groups based on genomic aberrations: numerical only, segmental only, MYCN amplified, numerical and segmental, MYCN and numerical. The tumors with only numerical alterations had the best prognosis. No breakpoint pattern was observed in the segmental-only group which contained up to 1000 breakpoints. Seven or more breakpoints portended a worse prognosis, and was an independent factor in multivariate analysis. More breakpoints were correlated with higher age at diagnosis, higher stage of disease, and higher risk of relapse.

Tumors with only numerical alterations at diagnosis frequently acquired segmental alterations upon relapse. This could not be strictly attributed to chemotherapy since tumors treated with surgery only had acquired segmental aberrations. The authors concluded that tumor progression is directly linked to an accumulation of segmental alterations.

References

1. J Clin Oncol. 2010 Jul 1;28(19):3122-30. Epub 2010 Jun 1. Accumulation of Segmental Alterations Determines Progression in Neuroblastoma. PMID: 20516441

2. J Clin Oncol. 2009 Mar 1;27(7):1026-33. Epub 2009 Jan 26.  Overall genomic pattern is a predictor of outcome in neuroblastoma. PMID: 19171713

3. British Journal of Cancer (2007) 97, 238–246.  Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. [free fulltext]

4. Am J Pathol. 2010 Jun;176(6):2616-25. Epub 2010 Apr 15. 2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics. PMID: 20395439

5. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4323-8. Epub 2010 Feb 9.  High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. [free fulltext]

6. N Engl J Med 2005; 353:2243-2253.  Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. [free fulltext]

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Report from Stockholm by John Rogers, PhD

The following report was prepared by Dr John Rogers after attending the ANR meeting. He is a physicist at the University of Kent, near Canterbury in the UK. His daughter recently finished frontline NB therapy in the UK and the ch14.18 study at Children’s Hospital of Philadelphia. Many thanks go to John for permission to share his keen insights from this significant meeting.

Advances in Neuroblastoma Research Conference 21-24 June 2010 Stockholm

Report by John Rogers, September 2010. The views expressed in his report are the author’s personal views and opinions.

Held every two years, the Advances in Neuroblastoma Research (ANR) conference for 2010 took place in Stockholm, Sweden. The 600+ participants represent the bulk of the world’s effort into treating and curing neuroblastoma. All of the presentations were spread over four days and this report details some of what was presented. The conference is aimed at researchers and clinicians.

This report is intended to give an outline of some of the major topics and talking points raised at this year’s conference. It is aimed at parents of children with (or who have had) neuroblastoma and others with a general interest, and is written without a medical background. Although written from a U.K and to some degree European point of view, as the effort is international and most new treatments appear to be coming from the United States, it is relevant for all.

General Interest

Over the course of the conference presentations were given detailing general advances in related fields that could have an impact on neuroblastoma. From a talk that touched on a type of Omega-3 (that could be nature’s own anti-cancer wonder drug) to talks that described viruses commonly present in cattle that could stimulate cancer in humans, they were wide ranging and were primarily designed to get people thinking and discussing the topics.

A more immediate presentation was from Dr. Maris, Philadelphia where he described the impact of genetic testing on finding the roots of neuroblastoma. The clear point made was that neuroblastoma is a genetic disease, and it must be stressed that this is not the same as hereditary. It is widely known that a very small subset of neuroblastomas are hereditary.

The point made here was that evidence is building (from genetic analysis) that there is a genetic basis for being at-risk for neuroblastoma. In other words, environmental factors will not just ’cause’ neuroblastoma, despite what was suspected just a few years ago at academic meetings or what ‘conspiracy theorists’ will still tell you today.

Another interesting presentation was given Dr. Pat Reynolds of Texas who presented some reasons why drug companies would find it difficult to invest in a drug exclusively for neuroblastoma. The numbers involved and the regulatory hurdles in place mean they could never have a chance of recovering costs (minimally estimated to be up to $100 million or more).

A large section of the conference was devoted to Cancer Stem Cells (or tumour initiating cells, TICs). This work is currently an academic subject, and though potentially important for long-term success, is still in early development. Ideas expressed at the conference revealed current controversy, but as far as how this affects treatments now, it appears there remains much work to be done.

Frontline Treatment

From my view there were three main areas of interest regarding frontline therapy. These were the success of the ‘new’ ch14.18 antibody treatment, the use of genetic testing (specifically ALK) and new analysis of survival.

ch14.18

This year’s conference marked the first ANR gathering since the announcement in March 2009 that there was a significant improvement in survival in those patients randomized to receiving ch14.18 antibody with cis-retinoic acid as per the COG study (within 100 days of transplant and with the two cytokines IL-2 and GM-CSF) versus those receiving only cis-retinoic acid.

Alice Yu presented the results of the study again, and some history is appropriate for the treatment and future direction.

The COG study result was without a doubt the major news of the conference (even though this is at the time of writing 15 months old) and its implications for future survival was obvious. Never in history has a 20% improvement in survival resulted from a single treatment for high-risk neuroblastoma. It was pointed out publicly at the conference the puzzling situation that has now arisen: the COG institutions offer one type of ch14.18 treatment (the proven antibody with both cytokines) whereas SIOPEN randomizes between a slightly different antibody (ch14.18/CHO which is made from hamsters as opposed to mice) only, or that antibody with IL-2 (administered differently). In addition, there are other slightly different German trials.

The question was asked ‘Does it make sense to all be asking slightly different questions?‘ I would have put it more bluntly with the additional statement of ‘knowing the result of the COG study’ the only reason the European institutions are suddenly offering the ch14.18 treatment is the result of COG study. Yet none of the European institutions currently include it in their trials, let alone offer it as a ‘standard’ treatment. Some reasons floated are the practical difficulties in introducing such a complex treatment across multiple sites, but ultimately, after thoroughly pursuing the question I found it was due to regulatory and paperwork issues. After speaking with Dr. Ladenstein (Austria), who is leading the SIOPEN trial, I was left very disappointed with the situation, so long after the COG results. I feel it is not an acceptable reason if this is the case.

ALK

The discovery of the ALK mutation in 80% of familial neuroblastoma (the very rare hereditary form of neuroblastoma, around 1% of all neuroblastoma cases), representing a minority of cases, was an important step in research in this field. It also demonstrated the power of genetic analysis to introduce new treatments quickly. A drug to target ALK was already available and this is now under trial at some COG institutions (presented by Dr. Mosse).

Further to this, it was presented that resistance is expected to develop to this treatment (has been modelled) and therefore a combination of the Pfizer drug together with a monoclonal antibody is prepared to overcome this. Without knowing the outcome of these trials it is difficult to assess how important the current trial of ALK targeted treatment will be for neuroblastoma.

The speed at which it has been implemented in the U.S. is quite stunning and is a good indicator for the future there (that new candidate drugs could be implemented quickly). In this sense, the ALK discovery is more important to talk of in the way genetic testing can and will be used for prognosis and treatment on an individual frontline basis as well as for research for new treatments (something that is a difficult but crucial problem for the INRG and something that UK Prof. Pearson touched upon in his presentation). What it means for European centres and U.K. is not clear as the implementation of genetic testing of the tumours for this and other mutations, together with new trials of target drugs, may take years on a U.K. or European setting given the current situation.

Analysis of Survival

There were some important presentations regarding updated figures and studies.

More than one presentation dealt with analysis of treatment stratification. The use of a ‘wait and see’ approach for the low and intermediate risk presentation was discussed in one report. The COG presented the latest figures for survival of children with stage III disease. Although the figures did not separate out children who received the antibody and those who did not, figures of long term EFS around 90% for non-mycn amplified disease and approximately 70% for mycn-amplified disease were reported.

Analysis of time to relapse was reported on: while a relapse is never good news, it was reported that from analysis of the INRG database the ‘worst’ time to relapse is between 6 and 18 months from diagnosis. It should be made clear that there are still survivors from this period too. Late effects of neuroblastoma treatments were reported on. A presentation from the United States reported on the increased incidence of chronic health problems in survivors (from the harsh treatment). One of the surprising specifics of the report was the increasingly recognized side effect of Accutane treatment. It can be thought of as increasing bone age, so in effect survivors’ growth is affected (there is a risk of this effect).

The proven benefit still outweighs this possible side effect as the alternative is possible relapse, but it will be something that physicians will weigh into their judgements. Similar presentations came from the UK and Germany. Both reports showed a minority of survivors living free from any side effects, though for most the side effects, though serious, are manageable. It appeared from the multiple presentations that touched on these areas that most of the side effects could be attributed to the high doses of chemotherapy. Recognised treatment areas that also contribute to long term side effects are radiotherapy, surgery, Accutane and stem cell transplant.

For some types of tumours (usually low risk) there were reports of success in the use of surgery only. The target for would be to reduce the need for radiotherapy and stem cell transplant for as many children as possible (treatments with recognized long term implications).

Relapse and Refractory Treatments

One of things that make neuroblastoma a ‘difficult’ disease for doctors and researchers to approach and treat is the very varied nature with which it presents and responds to treatments. An interesting presentation regarding relapse treatment was from Germany, where it was reported that a group of relapse patients who received a stem cell transplant are appearing to achieve around 20% long term survival. This is a key survival option in Europe where there is not the slew of new types of treatment available for relapse and refractory patients that seem to be appearing in North America. It should be noted that the numbers were small and although it is early days, it is a “relapse treatment” that is widely available.

MIBG treatment figures were reported on at the conference, with one study showing around 50% overall survival at 4yrs after relapse (a NANT study that included high dose chemotherapy with MIBG presented by Dr. K. Matthay).

Dr. Kushner from the Memorial Sloan-Kettering Cancer Center (MSKCC) presented updated results of the treatment offered at their institution, specifically 3f8 with GM-CSF and Accutane for consolidation of 2nd complete or very good partial remission. It was an interesting report and stood out for me in one area. This was relapse treatment. Presented was a comprehensive analysis of relapse treatments. I am sure most other institutions do have strategies, but it appeared to me that at MSKCC it was more developed. At least in the area of CNS relapse they do offer a unique treatment in the form of the 8H9 antibody.

Future Direction

As someone that is in a position of recently being very interested in front line treatment options and now is becoming aware of relapse options, the ANR conference was informative.

During one session senior figures from the COG, SIOPEN and GPOH presented their vision for where treatment will progress.

John Maris from Philadelphia spoke of how induction treatment would likely change. It would hopefully include molecularly targeted agents and more extensive testing would enable further risk stratification. He noted the current ch14.18 trial (with IL-2 and GM-CSF), which is now purely being run to collect toxicity data for FDA approval. Other ways treatment could be improved mentioned were: in future there would be the hope of improving the efficacy of the antibody (via a trial of hu14.18 vs. ch14.18), adjustment of combinations of chemotherapy to reduce toxicity, introduction of fenretinide as a substitute for Accutane and the integration of basic science into relapse treatment.

Ruth Ladenstein from Austria spoke for SIOPEN, and detailed the current ch14.18/CHO antibody trial in their areas (including the UK). This started accruing last year and randomizes between antibody only and antibody and subcutaneous IL-2. They continue to accrue children on this trial and see the next step to provide antibody for relapsed and refractory patients. As well as the antibody the introduction of new chemotherapy agents and combinations is seen as one of the next steps.

Thorsten Simon spoke for GPOH and detailed the positive steps taken to use banked tumours for research and prognosis stratification. The current survival of around 35% long term survival for the German NB97 protocol was mentioned (retrospective comparison of the NB90 protocol with the NB97 protocol was used to dismiss the ch14.18 antibody treatment several years ago).

Currently there are several trials running in Germany that include ch14.18 after SCT and trials that have ch14.18 with IL-2 subcutaneously. Future work is seen as; reintroducing the ch14.18 widely in some form, improvement of the risk stratification, reduction of the late effects and the introduction of targeted therapies.

There were too many other talks to mention that showed early in-vitro results that point to a more sophisticated future in neuroblastoma treatment.

Discussion

The ANR 2010 conference in Stockholm was one of the best organized and run conferences I have been to (I have been to a lot). The doctors and researchers worked hard and are as a rule, I think, committed and dedicated. If anyone reading is involved in raising money for researchers to cure this disease, then from what I saw, their commitment shouldn’t be questioned. For a very few, the performance may be another matter, as well as the common sense, but I’ll come to that.

The immunotherapy treatments are destined to be part of frontline treatments. Currently the only treatment in this category proven to work is the COG ch14.18 treatment with IL2 and GMCSF. Despite this, SIOPEN institutions and those in Germany are proceeding with modified trials in the hope of either reducing treatment toxicity or improving the benefit from the COG protocol. I personally have no doubt that this is unethical, but all the European institutions look set to proceed until they have a strongly statistically significant result.

That the COG study have still not published their updated results in a major medical journal 18 months after the public announcement of improvement in survival is a mystery. Once published, it would be hoped that collaboration would take over from the current situation.

MSKCC continue to offer 3f8 and this will continue to be a key treatment option if a child does not qualify for 14.18 trials. It is worth noting (though I have not seen anyone point this out) that the success of the COG Ch14.18 trial in frontline treatment is to some degree a vindication of the reports of 3f8 from MSKCC. Their use of immunotherapy for  neuroblastoma since the mid-eighties was ground breaking and means we should pay attention to what new treatment options are developed there.

The key news at this year’s ANR conference was the impact of genetic analysis. Some will tell you that everything from pollution to food additives causes neuroblastoma. They might be right, but it isn’t proved (as it isn’t proved mobile phones are dangerous or that living close to power lines is harmful or that eating organic food will stop you getting cancer if you get my point – only weak research that suggests this, but that is not the same as proved). What is being proved is that you can be genetically predisposed to developing  neuroblastoma. I think that is important for some parents who do and always will question ‘what they did wrong’. Nothing.

The way this new genetic testing is going to be implemented is a major challenge for the neuroblastoma clinicians. This is especially true in Europe where regulation is a drag on getting the latest treatments to clinic quickly.

The continuing situation with the ch14.18 treatment in Europe is amazing, so I’ll go into some detail.

Currently within SIOPEN, as far as I am aware, children in frontline treatment are still being randomised to receive either antibody only or antibody with IL-2. I heard a figure of 70 so far at the ANR. Concerns about the antibody-only treatment go back to the fact that research in Germany published in 2004 concluded this treatment did not work. [1] Why? Now it has been suggested that the original German trial was faulty and anyway was not a randomised trial.

Verbally at the ANR 2008 the same researchers in Germany reportedly commented that they had seen less late relapses in the group who received the antibody, and in 2010 at the ANR showed the same data as used to conclude the antibody only did not work.

Now, several further years out, the comment was ‘coming along nicely’. Now, again, children are receiving this treatment. Over in Germany today they give antibody with IL-2 in some places and antibody only in others, but have widened access to relapse patients and others. All of this activity has only happened because of the dramatic success of the COG trial. The strong evidence for the beneficial use of ch14.18 is in the COG protocol with the two cytokines (GM-CSF and IL-2). Ignoring the fact that the antibody used in Europe is technically a little different to that used in the COG, you would expect that children in frontline treatment would be offered the best available treatment.

When SIOPEN met to discuss the new trial in light of the COG result, I have to assume some left common sense at the door on the way in. If the intention was to reduce the toxicity of the treatment, they could have designed the new trial to start with the proven COG protocol and ‘drop down’ to the other treatments if toxicity proved to be a problem. Quite simply, an academic question to move the research forward and improve treatment for tomorrow should not come at the expense of children today (several dozen children across SIOPEN have received antibody only this year). From what I can tell this is the only explanation of the situation.

If the research is taking a ‘leap of faith’ that the original German results do show significant benefit (and therefore that ch14.18 without cytokines is a potent treatment), that ‘leap of faith’ should extend to a comparison of the COG results and the different protocol. If it ever becomes possible to directly compare the current European treatment to the current COG protocol, I do hope the treatments are as good if not better as hoped. But if any one of them is not, I for one will be pointing it out.

International co-operation and conferences like the ANR mean that, at least in western nations, treatment protocols are similar. A notable difference is the number of truly unique types of trials available for children in relapse in North America (I am thinking of trials such as those involving ABT-751 and fenretinide). I make a difference between number of trials and ‘truly unique’ because it is much easier path to tread for a researcher to adjust a protocol with different amounts of (already approved by health watchdogs) chemotherapy than use new drugs or treatments never used before in children. It is in this area where doctors and researchers can be helped to find the cure, encouraging further international collaboration and lobbying for the relaxation of restrictions on treatments where children are out of treatment options.

As a final thought, doctors and researchers are aware and do consider the facts of life in the  third world. Almost all the treatments presented at the ANR conference showing increasing rates of survival are just impossible there.

Further Information

In addition to the site www.nbglobe.com an incredibly useful email posting service can be found at: http://listserv.acor.org/SCRIPTS/WA-ACOR.EXE?A0=N-BLASTOMA

I would advise anyone involved in neuroblastoma to sign up for this service. It is “an unmoderated discussion list for patients, family, friends, researchers and physicians, to discuss clinical and non-clinical issues and advances pertaining to neuroblastoma.”

Disclosure

The 2Simple Trust paid for John Rogers’s conference registration fee. He covered his own travel, subsistence costs and hotel costs. His daughter recently finished treatment for neuroblastoma (III myc-amp) at The Royal Marsden, U.K. and The Children’s Hospital of Philadelphia, U.S.A.

J. Rogers

rogersjohna@gmail.com

Abbreviations

References (ch14.18 and cytokines)

1. J Clin Oncol. 2004 Sep 1;22(17):3549-57. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. PMID: 15337804

2. J Clin Oncol. 2009 Jan 1;27(1):85-91. Epub 2008 Dec 1. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children’s Oncology Group. www.ncbi.nlm.nih.gov/pmc/articles/PMC2645092/

3. Biochem Soc Trans. 2002 Aug;30(4):518-20. Targeted cytokine delivery to neuroblastoma. PMID 12196127

4. Blood. 2002 Jun 1;99(11):4166-73. Antidisialoganglioside/granulocyte macrophage-colonystimulating factor fusion protein facilitates neutrophil antibody-dependent cellular cytotoxicity and depends on FcgammaRII (CD32) and Mac-1 (CD11b/CD18) for enhanced effector cell adhesion and azurophil granule exocytosis PMID: 12010822

5. J Clin Oncol. 2000 Dec 15;18(24):4077-85. Phase I study of chimeric human/murine antiganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colonystimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children’s Cancer Group Study. PMID: 11118469

6. Cancer. 2000 Jun 15;88(12):2838-44. A phase I dose escalation of combination chemotherapy with granulocyte-macrophage-colony stimulating factor in patients with neuroblastoma. PMID: 10870069

7. Blood. 1989 May 15;73(7):1936-41. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. PMID: 2653466

Pilot study: 131I-MIBG radiotherapy with chemotherapy after induction for newly diagnosed

Dr Greg Yanik (University of Michigan) presented preliminary results of the NANT (New Approaches to Neuroblastoma Therapy) NANT-2001-02 phase 2 MIBG + CEM (131I-MIBG radiotherapy with carboplatin, etoposide, and melphalan) stem cell transplant trial on June 23rd 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden in the “Novel clinical strategies” session. The data are still under review and will be presented at the COG meeting next month. The trial has been completed but the NIH clinical trials listing has not yet been updated to reflect this.[1]

The results of 12 relapsed and refractory children treated in the phase I MIBG+CEM trial was published in 2002.[2]

The encouraging results in the phase II study with 50 refractory children who did not completely respond to induction provide promising expectations for a new pilot trial COG-ANBL09P1 using this concept for frontline therapy for newly diagnosed. The principal investigator is Dr Brian Weiss (Cincinnati Children’s) and the trial will soon begin, accruing 49 patients up to 30 years old in select locations.

Upon completing this protocol, children will also be eligible for the new phase III antibody study using ch14.18 + GM-CSF + IL2 COG-ANBL0931. This trial opened in January 2010 and will accrue 105 (currently open in 29 locations) to further establish safety and efficacy of the antibody ch14.18 given with cytokines GM-CSF and IL2 to obtain FDA approval. This trial is open to all ages.

Is this the first time MIBG will be used in frontline therapy for newly diagnosed (as opposed to just for those refractory at the end of induction)? In 2008 researchers in the Netherlands reported the use of MIBG as initial therapy before chemotherapy and surgery for 44 newly diagnosed high-risk children.

From the abstract:

The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months.

Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%.[3]

References

1. OR58 Phase II trial of MIBG with intensive chemotherapy and Autologous Stem Cell Transplant (ASCT) for high risk neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Study (p. 123 ANR Programme Abstract Book, June 2010)

2. J Clin Oncol. 2002 Apr 15;20(8):2142-9. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. PMID: 11956276

3. Eur J Cancer. 2008 Mar;44(4):551-6. Epub 2008 Feb 11. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. PMID: 18267358

C10 (p. 80) “Late effects in neuroblastoma”

Dr Lisa Diller (Boston Children’s/Dana-Farber Cancer Institute) reviewed recent published data on late effects and presented new data in the Neuroblastoma Update Course on June 21st, 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden. The session was organized by Sue Cohn and Andrew Pearson and chaired by Sue Cohn and Rani George.

The Childhood Cancer Survivor Study provided long-term survivorship data for those treated for neuroblastoma between 1970 and 1986, and results on 954 5-year survivors were published in Journal of the National Cancer Institute August 2009.[1]

Of the 954 children, 832 records were abstracted, and only about 10% were stage 4 survivors, so the vast majority (~90%) of the survivor data most likely represented low and intermediate risk survivors.  Only 38% of the survivors had surgery + chemotherapy + radiation.  Of all the survivors, at least 90% had 15 years of follow-up. Of 1358 there were 84 deaths (41 recurrences)  and higher risk of death if diagnosed over the age of 5 and had multimodal therapy. The children treated for neuroblastoma were compared to a cohort of 3899 siblings to determine if there was a higher incidence of health problems. There was a higher incidence of chronic health conditions involving the neurological, sensory, endocrine, and musculoskeletal systems in children treated for neuroblastoma.

Dr Diller also mentioned evidence from soon-to-be published institutional data that advanced bone age or epiphyseal closure is more common in children treated with cis-retinoic acid than children who did not have cis-retinoic acid. There is a theoretical toxicity proposed related to cis-retinoic acid given with anti-GD2 antibody (ch14.18) because of clearance issues, but this has yet to be verified.[2]

References

1. J Natl Cancer Inst. 2009 Aug 19;101(16):1131-40. Epub 2009 Jul 31. [fulltext]

2. ANR 2010 “Neuroblastoma Update Course” ANR 2010 Abstract Programme, p 80.

SEL11 (p 136) “High dose MIBG and haploidentical stem cell transplantation with cell therapy in therapy resistant neuroblastoma”

Janek Toporski presented (5 minutes) for the Swedish group in the “Clinical” session for selected posters at ANR Tuesday June 22 .

This was a very small study with only 10 patients. The purpose was to evaluate the feasibility of high dose MIBG radiation therapy followed by reduced-intensity conditioning and T-cell depleted haploidentical peripheral blood stem cells, donated from a parent.

Six relapsed children (4 had prior autologous stem cell transplant) and 4 refractory children were enrolled in the study. The children received high-dose MIBG on day -20, then fludarabine, thiotepa, and melphalan from day -8 to -1.  On day 0 haploidentical cells from a parent were infused, along with donor (n=7) or third party (n=3) mesenchymal stem cells. A single dose of rituximab was given on day +1. Seven children received donor lymphocyte infusion.

The abstract states:

Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor effect.

Treatment was well tolerated, with no treatment-related deaths. Two children had acute graft-versus-host disease (aGVHD), and five were treated successfully for aGVHD that developed after donor lymphocyte infusion.

Eight children are alive and 4 remain free of disease 53, 52, 8 and 5 months after transplant, and 4 are alive with stable/slowly progressive disease 52, 17, 5, and 4 months post transplant. Two children died of progressive disease 5 and 12 months after transplant.

Clinical and biological features predictive of survival after relapse of neuroblastoma: A study from the International Neuroblastoma Risk Group (INRG) Database.

Citation: J Clin Oncol 28:15s, 2010 (suppl; abstr 9518)

Wendy London is the Lead Statistician for neuroblastoma research for the Children’s Oncology Group (COG), and Data Center Statistics Committee Chair for the International Neuroblastoma Risk Group (INRG) project and has recently joined the team at Boston Children’s/Dana-Farber.

Dr London spoke on this topic at both ASCO 2010 (15 minute presentation on Monday for the Pediatric Oncology II session) and at ANR 2010 (25 minute presentation during the Monday Neuroblastoma Update Course)  and another 15 minute presentation on this same topic was given by by Victoria Castel on Thursday during the clinical plenary session. Three presentations–two at ANR!  This alone gives you an idea of the importance of this study–the largest ever done on this topic.

As I was preparing to report on this study, I saw that OncologySTAT.com (an excellent source of trustworthy oncology information by Elsevier, a world-leading publisher of medical information)  just released a report of their own. I highly encourage you to read their article.

Of 8800 INRG patients, 2266 experienced a “non-death first event.”

The INRG database includes all risk groups diagnosed from 1990 to 2002 in North America, Europe, Japan, and Australia.

Events are defined as relapse, progression, or second malignancy. Death as a first event was not included in this study.

Although prognostic factors are used to stratify treatment at diagnosis, no one has previously analyzed what factors are predictive of outcome post-relapse.  This study posed the question: is time-to-relapse a factor affecting outcome? Are there any other factors affecting outcome?

Of all the children who had events, median follow-up was 3.6 years (1 day to 13.7 years) and the characteristics of these children were:

• 73% ≥ 18 months old
• 72% were stage 4
• 33% were MYCN amplified

The median time to relapse for the 2266 children who had events was 13.2 months with a range of 1 day to 11.4 years. An anecdotal aside, I happen to know a fellow who relapsed 13.5 years after high-risk diagnosis, obviously not included in this data although he was diagnosed at Boston Children’s in 1991. He survived almost 5 years post-relapse.

The overall survival at 5 years after first event (all risk groups) is 20% ± 1%.

Those who had a first event in less than 1 year from diagnosis (n=1012) had approximately 25% overall survival and those who had first event after 1 year (n=1254) had about 10% overall survival.

When looking at those who relapsed before (n=2081) and after (n=184) 3 years, the gap closes at close to 20% survival.

The risk of death differs over time.

Time-to-first-event, age >18 mo, stage 4, MYCN amplified, diploidy, high MKI, undifferentiated grade, and 1p aberration were significantly predictive of death after relapse (p<0.0001), but not 11q aberration. Compared to children who had a first event more than 6 mo from diagnosis, those who relapsed 6-<18 mo from diagnosis had increased risk of death, while relapses ≥18 mo from diagnosis had decreased risk of death. Shorter time- to-first-event was not independently predictive of death after adjustment for undifferentiated grade, high MKI, MYCN amplification, or diploidy.

In a survival tree regression analysis that adjusted for time-to-relapse, disease stage was identified as the most highly significant variable for survival post relapse. Stage 4 patients (n=1578)  had a 5-year survival of 8% ± 1%, compared with 52% ± 3%  for those who were stage 1, 2, 3, or 4S (n=622).

Three groups were defined as salvageable for relapse treatment:

• stage 4, with nonamplified MYCN, and less than 18 months of age.
• stage 1, 2, 3, or 4S with MYCN amplification.
• stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4% ± 1% , compared with 12% ± 2% for stage 4 patients with nonamplified MYCN.

This information can help stratify children for relapse therapies.

NOTE: None of this data included how the children were treated for relapse. I am hoping this work will eventually lead to a rational plan for relapse therapy.

My take on this report? There WERE survivors in every group of relapse children….

SEL 10 (p. 136) “Persistence of disease in long-term survivors of high-risk neuroblastoma. Analysis of ENSG5 cooperative trial”

Presented by Lucas Moreno of UK

A report on long-term survivors of high-risk neuroblastoma with persistent (refractory) disease was presented at ANR by Lucas Moreno on Tuesday as one of the selected posters in the clinical session.

This is the first time persistence of disease in long-term survivors has ever been studied.

The European trial ENSG5 randomized 262 children from 1990 to 1999 (and an additional 177 children were not randomized) to two different induction regimens: same chemotherapy and dose, but different time schedule consisting of 21-day chemotherapy schedule (OPEC/OJEC) versus 10-day schedule (rapid COJEC), then all went on to autologous transplant. This study reports on children who did NOT reach remission at the end of induction and were alive 5 years after diagnosis.

In this study, 62 children with refractory neuroblastoma at the end of induction were alive at five years after diagnosis. Two groups were defined, those with persistent metastatic disease (group 1) and those with persistent primary disease (group 2).

Of those with persistent metastatic disease after 5 years, 2 had bone marrow disease up to 9 years after diagnosis, and 6 had persistent MIBG positive skeletal (bone) disease up to 16 years after diagnosis.

Of those with persistent primary site disease, 7 still had disease up to 16 years after diagnosis.

The group reports that “some patients can be long-term survivors despite persistent disease.”

I think this is encouraging news for refractory neuroblastoma.

MIBG non-avid at diagnosis = better outcome?

POC39 (p. 211) Neuroblastomas with non-avid I-123 MIBG scan and negative urinary catecholamine secretion: A single institute’s experience

PL30 (p. 102) Analysis of MIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma. A Children’s Oncology Group (A3973) report

Dui Yen Soh, Sylvain Baruchel, and Meredith Irwin at Sick Kids in Toronto reviewed 148 children diagnosed between 1999 and 2009 (all stages and risk groups). They confirmed the interesting observation that non-avid MIBG and negative urine catecholamines at diagnosis are associated with low stage and favorable outcome. Of the MIBG non-avid children, 5 were low risk, 3 were intermediate risk, and 3 were high risk. These numbers are too small to confirm better outcome for MIBG non-avid (at diagnosis) high-risk, but Greg Yanik (University of Michigan) mentioned an interesting observation of better survival for those high-risk children who are MIBG non-avid at diagnosis (of n= 280 enrolled in COG-A3973, 29 were MIBG negative at diagnosis) in his presentation on a new scoring method to stratify patients at the end of induction. He presented at ASCO 2010 Chicago, ANR 2010 Stockholm, and will present again next week at the CNCF Parent Conference in Chicago. More on Dr Yanik’s presentation to come.[1]

Any ideas why MIBG non-avid survival might be better? No answers proposed yet.

Tandem transplant in Korea

POC40 (p. 211) Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients with high-risk Neuroblastoma: a preliminary report of NB 2004 study at Samsung Medical Center (Republic of Korea)

Ki Woong Sung and group reported at ANR results of 47 children diagnosed 2004 to 2008 and enrolled on NB 2004.  Of the 44 patients that went through tandem transplant, 36 (82%) remain event-free after median follow-up of 3 years (14-72 months) with probability of 5 year overall and event-free survival determined to be 68% ± 20%  and 67% ±  16%, with no treatment-related deaths.  Another report from the same center in 2007 gave results of 52 children diagnosed from 1997 to 2005 (44 had second SCT with TBI).  That study had 15% treatment-related deaths, 33 (75%) were event-free with median follow-up of 53 months (19-117 mo) from diagnosis.[2]  A retrospective study of 141 patients enrolled 2000 to 2005 from the Korean Society of Pediatric Hematology-Oncology (KSPHO) published May 2010 also showed improved 5-year event-free survival in the tandem group over the single transplant group (51 ±12% vs. 31 ±12%, P=0.030).[3]

Korean single and tandem retrospective study 1997 to 2005

These studies show strikingly comparable results to a larger COG pilot (97 children diagnosed 1994 to 2002) reported in 2006, which was the rationale for the current frontline single-versus-tandem trial in the COG.[4]

Germans report no difference in outcome using cis-retinoic acid (Accutane) or ch14.18/CHO antibody

POC37 (p. 210) Comparison of anti-GD2-antibody ch14.18 and 13-cis-retinoic acid as consolidation therapy for high-risk neuroblastoma. Results of the German NB97 trial

Thorsten Simon and group from GPOH (German pediatric oncology study group) reported retrospectively on two similar—but not randomized groups—showing that the outcome was not statistically different with almost 8 years of median follow-up for 74 children who received only ch14.18 antibody (1997-2002) and 75 children who received only cis-retinoic acid (2002-2004). The 3-year event-free survival from diagnosis was 53% ± 6% and 51% ± 6% (p=.209) respectively. While this result is interesting with regard to single-agent efficacy, it is very important to note that none of the children received both antibodies and cis-retinoic acid, nor were the children given cytokines (IL2 or GM-CSF) with the antibody as in the current COG trial. The GPOH previously reported no advantage to ch14.18 (no cytokines) over oral maintenance chemotherapy.[5]  But at ANR 2008 (Japan) the GPOH group reported no late relapses in the ch14.18 group. At this 2010 ANR they also said they have now seen a difference in the retrospective study after 10 years with statistically significant improved survival for the ch14.18 group. During the Special Clinical Session at ANR on Tuesday Dr Thorsten Simon said the GPOH will be revisiting the question of ch14.18/CHO given the remarkable survival advantage shown in the COG study report from Mar 2009.[6]  They are now considering using subcutaneous administration of IL2 to reduce toxicity (as is SIOP in the UK and the rest of Europe), and exploring the use of other agents such as IL15 or lenalidomide with the antibody.

References

1. J Clin Oncol 28:15s, 2010 (suppl; abstr 9516)
2. Bone Marrow Transplant. 2007 Jul;40(1):37-45. Epub 2007 Apr 30. PMID 17468771
3. J Korean Med Sci. 2010 May;25(5):691-7. Epub 2010 Apr 21. PMID 20436703 [full text]
4. J Clin Oncol. 2006 Jun 20;24(18):2891-6. PMID: 16782928 [full text]
5. J Clin Oncol. 2004 Sep 1;22(17):3549-57. PMID: 15337804
6. J Clin Oncol 27:15s, 2009 (suppl; abstr 10067z)

INRG Task Force

In 1988 an international task force was formed to standardize the risk group classification for neuroblastoma. The reason this is so important is because international studies could not be compared to each other with different patient cohorts. One “high risk” study might actually include children considered to be intermediate risk by another group, and the outcomes reported may consequently look “better.”

Today there are 64 investigators in the INRG task force which includes North America, Australia, Europe, and Japan. A consensus for a pre-treatment risk assignment has been accomplished, which includes image-defined risk factors (IDRFs) for staging. This believed to be more reproducible with radiologists.

A database of 8800 children diagnosed between 1990 and 2002 was used to characterize the new risk assignment scheme. In all of these children, the EFS was 63% ± 1% for all risk groups. The percentage of children in each risk group for the entire database breaks down to:

• 28% were very low risk
• 26% were low risk
• 9% were intermediate risk
• 36% were high risk

So far there have been many studies and reports using this data set.  Any investigator is invited to submit a bid for the use of the database analysis.

The most significant changes in risk assignment from this work is using IDRFs and including 11q status.

The challenge now is to incorporate and analyze approximately 4000 more children diagnosed since 2004 and added to the database.  This brings the total to over 16,000. New data items included are gender, ethnicity, therapy, and other causes of death.

A web-based interactive INRG database network has been proposed, and the goal is to collect biological data, phenotype, clinical outcome, and have tumor samples available for further analysis. A question for the future: will clinical features be abandoned and only genetic features used to classify risk assignment? This could allow for tweaking frontline therapy for children who have genetic aberrations predicting poor response to a particular therapy.

Clearly, this ambitious project will continue to offer a rich source of data to better predict outcomes and required therapy for children with neuroblastoma.

References:

Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Matthay KK, Shulkin B, Ladenstein R, Michon J, Giammarile F, Lewington V, Pearson AD, Cohn SL. Br J Cancer. 2010 Apr 27;102(9):1319-26. Review.PMID: 20424613

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, Schleiermacher G, Speleman F, Spitz R, London WB, Cohn SL, Pearson AD, Maris JM. Br J Cancer. 2009 May 5;100(9):1471-82.PMID: 19401703

Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Beiske K, Burchill SA, Cheung IY, Hiyama E, Seeger RC, Cohn SL, Pearson AD, Matthay KK; International neuroblastoma Risk Group Task Force. Br J Cancer. 2009 May 19;100(10):1627-37. Epub 2009 Apr 28.PMID: 19401690

The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD; INRG Task Force. J Clin Oncol. 2009 Jan 10;27(2):298-303. Epub 2008 Dec 1.PMID: 19047290