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   Number 1: JCO After Hours: A Discussion With Michael Gnant and Kathy Miller

   Dr. Shannon Westin, Dr. Michael Gnant, and Dr. Kathy Miller discuss the results of the PALLAS trial.

   December 07, 2021·30min
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   Number 2: Is Dose-Adjusted EPOCH-R the Optimal Treatment for Children with Primary Mediastinal B-Cell Lymphoma?

   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 [MUSIC PLAYING] 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. [MUSIC PLAYING] 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.

   October 20, 2021·9min
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   Number 3: Can the Incorporation of Minimal Residual Disease Detection Enhance Post-CAR T Outcomes in Patients With Large B-Cell Lymphoma?

   Minimal residual disease positivity is predictive of disease progression in patients with large B-cell lymphoma treated with anti-CD19 CAR T-cells. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial' by Frank et al. My name is Patrick Reagan, and I am an Assistant Professor of Medicine at the Wilmot Cancer Institute, University of Rochester in Rochester, NY. My oncologic specialties are lymphoma and cellular therapy. I would like to disclose consultancy for Kite Pharma. Frank and colleagues present data from a prospective, multicenter trial examining serial testing of circulating tumor DNA in 72 patients with large B-cell lymphoma who received treatment with the anti-CD19 CAR T-cell, axicabtagene ciloleucel, abbreviated as axi-cel. These patients had circulating tumor DNA monitored in plasma prior to lymphodepletion chemotherapy, as well as at multiple times following axi-cel infusion. Ninety-six percent of patients had adequate DNA to identify a clonotype to track over time at study enrollment, and 60 patients had an adequate sample for analysis at day 28 after axi-cel infusion. There are several key findings in this study. The first key finding is that circulating tumor DNA may serve as a surrogate for tumor burden. A lower level of circulating tumor DNA was associated with both improved disease and toxicity outcomes. Patients who had a lower baseline circulating tumor DNA had improved progression-free and overall survival, as well as less severe cytokine release syndrome and immune effector cell associated neurotoxicity syndrome. A second key finding of this study is that circulating tumor DNA can serve as a marker for minimal residual disease in large B-cell lymphoma patients treated with CAR T-cells, and can be predictive of disease relapse. Seventy percent of patients who had durable response were negative for circulating tumor DNA one week following CAR T infusion. All patients with disease progression had at least one sample that was positive for minimal residual disease, and all but one were positive for minimal residual disease concurrently with radiographic progression. At day 28-post CAR T-cell treatment, negativity for minimal residual disease by circulating tumor DNA was strongly associated with improved progression-free and overall survival. A third key finding in this study was that positivity for minimal residual disease was highly predictive in patients who have a partial response or stable disease at day 28-post CAR T-cell treatment. Deepening of response over time has been reported with various CAR T-cell treatments suggesting that there are limitations of PET CT to assess response, particularly at early time points. In the patients who had stable disease or partial response who were positive for minimal residual disease at day 28 following axi-cel, 15 of 17 patients had a progression-free survival event, while only two of ten who were negative for minimal residual disease had a progression-free survival event. This study has multiple implications for future clinical research, which may influence routine clinical care over time. High tumor burden defined by the sum of product diameters or metabolic tumor volume has been associated with both treatment failure and excess toxicity with axi-cel, as well as tisagenlecleucel. As a potential surrogate for tumor burden, baseline circulating tumor DNA could be useful in determining high-risk groups to target for clinical trial participation. Additionally, this could be a stratification factor for randomized studies involving CAR T-cells. Additional studies with axi-cel as well as tisagenlecleucel and lisocabtagene maraleucel, which are also commercially available for large B-cell lymphoma, are important to confirm this observation. Management of patients who initially achieve a partial response or have stable disease at the first disease assessment is a common clinical problem in patients with large B-cell lymphoma treated with CAR T-cells. A proportion of patients with large B-cell lymphoma who initially have partial response or stable disease will go on to develop a complete response over time. This has been reported in all of the commercially available anti-CD19 CAR T-cell products. In the ZUMA-1, JULIET and TRANSCEND trials, approximately one third to one half of patients who initially had partial response or stable disease went on to achieve a complete response. Patients who ultimately have progressive disease have poor outcomes with a median overall survival of 180 days. Those who have stable or progressive disease as best response have a medial overall survival of only approximately 50 days. Predicting which patients are at risk to relapse is important given the small window of time to intervene. It would also potentially spare low risk patients from additional therapy, which may be difficult to tolerate given the acute toxicity of CAR T-cell therapy, as well as the prolonged hematologic toxicity seen in some patients. Disease progression following anti-CD19 CAR T-cell therapy is a pressing clinical problem in patients with large B-cell lymphoma and there is a need for clinical trials. Clinical trials should be considered in all patients who relapse following CAR T cell therapy. Early detection of relapse can help to facilitate enrollment prior to the development of complications related to progressive disease that may preclude their enrollment. There are now multiple clinically active, targeted therapeutics in large B-cell lymphoma, and a trial of maintenance or consolidative therapy could be considered in this population. This could target only the highest risk patients by using positivity for minimal residual disease as assessed by circulating tumor DNA as a criterion for inclusion. Alternatively, this could focus more broadly on the patients with stable disease or partial response, but given these results, outcomes by circulating tumor DNA status would be important secondary endpoints. Either way, circulating tumor DNA would be critical to the study design and interpretation of results. This concludes this JCO Podcast. Thank you for listening.

   July 10, 2021·7min
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   Number 4: ctDNA in DLBCL: A Blueprint for Better Clinical Trials?

   Current clinical characteristics and demographics are not sufficient to capture aggressive disease in clinical trials of newly diagnosed DLBCL. Novel tools, such as measurement of tumor burden via ctDNA, are needed. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Short Diagnosis-to-Treatment Interval is Associated with Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma" by Alig et al. My name is Matthew Maurer, and I am a statistician at the Mayo Clinic in Rochester, MN. My oncologic specialty is lymphoid malignancies. I have no relevant conflicts to disclose. The impact of any clinical research critically depends upon participating subjects being representative of the study population afflicted with the disease of interest and research efficiency is markedly enhanced when cohorts can be compared across studies. In newly diagnosed diffuse large B-cell lymphoma (DLBCL), there is a standard group of clinical variables that is typically captured and reported across studies. The International Prognostic Index, or IPI has been utilized as a prognostic model in aggressive lymphoma for nearly 30 years and remains relevant today. The IPI and its components, which consist of age, performance status, LDH, stage, and number of extranodal sites, provide the clinical characteristic backbone for trial eligibility and defining high risk disease in frontline DLBCL trials. Assessment of genomic features of the tumor using pathological techniques such as IHC and FISH can further identify high risk subsets of patients. However, despite these well-tested clinical tools to measure the aggressiveness of the disease, there remains significant heterogeneity in patient presentation and outcomes. Clinically, some patients will present with a real or perceived clinical urgency to initiate therapy as soon as possible. This clinical urgency often precludes these patients from enrolling on frontline trials. My colleagues from the University of Iowa / Mayo Clinic Lymphoma SPORE and I explored this phenomenon in our observational lymphoma cohort study by evaluating the time between a patient's diagnostic biopsy and their initiation of chemotherapy. We found that this simple measure of diagnosis to treatment interval, or DTI, was highly informative in the setting of newly diagnosed DLBCL. Patients with a shorter DTI were more likely to be symptomatic, have advanced stage disease, poor performance status, and elevated LDH. Further, patients with a short DTI had significantly inferior outcomes, even after accounting for the standard clinical details of the IPI. These results were validated in a cohort of clinical trial patients from the French Lymphoma Study Association as well as subsequent studies. These data suggest that clinicians are managing patients with aggressive disease more urgently, and our current set of clinical variables is not sufficient to describe and compare patients across studies. Despite its simplicity and retrospective prognostic ability, DTI lacks specificity as a clinical characteristic for future studies. It can be easily influenced in an individual patient by numerous aspects unrelated to disease biology, such as physician preference or a patient's available access to health care resources. In additional, the typical DTI can vary widely across health systems or institutions. In the paper accompanying this podcast, Alig and colleagues examine the relationship between DTI, conventional risk factors, circulating tumor DNA, and clinical outcomes. A strong association was observed between shorter DTI and increasing tumor burden as measured by baseline metabolic tumor volume and circulating tumor DNA. This is a key biologic confirmation that treatment urgency is directly related to disease biology. Importantly, the authors also showed that ctDNA was a highly informative variable in regards to prognosis in their dataset. ctDNA was an independent prognostic variable after adjusting for the IPI in Cox models for event-free and overall survival, and the prognostic ability of ctDNA was far superior to DTI in univariate models. The association between DTI and disease biology has direct implications for clinical trials in frontline DLBCL. Clinical trials that did not adequately enroll patients in need of urgent therapy were likely biased towards enrollment of patients with lower tumor burden. In particular, single arm trials of novel therapies are particularly at risk, as these results are often evaluated in light of conventional clinical characteristics and compared to previous studies and/or clinical experience. This may also have contributed to the better than expected outcomes on the control arms in recent randomized trials of newly diagnosed DLBCL. Evaluation of tumor burden using ctDNA or metabolic tumor volume should allow us to better understand the impact of a study's design on patient enrollment. The amount of tumor is a long-standing prognostic feature for newly diagnosed DLBCL. This has standardly been measured by broad clinical features such as stage, number of extranodal sites, and bulky disease. As the retrospective studies on DTI have shown, however, these features are not sufficient. Novel tumor burden measures like circulating tumor DNA are needed. ctDNA is not without its drawbacks in frontline DLBCL. It is not clinically available for real-time assessment and significant work remains to be done to make it a routinely available and standardized biomarker, which includes independent validation of the results reported by Alig and colleagues. However, as we continue to develop and test new treatment strategies for DLBCL, we must also develop and test novel prognostic and predictive tools. Alig and colleagues have shown us that ctDNA has the potential to identify features of aggressive disease that our current tools do not. Capturing these features more precisely is vital for us to understand and interpret clinical trial results, as well as ensure future trial designs are enrolling the study's intended patient population. As part of these efforts, clinical trials in newly diagnosed DLBCL should collect and store the necessary biospecimens to evaluate ctDNA in anticipation of a new generation of standard clinical characteristics. This concludes this JCO Podcast. Thank you for listening.

   April 10, 2021·7min
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   Number 5: How Can We Expand Eligibility Criteria for Diffuse Large B-Cell Lymphoma Clinical Trials to Serve More Patients?

   This podcast considers the impact of exclusion criteria on clinical trials, generalizability, and the complexity of modernizing eligibility while maintaining trial integrity. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Diffuse Large B-cell Lymphoma (DLBCL) Patients. Who Gets Left Behind?" by Khurana et al. My name is Richard Little, and I am at the National Cancer Institute. My oncologic specialty is lymphoid and myeloid malignancies. I am a federal employee with no conflicts of interest to disclose. The authors have contributed a timely and provocative analysis examining the lack of generalizability and disappointing results of repeatedly negative randomized phase 3 trials conducted over the past 15 years failing to improve on R-CHOP. The authors have proposed that these failures may be in part explained by enrollment onto clinical trials patients who are not really representative of those with the disease, because eligibility criteria too often unnecessarily eliminate patients with laboratory values that reflect organ impairment not pertinent to the agents under study. To test this inference, the authors leveraged a unique resource: The Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence, or SPORE. This SPORE is an NCI-funded research project initiated in 2002 and collects data in a uniform manner among consenting participants with newly diagnosed DLBCL who undergo treatment managed by their physician. This rich database enabled the evaluation of data in patients treated with R-CHOP or R-CHOP-like immunochemotherapy. The investigators were able to categorize the SPORE participants in reference to the eligibility criteria of the important phase 3 studies recently conducted as either meeting eligibility of the phase 3 studies or not meeting eligibility due to out-of-range laboratory values. Additionally, the SPORE data in some ways mimics clinical trial data in that events such as disease progression and death are captured, and these outcomes could be evaluated comparatively between patients categorized as clinical trial eligible and not eligible. They indexed 7 trials, and for example, found that 12.9% of the SPORE participants did not meet eligibility for the PHOENIX study—that is the phase 3 trial of ibrutinib-R-CHOP vs placebo-R-CHOP showing no benefit of the addition of ibrutinib. Not surprisingly, those scored as ineligible had worse outcomes compared to those scored as eligible. For example, indexing eligibility for the PHOENIX trial, the overall survival hazard ratio for those scored not eligible versus eligible was 1.49 with a p-value of .002. The median survival of the SPORE cohort scored as ineligible for PHOENIX had a median overall survival of around 80 months, and the median survival for those sored as eligible had not yet been reached. Interestingly, treatment-related deaths were not found to be increased in the SPORE patients scored as ineligible compared to those scored as eligible, but death due to progressive lymphoma was higher among those scored as ineligible. So how does this relate to the inability to improve upon standard DLBCL therapy? Khurana and colleagues' data highlight several features of clinical trials conduct related to trial outcomes. The unnecessary exclusion of patients based on criteria not specific to the treatment can translate into eligible patients having a more favorable prognosis compared to individuals with the disease who are excluded from studies, but who nevertheless are treated with standard therapy used as a control in DLBCL clinical trials. Populating randomized trials with the best prognosis patients can lead to reduced power to detect an outcome difference, even if one exists. But what about the unnecessary exclusion of patients from clinical trials based on laboratory values that reflect organ dysfunction and poor outcomes as shown in the SPORE patients? The authors document unequivocally that those patients deemed ineligible are at higher risk of death due to treatment failure: that is they die due to progressive lymphoma more than the SPORE patients scored as meeting clinical trial eligibility criteria. What we don't know from the study as presented, is whether there were more dose delays and dose reductions among those scored as ineligible. This is fundamental toward an improved understanding of how to repair our clinical trials enterprise in DLBCL. And what I mean by repair, is to broaden and expand clinical trials access to as many patients as possible and to have rigorous design and conduct of trials to detect true signals. There are two essential elements to address, and this data points the way but does not fully answer the questions. To make trials generalizable, we must include as broadly as possible those patients with DLBCL. However, if the SPORE outcomes are explained by an inability to administer therapy as planned in those scored as trial ineligible, then just broadening eligibility criteria could undermine the ability to detect a difference with new effective treatment by including too many patients unable to tolerate the therapy. For example, some have suggested the negative results of the PHOENIX trial may be due to treatment intolerance among those aged 60 years and over. So it appears that trials increasing generalizability and reaching a positive trial endpoint for a novel treatment have a complex interaction, to say the least. It will be essential as diffuse large B-cell lymphoma therapeutic trials are developed to be mindful of differential prognosis and perhaps interrelated treatment tolerance of patients due to multiple factors, including degree of organ dysfunction. The exclusion of patients with the disease understudy from clinical trials should be minimized. Efforts to modernize clinical trial eligibility are being embraced by most stakeholders, and in my opinion is an essential social and medical responsibility for clinical trialists to meet. The challenge is how to accomplish this important objective and appropriately design studies to enhance the ability to detect the desired study endpoint. To answer the question posed by the authors, we must endeavor to leave no one behind. We can accomplish this through statistical designs such as stratification of the randomization, powered for the groups of interest -- as one such solution. Separate and specific trials for older or more frail patients is another solution. And I dare say, we should focus on efforts to eliminate the CHOP backbone and develop better-tolerated therapy that those with organ dysfunction can benefit from. The VIPOR regimen presented by Melani and colleagues at the 2020 ASH meeting provides an example of the type of DLBCL research that could be of interest. The challenge of generalizability and its relevance to negative clinical trial results is becoming clearer if only to recognize the increasing complexity in meeting the needs of our patients. But isn't that what motivates us? This concludes this JCO Podcast. Thank you for listening.

   March 10, 2021·10min
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