Dr Ruth Ladenstein presents data in Plenary Session on randomized trial comparing BuMel vs CEM for transplant after Rapid COJEC induction

Considering that neuroblastoma accounts for 7% of pediatric cancers, and pediatric cancers comprises only 1% of adult cancers (that is .07% of all cancers, and high-risk NB makes up only half that number), it is really quite remarkable when highlighted presentations at ASCO focus on neuroblastoma.  This is on the heels of the ch14.18 results which was also big news at ASCO in 2009.

The European SIOPEN trial accrued 1,577 high-risk children since 2002.  Only 43% of these children were randomized for transplant regimen. The randomization was stopped after review showed superiority of BuMel (busulfan + melphalan) over CEM (carboplatin + etoposide + melphalan) in survival. Toxicity was greater in CEM arm, although more VOD (veno-occlusive disease) was observed in BuMel arm.

Dr Julie Park presented data as discussant comparing outcomes with the COG CEM transplant regimen. Clearly BuMel is better than CEM after Rapid COJEC induction, but a question remains if this would be true for the COG induction, which is very different (21 day schedule vs 10 day schedule which presents a different toxicity profile, higher cisplatin use in SIOPEN and no carboplatin is used in COG induction).

This treatment is now standard in SIOP, and COG is incorporating BuMel in a pilot trial.

For more information, see “Can New Standard of Care in Neuroblastoma Be Used in the US?” by Medscape.

http://abstract.asco.org/AbstView_102_79897.html

Abstract:

Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS).

Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m² in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m²/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m²day or 4x200mg/m²/day*], melphalan [3x70mg/m²/day or 3x60mg/m²/day*. *reduced if GFR<100ml/min/1.73m²]). A minimum of 3x10E6 CD34/kgBW PBSC were requested. VOD prophylaxis included ursadiol, but not prophylactic defibrotide. Local control included surgery and radiotherapy of 21 Gy. A total of 598 patients were randomised (296 BuMel, 302 CEM). The median age at randomisation was 3 years (1-17.2) with a median follow up of 3 years.

Results: At the last analysis, the Peto rule of p<0.001 was met. A significant difference in EFS in favour of BuMel (3-years EFS 49% vs 33%) was observed as well as for overall survival (3-years OS 60% vs 48%, p=0.004). This difference was mainly related to the relapse and progression incidence, which was significantly (p<0.001) lower with BuMel (48% vs 60%). The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p=0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute MAT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%). Based on these results and following advice from the DMC, the randomisation was closed early.

Conclusions: BuMel was demonstrated to be superior to CEM and hence is recommended as standard treatment.

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

.

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.

.

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.”

.

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-

New donor transplant trial open for relapsed or refractory neuroblastoma

Dr Sandeep Soni spoke at CNCF (Children’s Neuroblastoma Cancer Foundation) Parent Conference in Chicago July 10, 2010. Dr Soni is a member of the Pediatric Blood and Marrow Transplant program at Nationwide Children’s Hospital and an Assistant Professor of Clinical Pediatrics at Ohio State University College of Medicine in Columbus.

Dr Soni presented the novel allogeneic transplant trial now open for relapsed and refractory neuroblastoma in Columbus:

Fludarabine, Busulfan, and Antithymocyte Globulin Followed By Donor Stem Cell Transplant in Treating Young Patients With High-Risk Neuroblastoma That Has Relapsed or Not Responded to Treatment

This is a phase II study with a planned accrual of 25 children 1 to 18 years old. The goals of this study are to determine the feasibility of this protocol using a reduced-intensity conditioning regimen, engraftment, transplant-related mortality, and development of acute and chronic graft-vs-host disease. Secondary goals are to learn about the role of natural killer (NK) cells as effectors of graft-vs-tumor effect in these patients, and the role of killer immunoglobulin-like receptor (KIR) mismatches in the donor-recipient pairs on the outcomes of these patients.

Dr Soni explained that the role of NK cells are much better understood today, and recently the potential importance of mismatch in KIR is being explored. He also noted that depleting T-cells reduces the risk of graft-versus-host disease (GVHD) whereas in leukemia T-cells are required for graft-versus-tumor effect. In neuroblastoma, there is evidence that NK cells are more important for graft-versus-tumor. Modified T-cells have also been explored by investigators at CHOP (Children’s Hospital of Philadelphia).

History of allogeneic transplants in neuroblastoma

While allogeniec transplants have been used much less frequently in solid tumors, research continues to explore the potential for graft-versus-tumor effect seen in liquid tumors, primarily leukemia.

In February 2010 Dr Stephen Grupp and colleagues from CHOP published a review of “Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors” including the work on modified T-cells:

Chimeric immunoreceptor (CIR). The CIR is an engineered T-cell receptor (TCR) comprised of an antibody-like extracellular domain fused to an intracellular, functional TCR domain. The CIR was first described by Eshhar in 1993, and has been developed and extended over the last 15 years. The first report of CIR-modified T cells specific for neuroblastoma was published in 2001, and research since that time has led to an early-phase clinical trial published in 2007. To redirect T cells safely against a tumor, the CIR must target a tumor-specific antigen that is minimally expressed on normal tissues.

These trials, and others examining the use of CIR-modified T cells in other malignancies, have shown the feasibility of using genetic modification to redirect autologous T cells against malignancies. As technologies improve, and the experience with CIRs increases, harnessing a patient’s own immune system in the treatment for high-risk pediatric cancers will likely become a promising new therapeutic frontier.[1]

Dr Grupp also published a review of transplants for neuroblastoma in January 2008 (fulltext is available):

Finally, as an alternative to autologous SCT, some groups have studied allogeneic SCT in an attempt to harness an immunotherapeutic effect. A graft-versus-malignancy effect has been well described in allogeneic transplant for liquid tumors, but has not yet been convincingly demonstrated in the setting of solid tumors. Although initial studies of conventional allogeneic SCT for high-risk neuroblastoma failed to show clear benefit, the advent of nonmyeloablative conditioning regimens has provided hope that reduced intensity conditioning will reduce TRM and allow for the detection of a therapeutic benefit. As a result, institutions are beginning to explore the possibility of an allogeneic effect in neuroblastoma. At this point, this is still an investigational and unusual application of allogeneic transplant, with 38 such cases reported to the EBMT from 1991 to 2002. Some recent case reports have provided preliminary evidence for a graft-versus-tumor effect in neuroblastoma. A 2003 case report described a patient who underwent allogeneic SCT after a relapse. Although the patient received further chemotherapy after the allogeneic transplant and response could not be correlated to GVHD, the patient did enter a CR sustained for at least 4 years. In a more recent report, development of GVHD correlated temporally with disease response in a patient who had undergone a reduced-intensity allogeneic bone marrow transplant. In a similar regard, the group at Columbia has been testing reduced intensity allogeneic cord blood transplants in patients with a wide range of diagnoses, including neuroblastoma.[2]

The use of allogeneic transplants may hold promise in neuroblastoma, with progress being made in reducing the risk of acute graft-versus-host disease and reduced treatment-related mortality with reduced intensity regimens. Families who are interested in pursuing this treatment choice for a child with relapsed or refractory neuroblastoma should be aware that some therapies available in current clinical trials prohibit prior donor transplants as part of the eligibility, but many current clinical trials do allow prior allogeneic transplant.

1. Pediatr Clin North Am. 2010 Feb;57(1):47-66. Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors. PMID: 20307711

2. Bone Marrow Transplant. 2008 January; 41(2): 159–165. Stem cell transplantation for neuroblastoma. PMCID: PMC2892221 [fulltext]

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

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.

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)

The 2010 ASCO meeting is in full swing.  Attending a meeting with more than 30,000 cancer specialists from around the world is an incredible experience and provides an unparalleled opportunity to learn about cancer. The organization, logistics, and technology displayed are absolutely mind boggling. The vast exhibitor hall has spectacular booths set up by every pharmaceutical company ever heard of. There are 350 patient advocates here–and the vast majority are focused on adult cancers. On my first shuttle ride to the conference I visited with a charming adult oncologist from Slovakia, on the return trip I chatted with a lovely young French-speaking oncologist from Montreal. The whole city of Chicago appears to be populated by oncologists!

To say the meeting is overwhelming is an understatement. I decided to purchase the Virtual Meeting as well so I can review the sessions I have heard, as well as see other presentations happening simultaneously. This means that there will be ample opportunity to carefully review the material and update this site with much more meaningful information over the next few weeks.

Day 1 and Day 2 consisted of the following presentations (termed Education Sessions).

Childhood Cancer Survivorship: Lessons Learned and Future Steps
Kevin C. Oeffinger, MD
~ Current guidelines for follow up of the survivors of pediatric cancers.
Current new areas of research including issues related to genetic
susceptibility to toxicities
Smita Bhatia, MD, MPH
~ Long-term psycho-social effects following the treatment of pediatric
cancers.
Christopher Recklitis, MPH, PhD
~ Discussion of the Childhood Cancer Survivor Study (CCSS)
Gregory T. Armstrong, MD, MSCE

Current Challenges for Cellular Therapies
~ When should immunablative therapies be considered in the treatment of
pediatric cancer?
John M. Cunningham, MBBS
~ Adoptive cellular therapies utilizing gene modified lymphocytes
Laurence Cooper, MD, PhD
~ The role of NK cells in transplant and the non-transplant scenario
Wing H. Leung, MD, PhD

The Expanding Role of Antibody-based Therapy in Children,
Adolescents, and Young Adults with Cancer
~ Progress in treatment of high-risk neuroblastoma with immunotherapy
Alice L. Yu, MD, PhD
~ Update on Immunotherapy Strategies in the Treatment of Lymphomas in
children, adolescents and young adults
Mitchell S. Cairo, MD
~ The efficacy of epitope-specific IGFR1 antibodies in therapy of pediatric,
adolescent and young adult solid tumors
Douglas Yee, MD

New Treatments for Sarcoma in Children, Adolescents, and Young Adults
~ Optimal approaches for achieving local control in children, adolescents, and
young adults with sarcoma
R. Lor Randall, MD, FACS
~ Optimal strategies for controlling metastatic disease in children,
adolescents, and young adults with sarcoma
Douglas S. Hawkins, MD
~ Treatment of childhood, adolescent, and young adult sarcoma. Where do
we go from here?
Stephen X. Skapek, MD

Last session today was a terrific presentation on how pediatric oncology clinical trials serve as a model for “comparative effectiveness research.” More on this later.

Brief comments on sessions so far:

Genetic predisposition for heart damage in some children

The most important finding shared about late effects was the genetic mutations discovered that predispose a child for cardiotoxicity from low-dose anthracyclines, and this is significant for NB parents because almost all NB kids get doxorubicin as part of induction. There is consideration now of testing children in future trials for the mutations, and if one is found, reducing or eliminating anthracyclines from frontline therapy, or using a cardioprotectant. Further information will be presented on this topic on Monday morning session.[1]

Reduced-intensity allogeneic transplants and NK and T cell therapies

The discussion on reduced intensity transplant was really interesting and I look forward to looking at the data more closely. Many studies in adults have been completed for different diseases, and most show lower toxicity and better survival. Tomorrow there is a poster presentation on a study from Italy in NB kids. I will follow up with data and referenced studies. There has been so much work on NK cell therapies it is very exciting to see the possibilities emerging for NB. If you do a search for NK cell therapies on the National Institutes of Health site (www.clinicaltrials.gov) there are more that 200 open trials for various cancers. Memorial Sloan-Kettering is currently accruing for their NK cell therapy trial, but this trial was not discussed in any detail. MD Anderson also has an open Phase II study using donor NK cells for those who relapse or are refractory after stem cell transplant. Several papers have been recently published and after reviewing them I can report more fully on this topic. It was encouraging to hear the discussant Dr Leung say that he sees NK cells as an ideal treatment after frontline induction and consolidation, before antibody treatment. He believes this could be the next big jump in survival for frontline therapy.[2]

Antibody update

Dr Yu gave an excellent presentation updating on all things anti-GD2. She reviewed the history of all antibodies for NB, and said that two humanized antibodies (hu14.18-IL2 and hu14.18K332A) and a new anti-iodiotype antibody 1A7 are all considered for future trials. The 1A7 is interesting because it works like a vaccine. Instead of injecting antibodies into a child, this antibody induces the production of antibodies against GD2 continuously. After the session I asked her about the supply of ch14.18. The supply is good for two years since NCI made two more “batches” and a manufacturer has committed to produce the ch14.18. Then we discussed the trouble in the UK with access to GM-CSF for use with the ch14.18 antibody, and she said that she was going to speak to the Genzyme representative since they recently “inherited” the drug. Later I went to talk to Genzyme too. Genzyme said that there are regulatory issues with the UK (not the US) that prohibit the importing of the drug. He said to tell families interested in working with their doctor to contact Idis (www.idispharma.com) because Idis is an expert in getting access to drugs. They developed a program called Named Patient Program (see http://idispharma.com/patients.php ) to help gain access to drugs blocked by regulatory hurdles. Another question I have though, and could not be answered yet, is will SIOP rewrite the protocol to include GM-CSF? Dr Yu mentioned they are currently using IL2 (subcutaneously). Perhaps this can be further clarified for us by the families in the UK who are on the SIOP trial. Another question I have is whether the access to GM-CSF affects the other countries in Europe.

1.  J Clin Oncol 28:7s, 2010 (suppl; abstr 9512)

2.  Leung, Wing. The Role of Natural Killer Cells in Transplant and the Nontransplant Scenario. ASCO 2010 Educational Book, p 377-381