Is tandem transplant appropriate for patients with high-risk neuroblastoma?
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Neuroblastoma is marked by wide clinical and biological heterogeneity. Treatment of high-risk neuroblastoma in North America largely is driven by the experience of Children’s Oncology Group (COG), the world’s largest pediatric cancer cooperative group.
During the past 4 decades, outcomes for children with high-risk neuroblastoma have improved by better identification of high-risk groups and therapy intensification for these patients. One of the most significant improvements in risk for relapse among patients with high-risk neuroblastoma came with the introduction of myeloablative chemotherapy with autologous hematopoietic stem cell rescue.
More than 20 years ago, Matthay and colleagues first reported an improvement in EFS in a randomized phase 3 trial for patients who received myeloablative therapy compared with patients who received continuing chemotherapy. Building off this finding, Park and colleagues reported outcomes of children enrolled on the randomized phase 3 ANBL0532 trial, in which children with high-risk neuroblastoma were randomly assigned to one or two consolidative myeloablative treatments with autologous stem cell rescue. Patients in the tandem transplant group had superior 3-year EFS outcomes (61.6% vs 48.4%; P = .006). Children who received post-consolidation immunotherapy with dinutuximab demonstrated further improvements in 3-year EFS (73.3% for tandem vs. 54.7% for single; P = .004) and OS (84% for tandem vs. 73.4% for single; P = .04).
Despite these highly encouraging outcomes, caution is warranted before declaring tandem myeloablative transplants as the standard of care for all patients with high-risk neuroblastoma.
In ANBL0532, only patients with chemotherapy-responsive disease, defined as an end-induction response of stable disease or better, were eligible for transplant randomization. Only 47% of patients in ANBL0532 were eligible for or received myeloablative consolidation; the majority of these patients refused randomization and a smaller proportion (9.5%) were ineligible for myeloablative therapy due to nonresponsive disease, death or toxicity. In addition, a small cohort of patients with high-risk neuroblastoma with historically favorable clinical outcomes — defined as patients older than 18 months with localized disease, unfavorable histology and nonamplified MYCN status — were nonrandomly assigned to receive single transplant. Finally, tandem transplant has not yet been evaluated in the context of other induction strategies, such as the dose-dense European standard of the Rapid COJEC trial.
Taken together, tandem transplant should be considered standard for all children with biologically unfavorable high-risk neuroblastoma who respond to COG-like induction chemotherapy. Future studies hopefully will identify strategies equally as effective as, and with less long-term morbidity than, the current COG approach.
References:
Ladenstein R, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.27.3524.
Matthay KK, et al. N Engl J Med. 1999;doi:10.1056/NEJM199910143411601.
Moroz V, et al. Eur J Cancer. 2011;doi:10.1016/j.ejca.2010.10.022.
Park JR, et al. JAMA. 2019;doi:10.1001/jama.2019.11642.
Pinto NR, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.59.4648.
Navin Robert Pinto, MD, is a pediatric hematologist-oncologist at Seattle Children’s Hospital. He can be reached at navin.pinto@seattlechildrens.org.
No
Extensive data suggest tandem transplant is not helpful for high-risk neuroblastoma.
In the only reported randomized trial involving tandem transplant, comparison was with single transplant. Tandem showed better EFS; however, OS — the gold standard for evaluating treatment efficacy — was not significantly different. The low randomization rate of the trial strongly detracted from the results.
A more fundamental issue is whether transplant — single or double — is warranted for high-risk neuroblastoma.
Once considered an exciting treatment for solid tumors, transplant proved disappointing as experience showed exorbitant toxicity without survival benefit. Among children, transplant was discontinued for all extracranial solid tumors aside from high-risk neuroblastoma, for which it became standard because favorable results emerged in the only randomized neuroblastoma research comparing transplant with no transplant.
However, the three transplant/nontransplant studies included patients treated long ago — in 1982 and 2002 — and have limited contemporary relevance because of their outmoded induction chemotherapy and the absence or irregular use of local radiotherapy and anti-GD2 antibody, including treatments with proven anti-neuroblastoma efficacy. Patients in the control arm in one study received no therapy and, in another, they received only oral cyclophosphamide. Moreover, cytoreduction therapy was variable, ranging from single-agent to multiple agents plus total body irradiation, which is not used for neuroblastoma.
Additional compelling reasons to revisit the transplant issue include the update of the landmark CCG-3891 trial, which revealed no OS advantage with transplant, and a meta-analysis showing that transplant for high-risk neuroblastoma did not improve OS. Another consideration is the low likelihood of transplant agents ablating neuroblastoma that survived exposure during induction therapy to dose-intensive chemotherapy. Thus, in the COG study documenting no advantage to ex vivo purging, neuroblastoma contamination of harvested stem cells is rare, suggesting that relapse could be from the failure of myeloablative therapy to eradicate post-induction residual neuroblastoma.
Fortunately, chemoresistant neuroblastoma is highly responsive to treatments far less toxic than myeloablative therapy — namely, anti-GD2 antibody plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with or without low-dose chemotherapy.
Well-recognized transplant-related early and long-term toxicities — some lethal — remain a major concern. Acute complications, such as sinusoidal obstructive syndrome and microangiopathy, may increase risk for relapse by preventing timely implementation of local radiotherapy and immunotherapy.
In sequential studies at Memorial Sloan Kettering Cancer Center, transplant did not improve OS, whereas anti-GD2 murine antibody 3F8 plus GM-CSF did. These findings, plus considerations noted above, prompted discontinuation of transplant at my institution in 2003. Subsequently, the same consolidation with 3F8 plus GM-CSF was available for post-induction patients and post-transplant patients referred to the institution.
The large cohort of nontransplant patients may well be unique because transplant has been part of major high-risk neuroblastoma studies elsewhere since 2000. The Memorial Sloan Kettering clinical trial showed similar outcome with or without prior transplant for metastatic and MYCN-amplified localized neuroblastoma. At my institution, post-induction systemic treatment continues without transplant, instead relying on anti-GD2 antibody followed by anti-neuroblastoma vaccine.
References:
Bagatelli R and Irwin MS. JAMA. 2019;doi:10.1001/jama.2019.11641.
Berthold F, et al. Lancet Oncol. 2005;doi:10.1016/S1470-2045(05)70291-6.
Cheung NK, et al. J Clin Oncol. 2012;doi:10.1200/JCO.2011.41.3807.
Ellis LM, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.53.8009.
Kreissman SG, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70309-7.
Kushner BH, et al. Oncotarget. 2017;doi:10.18632/oncotarget.20513.
Kushner BH, et al. JAMA Oncol. 2018;doi:10.1001/jamaoncol.2018.4005.
Matthay KK, et al. N Engl J Med. 1999;doi:10.1056/NEJM199910143411601.
Matthay KK, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2007.13.8925.
Pritchard J, et al. Pediatr Blood Cancer. 2005;doi:10.1002/pbc.20219.
Yalcin B, et al. Cochrane Database Syst Rev. 2013;doi:10.1002/14651858.CD006301.pub3.
Zhuang SH, et al. Cancer J. 2009;doi:10.1097/PPO.0b013e3181be231d.
Brian H. Kushner, MD, is a pediatric oncologist at Memorial Sloan Kettering Cancer Center. He can be reached at kushnerb@mskcc.org.
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