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Journal of Clinical Oncology recognizes that readers do not always have time to review an article in depth, and yet they still wish to understand how the results will influence their clinical practice or research. To address this need, we offer podcasts that will enhance the readership experience by presenting the key results of high-profile publications in a convenient audio format. Our podcasts are designed to place selected articles into a clinically useful perspective that is easy to listen to in the office or while on the road.

Life is busy, and it’s hard to get it all done during business hours! Journal of Clinical Oncology recognizes that you do not always have time to review an article in depth, and yet you wish to understand how the results will influence your clinical practice or research. JCO After Hours is a podcast intended to enhance the readership experience by presenting key results of high-profile publications in a convenient audio format, placing selected articles into a clinically useful perspective that you can listen to in the office or on the road.

Oct 20, 2021

This podcast will discuss data from a phase II trial evaluating the dose-adjusted EOPCH-R chemo-immunotherapy regimen for the treatment of primary mediastinal B-cell lymphoma in children.

 

TRANSCRIPT

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LISA GIULINO-ROTH: This JCO podcast provides observations and commentary on the JCO article "Dose-Adjusted Rituximab Therapy in Children and Adolescents with Primary Mediastinal B-cell Lymphoma, a Multicenter Phase II Trial" by Burke et al. My name is Lisa Giulino-Roth, and I am a pediatric oncologist at Weill Cornell Medical College in New York. My oncology specialty is lymphoma in children, adolescents, and young adults. I have no relevant disclosures.

Primary mediastinal B-cell lymphoma, or PMBCL, is an aggressive non-Hodgkin lymphoma derived from thymic B-cells. While previously classified as a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as a distinct clinical and pathologic entity. Unlike diffuse large B-cell lymphoma, PMBCL has a peak incidence among adolescents and young adults and is more common in females.

PMBCL also shares many molecular characteristics with Hodgkin lymphoma, including alterations in JAK-STAT pathway signaling and amplification of the 9p24.1 locus, leading to upregulation of PD-L1. Adults with PMBCL have historically been treated on regimens designed for diffuse large B-cell lymphoma, which in the US was most commonly R-CHOP and radiation therapy. More recently, adult patients have been treated with a dose-adjusted EPOCH-R regimen, which is composed of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab.

This radiation-free approach is of interest, given this young and predominantly female population who are at risk for significant long-term toxicity from chest radiation. In a single center NCI-led study by Dunleavy and colleagues, dose-adjusted EPOCH-R was administered for six to eight cycles without radiation therapy and resulted in excellent outcomes with a five-year event free survival of 93% and overall survival of 97% among 51 adult patients.

Pediatric patients with PMBCL have historically been treated on regimens designed for mature B non-Hodgkin lymphoma, which in pediatrics is most commonly Burkitt lymphoma or diffuse large B-cell lymphoma. These dose intensive multi-agent regimens include doxorubicin, high dose methotrexate, and intrathecal chemotherapy without radiation.

Outcomes for children with PMBCL treated on these regimens are inferior to pediatric patients with diffuse large B-cell lymphoma treated on the same protocol. Children with PMBCL have a five-year event-free survival ranging from 65% to 75% in different international series. Given the excellent outcomes observed with dose-adjusted EPOCH-R in the adult NCI trial, an international phase II trial of this approach was conducted by two cooperative groups, The European Intergroup for Childhood Non-Hodgkin Lymphoma and the Children's Oncology Group.

This single arm trial enrolled patients age 18 and under with primary mediastinal B-cell lymphoma. All patients were treated with six cycles of dose-adjusted EPOCH-R without radiation. The primary endpoint was event-free survival with events defined as any of the following-- viable cells in any residual mass after six cycles of treatment, relapse, progressive disease, secondary malignancy, or death from any cause. The four-year event-free survival from this trial would be compared with the event-free survival from historic controls, which was estimated at 67%.

A total of 46 pediatric patients were enrolled between 2012 and 2016. All patients received six cycles of dose-adjusted EPOCH-R without RT. At a median follow-up of 59 months, there were 14 events, including four patients with viable cells in the residual mass at the completion of therapy, eight progressions or relapses, and two secondary malignancies, including one case of Hodgkin lymphoma and one case of acute promyelocytic leukemia.

The event-free survival of the entire cohort at four years was disappointing at 69.6% with a 95% confidence interval of 55.2% to 80.9%. This was not statistically different than historic controls treated on pediatric mature B and HL regimens. Overall survival at four years was 84.8% with a 95% confidence interval of 71.8% to 92.4%.

The authors acknowledge several limitations in the current study and challenges when comparing this study to the NCI trial. Not all patients adhered to the dose escalation rules, and 29% should have received a higher dose level in at least one course of treatment. Among the 10 cases of local relapse or primary refractory disease, five were noted to have a failure to dose escalate, including one patient with a clinical complication that precluded dose escalation.

Comparing this trial to the NCI trial is challenging due to several important differences. Adults in the NCI trial were treated with six or eight cycles of dose-adjusted EPOCH-R based on the response between cycles 4 and 6. In pediatrics, eight cycles was not deemed appropriate, given the potential for greater than 600 milligrams per meter squared of cumulative doxorubicin exposure and concern for significant long-term cardiac toxicity at this exposure level. In addition, the NCI trial did not consider residual viable cells or secondary malignancy as an event, both of which were defined as events in the current pediatric trial.

In a reanalysis of the pediatric data using the NCI event definitions, there was only a modest change in event-free survival with a four-year event-free survival of 73.9%. So where does this leave dose-adjusted EPOCH-R and the management of pediatric patients with PMBCL? In my opinion, there's no single superior regimen to treat pediatric PMBCL. Outcomes are similar across regimens. However, the toxicities are different. Dose-adjusted EPOCH-R offers significantly less short-term toxicity, but the potential for a higher cumulative doxorubicin dose compared to pediatric mature B and HL regimens.

Regardless of the chemotherapy backbone, it is clear that for children with PMBCL, outcomes remain suboptimal, and further studies are needed to advance treatment. Given the rare nature of PMBCL and the peak incidence in the AYA population, combined pediatric and adult trials may allow us to evaluate novel agents and advance outcomes.

Both children and adults with PMBCL may benefit from the incorporation of novel agents. Retrospective multicenter data from adults treated with dose-adjusted EPOCH-R have also failed to reproduce the excellent outcomes observed in the NCI trial. In two large retrospective series, adults with PMBCL treated with dose-adjusted EPOCH-R had a two- and three-year progression-free survival of 85% and 87% respectively.

To advance outcomes in PMBCL across age groups, our team at the Children's Oncology Group in collaboration with Alliance and the National Clinical Trials Network is conducting a randomized phase III trial of the checkpoint inhibitor nivolumab in combination with chemo immunotherapy for adult and pediatric patients with PMBCL. Checkpoint inhibitors, including pembrolizumab and nivolumab, have demonstrated efficacy and PMBCL in the relapsed setting. And pembrolizumab is FDA approved for children and adults with relapsed PMBCL after two or more lines of therapy. However, these agents have not been evaluated in the upfront setting.

In this trial, the treating physician will choose between R-CHOP and dose-adjusted EPOCH-R as the chemotherapy backbone. And patients will then be randomized to standard of care with six cycles of chemo immunotherapy alone or six cycles of nivolumab plus chemo immunotherapy. We are optimistic that this will define the role for checkpoint inhibition in the upfront management of PMBCL and work towards improved outcomes for both adult and pediatric patients.

This concludes this JCO podcast. Thank you for listening.

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.