Neuroblastoma Family Information Day

March 9th, 2018   |   Posted in Research,Treatment,Uncategorized   |   By: Antonia Palmer   |   0 comments

Hosted by The James Fund for Neuroblastoma Research and the Hospital for Sick Children, Garron Family Cancer Centre
Saturday January 20, 2018

The first Neuroblastoma Family Information Day brought together families, patients, oncologists, researchers, nurses, and a wide variety of specialists to discuss the successes, challenges and future of neuroblastoma treatment.  It is important to note that the majority of the day focuses on high-risk neuroblastoma.  The following is a summary of the talks provided during the day.

Dr. Julie Park
Therapy for High Risk Neuroblastoma
Link to Slides (PDF)

High-risk neuroblastoma is treated with a wide array of therapy modalities including chemotherapy, surgery, mega-dose chemotherapy with stem cell transplant, radiation, and immunotherapy.  The first stage of treatment for newly diagnosed high-risk neuroblastoma patients is called induction.   The Children’s Oncology Group (COG) has developed a careful combination of cyclophosphamide, topotecan, etoposide, cisplatin, vincristine and doxorubicin chemotherapies given over the course of five or six cycles during induction.  However, even with this intensive treatment during induction, 20% of patients will not have a sufficient response and 1% of patients will die from the treatment.

The second stage of treatment is called consolidation which includes mega-dose chemotherapy delivered in single or tandem (two) autologous stem cell transplants (ASCT).  There are different chemotherapy combinations which can be given: CEM – carboplatin, etoposide and melphalan, or BuMel – busulfan and melphalan.  The goal is to destroy any remaining neuroblastoma cells. The chemotherapy also dramatically affects the patient’s bone marrow and this is rebuilt with an infusion of the child’s own stem cells that were harvested earlier during induction.  However, even with this extreme therapy, patients can still have progressive disease and 3% of patients will die from the treatment.

In 2016, data was presented at the American Society of Clinical Oncology (ASCO) conference on the comparison of patients who underwent a single ASCT using the CEM chemotherapies versus patients who underwent a tandem ASCT using cyclophosphamide and thiotepa (CT) chemotherapies for the first transplant and a modified (lower) dosing of CEM for the second transplant.  The treatment benefit was seen post immunotherapy for these patients.[1],[2]

 

  Event Free Survival (EFS)* at 3 Years Overall Survival (OS)** at 3 Years
Pre-Immunotherapy Post-Immunotherapy Pre-Immunotherapy Post-Immunotherapy
Single ASCT CEM 48.4% 56.0% 69.1% 74.4%
Tandem ASCT 61.4% 73.3% 74.0% 83.7%

 

* EFS is the amount of time after treatment that a patient remains without the disease returning/ progressing.
** OS is the percentage/number of patients alive in a study at the time of reporting, either with or without active tumor.

The European childhood cancer consortium, SIOPEN, conducted their own clinical trial into the use of the BuMel chemotherapy combination for ASCT, compared to the usual North American standard of CEM.  It is important to note that SIOPEN utilizes slightly different induction chemotherapies. Three different courses of chemotherapies given every 10 days, over the course of 10 weeks.  This is called Rapid COJEC — cisplatin (C), vincristine (O), carboplatin (J), etoposide (E), and cyclophosphamide (C).  They found that BuMel had a 3 year event-free survival of 49.3% versus 33.3% with that of CEM. Although this study showed that BuMel was better than CEM after the SIOPEN induction, it is not known whether this is the case after the North American induction chemotherapy.
The third stage of treatment is called post-consolidation or maintenance and involves five cycles of dinutuximab immunotherapy with a cytokine called IL-2 (for two cycles) and/or GM-CSF (for remaining 3 cycles).  The patient also receives two weeks of oral Accutane (13-cis-retinoic acid) after each cycle of immunotherapy, for a total of six cycles.  However, even at this stage, 35% of patients will have disease progression.

COG is currently developing a new Phase 3 clinical trial for high-risk neuroblastoma that is targeted to open in 2019.  The goal is to incorporate MIBG therapy and target disease at the molecular level (e.g., ALK) into the induction stage of treatment. The new COG study will have five different arms for treatment:

  1. MIBG therapy during induction with CT/CEM tandem stem cell transplant in consolidation.
  2. CT/CEM tandem stem cell transplant in consolidation with no MIBG therapy in induction.
  3. MIBG therapy during induction with BuMel single transplant in consolidation.
  4. ALK mutation positive patients to receive crizotinib and CT/CEM tandem transplant. (10-14% of patients have disease with an ALK mutation that can be specifically targeted with ALK inhibitor drugs such as crizotinib.)
  5. MIBG negative patients will not be randomized and will receive CT/CEM tandem stem cell transplant in consolidation with no MIBG therapy in induction.

Moving forward, it will be critical to quickly understand what disease will not respond to therapy and to integrate novel therapies into induction (e.g., immunotherapy) while working to address the amount of treatment patients receive to reduce long-term effects without impacting killing the cancer.  The goal is to understand what disease will not respond to the different treatment modalities and consider how to improve the effectiveness of all treatments for high-risk neuroblastoma.

 

Dr. Daniel Morgenstern
Immunotherapy for Neuroblastoma
Link to Slides (PDF)

In 2009, immunotherapy was established as standard of care for high-risk neuroblastoma patients treated at Children’s Oncology Group (COG) institutions.  After years of dedicated research lead by Dr. Alice Yu, ch14.18 was first administered in 1989, and 20 years later the immunotherapy called ch14.18 was established as a new pillar of neuroblastoma therapy.  Ch14.18 is now known as Unituxin or dinutuximab, and is a monoclonal antibody that is designed to bind to neuroblastoma cancer cells at the site of the cancer antigen called GD2.  This allows the immune system to recognize the cancer cell and then target it to be killed.

For patients in frontline treatment, immunotherapy treatment is the last stage of therapy with the goal to consolidate response by killing any remaining cancer and minimal residual disease (MRD).  For patients receiving treatment for relapsed or refractory disease, immunotherapy is also offered in combination with chemotherapy (temozolomide/irinotecan).

It is possible that in the future, immunotherapy will be added to the induction phase of treatment, giving it in conjunction with the initial cycles of chemotherapy.  A trial that has been running at St. Jude Children’s Hospital for a number of years combines their anti-GD2 immunotherapy called hu14.18K322A with various types of chemotherapy and has shown that this is feasible.[3]

For frontline high-risk neuroblastoma treatment, patients receive five cycles of immunotherapy – two cycles with a cytokine called IL-2, and three cycles with GM-CSF.  These cytokines work to stimulate the immune system to help it react if any cancer cells are found in the body.  However, there are still open questions as to how important these cytokines are in conjunction with immunotherapy and whether there could be other methods to help stimulate the immune system (e.g., lenalidomide[4]) without the challenging side-effects and allergic reactions. In addition, immunotherapy is a treatment with many side-effects, the most common being pain.  Research out of Europe shows that a slower continuous infusion of immunotherapy reduces the pain experienced by patients without reducing the impact on disease reduction.  More work needs to be done to determine how to address the many side-effects produced by treatment and to understand if any of these have a long-term impact on the patient.

There are many emerging targeted therapies for cancer in the adult and pediatric world.  These new treatments identify and kill cancer cells in different ways; however, they have not yet been optimized for solid tumours or neuroblastoma in particular.  Some of these novel treatments are the following:

  1. Immunotherapy: Enoblituzumab, anti-B7H3[5]
  2. Immune Checkpoint Inhibitors: PD-1 and PD-L1 inhibitors[6]
  3. Cellular Therapies: CAR T-Cell Therapy (good responses in blood cancers)

 

Dr. Meredith Irwin
Understanding Precision Medicine and Gene Sequencing for Neuroblastoma
Link to Slides (PDF)

Precision medicine uses tumour samples and blood to look for genetic changes and distinct molecular characteristics of cancer to help better target treatments for a patient’s individual disease.  Precision medicine can be used to molecularly profile a disease to understand how well a patient’s disease may respond to treatment and possibly predict side-effects of a therapy.

Cancer occurs when genes in cells change giving the cell the ability to grow quickly, spread and form tumours.  These changes are called mutations or alterations, and they can be inherited (initiated at birth) or newly formed where they occur at some point in the body’s development (after birth).  Genomic profiling technology allows researchers to sequence all of the genes (DNA and RNA) of a cancer cell to identify any changes that could be exploited to help direct treatment for a patient.

Unfortunately, childhood and adolescent cancers have much fewer mutations than adult cancers which means that there are not as many molecular mutations that can be targeted.  In neuroblastoma, this holds true; however, there are a number of identified mutations such as ALK (approximately 10% of patients), ATRX, and others, with some variants of the ALK mutation that can be targeted with the drug crizotinib (and newer ALK inhibitor drugs).  Interestingly, one of the first genetic changes identified in neuroblastoma was amplification (many copies) of the MYCN gene;; however, targeting MYCN with treatment has proven to be very challenging.  In addition, the number and type of mutations often increase at relapse which is why sequencing is often done at the time of progression in hopes of identifying more treatment options for patients.

At the Hospital for Sick Children, the KiCS: Kids Cancer Sequencing Program began in 2016 and is lead by Drs. David Malkin and Adam Shlien with Dr. Meredith Irwin involved in the efforts to sequence neuroblastoma patient tumors (and blood).  As of February 2018, they have been able to complete almost 200 genetic sequences and neuroblastoma has been one of the most common tumors.  This work has lead to the identification of targeted therapies for patients and has been able to guide future therapy decisions.

In 2017, a Canadian national genomic sequencing program was initiated called PROFYLE – Precision Oncology for Young People.  PROFYLE is a significant initiative integrating more than 30 different pediatric (and young adult) oncology research and funding institutions to help children and adolescents with relapsed and refractory cancer find personalized treatment options.[7]  PROFYLE aims to enroll and molecularly profile approximately 450 patients within 5 years and work to develop strategies for patients to access therapies for hard to treat cancers.

 

Dr. Paul Nathan
Long-Term Outcomes in Survivors of Neuroblastoma
Link to Slides (PDF)

The treatment for high-risk neuroblastoma is long and intensive, during a critical time of childhood development and growth.  This can cause long-term health problems that follow the completion of treatment.  Some long-term effects may occur soon after treatment, and others may not appear until years or decades later.  They can by physical or psychological and can impact quality of life in a wide variety of ways.

Some physical late effects may include changes in organ function (e.g., heart, lungs), growth and development, secondary cancers, fertility and others.  Some psychosocial late effects may include mental health, body image issues, social interaction, and others.  Within the treatment protocol for high-risk neuroblastoma, there are a number of drugs that are known to cause late effects:

  1. Cyclophosphamide: Bladder, and hormone damage
  2. Melphalan: Infertillity
  3. Doxorubicin: Heart damage
  4. Radiation: Secondary cancers, breathing problems (lungs), learning issues (brain)
  5. Cisplatin/Carboplatin: Hearing loss, kidney damage

In particular, high-risk neuroblastoma survivors have a significant endocrine burden in terms of:

  1. Short stature, reduced growth, and growth abnormalities
  2. Hypothyroidism (underactive thyroid)
  3. Delayed/abnormal puberty

In 2018, a new trial called LEaHRN, Late Effects after High Risk Neuroblastoma (COG ALTE15N2), will be opening to closely track late effects and their impact on the quality of life, and to develop a biobank of survivor samples for future research.  The study will involve only a small amount of blood work and a full day clinic evaluation which can be tied to the regular visit to the child’s Aftercare clinic. This will be the first late effects study that specifically focuses on patients with high risk neuroblastoma.

Ontario has a strong Aftercare network with AfterCare Clinics in London, Hamilton, Toronto, Kingston and Ottawa.  The goals of Aftercare are to educate patients about the treatments they have received so that they can advocate for themselves throughout their entire lives.  It is to monitor the health of the patient to ensure early detection of problems and promote a healthy lifestyle.  And, to carefully transition the patient to the adult care system when they are 18 years old.  Aftercare is supported and informed by guidelines from the Children’s Oncology Group.[8]

 

References:
[1] http://www.ascopost.com/issues/june-25-2016/for-high-risk-neuroblastoma-two-transplants-may-be-better-than-one/
[2] https://www.asco.org/about-asco/press-center/news-releases/double-stem-cell-transplant-improves-outcomes-children-high
[3] Interested in knowing how ch14.18 is different from hu14.18K322A?  Here is a excerpt from a 2013 interview done with Dr. Wayne Furman who is leading the St. Jude trial integrating immunotherapy into upfront induction chemotherapy: “The antibody currently used by COG is ch14.18 which is a chimeric (~25% mouse and 75% human) mAb.  Hu14.18 is identical to ch14.18 except the Fab ends involve fully human amino acid sequences for IgG1 heavy and kappa light chains, and the complementarity determining regions correspond to the antigen binding sequences of the murine 14.18 mAb. The resulting hu14.18 mAb is approximately 98% derived from human genes, yet maintains the specificity of the murine ch14.18 mAb.  In addition, hu14.18K322A also has a single point mutation (K322A) reducing complement-dependent lysis.  hu14.18K322A is also produced in a differed type of cell which results in decreased fucosylation (adding fucose to a molecule) and this has been shown to increase ADCC (antibody dependent cellular cytotoxicity), which is how all anti-GD2 mAbs are thought to kill neuroblasts.”
[4] https://clinicaltrials.gov/ct2/show/NCT01711554?term=lenalidomide&cond=neuroblastoma&rank=1
[5] https://www.macrogenics.com/enoblituzumab-anti-b7-h3/
[6] https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html
[7] http://www.terryfox.org/recent-posts/profyle/
[8] https://childrensoncologygroup.org/index.php/survivorshipguidelines

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