Issue: July 10, 2020
Disclosures: Marachelian, Seibel, Sholler and Shusterman report no relevant financial disclosures.
July 10, 2020
12 min read

Despite treatment advances, ‘much to improve upon’ in high-risk neuroblastoma

Issue: July 10, 2020
Disclosures: Marachelian, Seibel, Sholler and Shusterman report no relevant financial disclosures.
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An estimated 800 new cases of neuroblastoma are diagnosed in the United States each year.

Although rare, it is the third most common cancer among children — behind only leukemia and brain/spinal cord tumors — and accounts for 6% of pediatric malignancies. It is by far the most common malignancy among infants.

As outcomes for high-risk neuroblastoma improve, refining treatment approaches in order to reduce late-term effects will be key, according to Giselle Sholler, MD.

As outcomes for high-risk neuroblastoma improve, refining treatment approaches in order to reduce late-term effects will be key, according to Giselle Sholler, MD.

Source: Aaron Hurley.

Some cases are easily treatable.

However, the majority are extremely aggressive and require intensive therapy to increase the likelihood of cure. The scientific community has intensified efforts to identify more effective and less toxic therapeutic strategies for this subset.

“Patients with high-risk neuroblastoma are a challenging population for which we have much to improve upon in terms of treatment,” Giselle Sholler, MD, director of the solid and rare tumor program at Levine Children’s Hospital at Atrium Health, told HemOnc Today. “One of the exciting aspects of neuroblastoma right now is that there is a lot of research being conducted [in hopes of benefiting these patients]. This research needs to happen.”

HemOnc Today spoke with pediatric oncologists about neuroblastoma incidence and prognosis, the effectiveness of available treatments, and the research underway on oral therapies and other novel treatment strategies.

Current landscape

Neuroblastoma originates in immature nerve cells within the sympathetic nervous system. The cause is unknown.

Median age at diagnosis is 19 months. One-third of cases are diagnosed among infants, and nearly 90% of cases are diagnosed among children aged younger than 5 years. Diagnosis after age 10 years is rare.

Suzanne Shusterman, MD
Suzanne Shusterman

“Neuroblastoma is notable for being a significant, heterogeneous disease,” Suzanne Shusterman, MD, assistant professor of pediatrics at Harvard Medical School, told HemOnc Today. “Treatment and prognosis are based upon clinical and biological factors that are used to determine risk groups.”

Children’s Oncology Group classifies patients into one of three risk groups: low, intermediate or high.

Some patients with low-risk neuroblastoma require no treatment, as tumors mature or dissipate on their own. Others undergo surgery, either alone or with a short course of chemotherapy.

Patients with intermediate-risk disease undergo surgery, typically with four to eight cycles of low-intensity neoadjuvant or adjuvant chemotherapy. Radiation is used for tumors that do not respond to chemotherapy.

High-risk neuroblastoma — which accounts for approximately 70% of cases — often requires intensive multimodal treatment administered in three phases: induction chemotherapy followed by surgery; consolidation with high-dose chemotherapy, followed by stem cell transplant, immunotherapy and radiation; and maintenance with retinoid therapy and sometimes immunotherapy to reduce risk for recurrence.

Treatment for patients with high-risk disease can take 15 to 18 months.


Approximately 90% to 95% of patients with low- or intermediate-risk disease survive at least 5 years after diagnosis. However, only about half of patients with high-risk disease live that long.

Nita L. Seibel, MD
Nita Siebel

“Children with high-risk neuroblastoma comprise a challenging patient population to treat,” Nita L. Seibel, MD, head of pediatric solid tumor therapeutics in NCI’s Cancer Therapy and Evaluation Program, told HemOnc Today. “We are searching for anything that looks promising ... because we are not satisfied with the current 50% survival rate.”

Disease stage, determined by local aggressiveness of the primary tumor and whether it has spread, is a key factor in risk classification.

Other factors include tumor histology, DNA index and chromosome changes, as well as MYCN status. Tumors with amplification of the MYCN gene, which regulates tumor cell growth, tend to behave more aggressively.

Age also is prognostic.

Younger children — those aged 12 to 18 months — are more likely to be cured than older children.

“One factor that is rather unique about neuroblastoma is that it has significant age-related variability,” Seibel said. “Depending upon the age of a patient at diagnosis, their outcomes can differ significantly.”

‘Exciting’ trials

Because neuroblastoma is characterized by considerable heterogeneity, much of the research underway is designed to determine how an individual patient’s disease biology can inform appropriate therapy.

Araz Marachelian, MD
Araz Marachelian

Inhibition of the anaplastic lymphoma kinase (ALK) via oral therapies is one of the most advanced strategies, according to Araz Marachelian, MD, director of the neuroblastoma program at Children’s Center for Cancer and Blood Diseases at Children’s Hospital of Los Angeles.

“The identification of the ALK gene is one prime example of the heterogeneity in the neuroblastoma patient population,” Marachelian told HemOnc Today. “We are now looking at different ways to add an inhibitor of the ALK gene into the treatment scope, which is one way to approach therapy that is more individualized.”

Yael P. Mossé, MD, attending physician with the Cancer Center at Children’s Hospital of Philadelphia, and colleagues have conducted extensive research into the role of ALK in several pediatric malignancies.

More than a decade ago, the team determined mutations in the ALK gene are a major cause of the inherited form of neuroblastoma, and that approximately 14% of patients with the most aggressive form of the disease have these mutations.

They conducted phase 1/phase 2 studies to evaluate the ALK inhibitor crizotinib (Xalkori, Pfizer) as treatment for children with ALK-driven relapsed or refractory neuroblastoma. The findings laid the groundwork for a Children’s Oncology Group phase 3 trial evaluating crizotinib plus chemotherapy for patients with high-risk, ALK-positive disease.


In another study published last year in Science Translational Medicine, Mossé and colleagues showed native ALK — in the absence of a mutation — is present on the majority of neuroblastoma tumors. The discovery creates “an exciting opportunity” to target ALK in most patients, according to Mossé.

“If there is an ultimate ‘bad guy’ of neuroblastoma cell surface proteins — present on most tumors, but not on healthy tissues, and also vulnerable to immunotherapeutic targeting — this just may be it,” Mossé said in a press release. “This study is proof of concept that the ALK protein is a good immunotherapy target and — as we optimize this approach for the clinic — has the potential to be useful for the majority of aggressive neuroblastomas and to minimize the harsh consequences of therapy.”

In another nonrandomized trial, Sholler and colleagues assessed the use of maintenance difluoromethylornithine — which targets specific cancer stem cell pathways and “turns off” cancer cells — among children with high-risk neuroblastoma treated at one of 20 children’s hospitals from June 2012 to February 2016.

The intention-to-treat analysis included 100 patients who received 2 years of oral difluoromethylornithine dosed at 750 mg/m2 ± 250 mg/m2 twice daily. EFS and OS served as the primary endpoints.

Results showed a 2-year OS rate of 97%, and over 80% of the cohort remained in remission after 4 years of follow-up.

Additional work is underway at Memorial Sloan Kettering Cancer Center, where researchers are testing a vaccine administered at the end of the treatment course for patients with high-risk disease, Sholler said.

“The thought here is to harness the immune system to prevent relapse,” Sholler said. “It will be exciting to see the results of this trial and potentially combine the vaccine with difluoromethylornithine to see if we can achieve even better results.”

Other studies are examining a variety of other novel treatments for high-risk disease, including chimeric antigen receptor T-cell therapy; the radiopharmaceutical iobenguane I 131 (Azedra, Progenics); the monoclonal antibody dinutuximab (Unituxin, United Therapeutics) combined with induction chemotherapy; and alisertib (MLN8237, Takeda/Millennium) — an oral selective inhibitor of Aurora kinase A — in combination with chemotherapy.

Phase 1 data on another ALK inhibitor, lorlatinib (Lobrena, Pfizer), were presented during this year’s ASCO20 Virtual Scientific Program, showing antitumor activity and manageable toxicity.

Other trials are evaluating the combination of immunotherapy and chemotherapy in the upfront setting.

“There are so many ongoing trials that are quite exciting right now,” Marachelian said. “Combining chemotherapy and immunotherapy for patients with relapsed disease has changed a lot of what we are doing for our patients with relapsed neuroblastoma and for those who do not respond well to upfront therapy. In the general sense, the relapsed/refractory setting is where a lot of the novel ideas are being tested. The hope is that we will be able to move these agents up in the pipeline faster so that our patients can gain access to them faster.”


Tandem transplants

A study published last year in JAMA yielded encouraging findings about the potential of tandem autologous stem cell transplant for patients with high-risk neuroblastoma.

Standard care for these patients consists of induction chemotherapy followed by high-dose therapy with autologous stem cell transplantation and subsequent anti-disialoganglioside antibody immunotherapy. However, survival remains poor.

Park and colleagues conducted a randomized controlled trial to evaluate whether tandem autologous transplant improved EFS compared with single transplant.

The analysis included 355 patients aged 30 years or younger (median age, 36.1 months; 57.2% male) treated from November 2007 to February 2012 at 142 Children’s Oncology Group centers in the United States, Canada, Switzerland, Australia and New Zealand.

Researchers assigned patients to tandem transplant with thiotepa/cyclophosphamide followed by dose-reduced carboplatin, etoposide and melphalan (n = 176) or single transplant with carboplatin, etoposide and melphalan (n = 179).

Follow-up continued until June 29, 2017. EFS served as the primary outcome.

Researchers reported a significantly higher 3-year EFS rate in the tandem transplant group (61.6% vs. 48.4%; P = .006).

After consolidation therapy, 250 patients — 121 who underwent tandem transplant and 129 who underwent single transplant — received isotretinoin plus immunotherapy with an anti-GD2 chimeric antibody and cytokines.

For these patients, rates of 3-year EFS — considered a key benchmark because the majority of recurrences occur within 3 years — were 73.3% with tandem transplant vs. 54.7% with single transplant.

Rates of mucosal toxicities (11.7% vs. 15.4%) and infectious toxicities (17.9% vs. 18.3%) were comparable between the tandem- and single-transplant groups.

The trial was not powered to detect a difference in OS. A post-hoc analysis showed no OS difference in the overall cohort, although researchers observed a benefit with tandem transplant among patients who received immunotherapy.

Still, Marachelian described the improvement in EFS as “phenomenal,” noting the only other treatment to accomplish this was the addition of immunotherapy.

“Since the results [of the tandem transplant trial] have come out, practice has completely changed,” Marachelian said. “Relapse is less common than it once was. The celebration is that we are now seeing plenty of children who are not relapsing, but instead living normal lives. This is quite gratifying. Our hope is to continue moving the needle so eventually we get to 100% who don’t relapse.”

Despite the encouraging results, key questions remain.

The study demonstrated tandem transplant is more effective than single transplant “in the context of the induction and post-consolidation therapies administered,” but the EFS advantage has not been established for patients treated with other high-risk regimens, Rochelle Bagatell, MD, of Perelman School of Medicine at University of Pennsylvania and Meredith S. Irwin, MD, of The Hospital for Sick Children at University of Toronto, wrote in an accompanying editorial.


The benefit is unknown for patients treated with a dose-dense induction regimen — commonly used in Europe — or for patients who receive different high-dose chemotherapy conditioning regimens, immunotherapeutics or targeted therapies.

“High-risk patients are a heterogeneous group,” Bagatell and Irwin wrote. “Improved classification of high-risk patients also could determine which patients truly benefit from tandem high-dose chemotherapy with autologous stem cell transplant, which patients fare well without intensive therapy and which patients are candidates for new strategies.”

Another alternative

Another study, conducted in Europe, aimed to determine which high-dose chemotherapy regimen prior to single HSCT conferred the greatest EFS benefit for patients with high-risk neuroblastoma.

The randomized phase 3 trial included 598 children from 20 countries who had stage IV disease.

Ladenstein and colleagues randomly assigned 296 children to busulfan and melphalan followed by transplant. They assigned the other 302 to carboplatin, etoposide and melphalan followed by transplant.

After median follow-up of 7.2 years, researchers reported a significantly higher 3-year EFS rate among patients assigned busulfan and melphalan (50% vs. 38%; P = .0005).

A lower percentage of patients assigned busulfan and melphalan developed severe life-threatening toxicities (4% vs. 10%). They also were less likely than those assigned carboplatin, etoposide and melphalan to experience grade 3 or grade 4 infection (19% vs. 27%) or stomatitis (49% vs. 59%).

“Both of these trials were great in showing improvements when therapy is intensified,” Sholler said. “What is still [undetermined] is whether the tandem transplant or the single European transplant plus the high-dose myeloablative regimen is better. This has not yet been studied so, depending on the U.S. cancer center at which a patient with neuroblastoma is treated, they may receive one [of these treatments] or the other. Either regimen results in better outcomes from ... single transplant.”

Children’s Oncology Group has launched a phase 3 trial designed to evaluate multiple treatment strategies — including busulfan plus melphalan, followed by transplant — for children with newly diagnosed high-risk neuroblastoma. The protocol also dictates the random assignment of patients whose tumors take up metaiodobenzylguanidine to that therapy during induction.

Late effects

As neuroblastoma treatment evolves, outcomes appear to be improving.

Tas and colleagues used Netherlands Cancer Registry data to assess neuroblastoma incidence and survival in that country from 1990 to 2014.

Results — published earlier this year in European Journal of Cancer — showed increasing incidence over time, for reasons that could not be explained. Investigators hypothesized that Western lifestyle or environmental factors may have contributed to the increase.


However, results also showed statistically significant improvements in 5-year OS during the study period for all patients aged 18 months or older (44% to 61%; P < .01) and for those with stage IV disease (19% to 44%; P < .01).

Multivariable analysis revealed the survival increases were linked to the introduction of high-dose chemotherapy followed by autologous stem cell rescue (HR = 0.46; P < .01), as well as anti-GD2-based immunotherapy (HR = 0.37; P < .01).

“Fortunately, the outcome is positive in the end: More children survive this disease,” study researcher Max van Noesel, MD, PhD, of the department of pediatric oncology/hematology at Erasmus University Medical Center, said in a press release. “That is the result of many international investments of oncologists and researchers [who have investigated] new treatment methods and [adjusted] treatment strategies.”

As patients survive longer, management of potential late effects from treatment will become a formidable challenge.

Children’s Oncology Group is leading the LEAHRN study, the acronym for which stands for Late Effects After High-Risk Neuroblastoma.

The study is open to patients diagnosed with high-risk disease after Jan. 1, 2000, who are at least 5 years beyond their diagnosis and have not received any neuroblastoma treatment for at least 2 years. All participants must have received treatment with modern therapy.

The study — led by Tara Henderson, MD, MPH, of The University of Chicago Comprehensive Cancer Institute, and Lisa Diller, MD, of Dana-Farber Cancer Institute — will assess organ dysfunction, second cancers and growth impairment, as well as other adverse effects. Investigators hope to identify clinical and treatment risk factors that may lead to these late complications, as well as the effects of newer therapies, including immunotherapy.

In addition, NCI researchers hope to establish a cohort of survivors of high-risk neuroblastoma who received treatment with multimodal therapies and have stored peripheral blood samples. The goal is to create a source bank for future research.

The research community also has intensified its efforts to identify effective treatment strategies that are less toxic than current approaches.

Twist and colleagues with Children’s Oncology Group sought to use a biology- and response-based algorithm to assign treatment duration for children with intermediate-risk neuroblastoma. The objective was to reduce therapy intensity while maintaining 3-year OS of 95% or more for the entire cohort.

The analysis included 404 evaluable patients. Results showed the potential to reduce treatment — compared with legacy Children’s Oncology Group studies — for subsets of patients without compromising efficacy. Researchers reported 3-year EFS of 83.2% and 3-year OS of 94.9%.


All patients with localized disease survived at least 3 years. However, among infants with stage IV tumors, those with favorable biology were significantly more likely than those with unfavorable biology to achieve 3-year EFS (86.9% vs. 66.8%; P = .02), highlighting the ongoing need for more effective treatment strategies for those with unfavorable biologic features.

“Pediatric oncologists have been at the forefront of working collaboratively and, over the past 50 years, we have conducted a series of sequential clinical trials testing treatments for pediatric cancer that have resulted in new standards of care and remarkable improvement in outcome,” study co-author Susan L. Cohn, MD, chief of the section of pediatric hematology, oncology and stem cell transplant and professor of pediatrics at The University of Chicago, said in a press release. “Collating the clinical trial results conducted around the world and linking these clinical data with genomic, imaging and other data sets ... will enable additional research advances that are likely to ultimately change our treatment strategies and further improve the outcome of children with cancer.”

Sholler agreed that collaboration is key.

“The outlook for neuroblastoma is improving with an increase in research across the globe,” she told HemOnc Today. “My hope is that researchers will support one another to continue to make a difference for the children we treat.

“As outcomes improve, it will be important for us to try to minimize the long-term toxicities from our current aggressive therapies,” Sholler added. “I am looking forward to seeing the refinement of therapy and advances in the years to come.” – by Jennifer Southall


American Cancer Society. Neuroblastoma. Available at: Accessed on March 31, 2020.

Bagatell R and Irwin MS. JAMA. 2019;doi:10.1001/jama.2019.11641.

Cancer.Net. Neuroblastoma — Childhood: Statistics. Available at: Accessed on June 19, 2020.

Children’s Hospital of Philadelphia Research Institute. Antibody-drug conjugate shows efficacy against cell surface protein in neuroblastoma. Available at: Accessed on June 19, 2020.

Children’s Neuroblastoma Cancer Foundation. What is neuroblastoma? Available at: Accessed on June 19, 2020.

Children’s Oncology Group. In treatment. Available at: Accessed on June 19, 2020.

Goldsmith KC, et al. Abstract 10504. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.

Ladenstein R, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(17)30070-0.

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Tas ML, et al. Eur J Cancer. 2020;doi:10.1016/j.ejca.2019.09.025.

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For more information:

Araz Marachelian, MD, can be reached at Children’s Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027; email:

Nita L. Seibel, MD, can be reached at NCI Cancer Therapy and Evaluation Program, 9609 Medical Center Drive, Bethesda, MD 20892; email:

Giselle Sholler, MD, can be reached at Levine Children’s Hospital, 1000 Blythe Blvd., Charlotte, NC 28203; email:

Suzanne Shusterman, MD, can be reached at Harvard Medical School, 25 Shattuck St., Boston, MA 02115; email: