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    Health & Fitness

    Journal of Clinical Oncology (JCO) Podcast

    The Journal of Clinical Oncology Podcast presents analyses and discussions centered on the latest findings published in ASCO’s flagship Journal of Clinical Oncology. Host Dr. Davide Soldato facilitates interviews and scholarly discourse on the most impactful published findings. The Journal of Clinical Oncology Podcast is the trusted resource that empowers you to integrate cutting-edge evidence into clinical practice.

    The year’s fellows interview authors and summarize the top Journal of Clinical Oncology articles in the series, JCO Article Insights.

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    Copyright: © Copyright by the American Society of Clinical Oncology

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    Latest Episodes:
    Moving Forward With Venetoclax-Based Combinations in Younger Adults With Acute Myeloid Leukemia Jun 20, 2021
    Show notes

    Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy.

    TRANSCRIPT

    This JCO Podcast provides observations and commentary on the JCO article "Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia" by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King's College London and Consultant Hematologist at Guy's Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie.

    The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question.

    In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML.

    Karol and colleagues from St. Jude's Children's Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%.

    In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%.

    The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%.

    The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively.

    Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeared to do particularly well, with a composite CR rate of 100% and 80% of patients testing negative for MLL fusion transcripts by PCR. One-year overall survival in this group was 80%, possibly highlighting MLL-rearranged leukemias as an additional group with particular sensitivity to BCL2 inhibition. This signal was not apparent in earlier trials using low doses of chemotherapy, perhaps because MLL rearrangements are much less frequent in older adults, or alternatively perhaps because this lesion requires higher doses of chemotherapy to synergise with BCL2 inhibition to overcome the apoptotic threshold.

    On the other hand, there appeared to be some groups with less favorable responses. Patients with core-binding factor leukemias appeared to do less well than expected, with a median overall survival time of 7.6 months. Patients with these leukemias were excluded from the earlier phase 2 and 3 studies of venetoclax, so there is no prior clinical data regarding their sensitivity to BCL2 inhibition; however, this finding does concur with in vitro data suggesting a lack of sensitivity.

    The outcomes for patients with TP53 mutations were disappointing with a median overall survival time of 9 months for newly diagnosed and 7 months for relapsed patients. Interestingly, even in the four TP53-mutated patients who tested MRD negative by flow cytometry, the TP53 mutation was still detectable by next-generation sequencing after treatment. The number of patients in these groups were small and will require confirmation in larger studies; however, alternative treatment strategies might be required for these patients.

    Overall, these results appear extremely promising and suggest that venetoclax may have significant activity when used with intensive induction or salvage chemotherapy schedules in younger adults. This now needs to be confirmed in randomized trials comparing intensive chemotherapy with and without venetoclax in both the front-line and salvage settings. If these trials are positive, further comparative studies will be needed to define the best chemotherapy schedule to combine with venetoclax. While limited data indicate that standard doses of cytarabine are likely inadequate, the optimal dose of cytarabine, and the additional value of fludarabine and anthracyclines remains to be defined. Nevertheless, the study by DiNardo and colleagues represents a significant step forward in the deployment of venetoclax in young fit adults, with the hope that this will increase the rate of long-term cures from this aggressive and frequently fatal hematological malignancy.

    This concludes this JCO Podcast. Thank you for listening.


    A Deep Dive Into HLA Typing For Unrelated Donor Hematopoietic Cell Transplantation May 20, 2021
    Show notes

    This podcast comments on a large registry study evaluating the effect of ultra-high-resolution HLA typing on outcomes of unrelated donor transplantation.

    TRANSCRIPT

    This JCO Podcast provides observations and commentary on the JCO article 'Impact of Previously Unrecognized HLA Mismatches Using Ultra-High-Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation" by Mayor et al. My name is Navneet Majhail, and I am the Director of the Blood and Marrow Transplant Program and the Vice-Chair for the Department of Hematology and Medical Oncology at the Taussig Cancer Institute, Cleveland Clinic. My oncologic specialty is transplantation and cellular therapy.

    For patients who are potential candidates for allogeneic hematopoietic cell transplantation, the first critical step is finding an HLA-matched donor. The HLA genes are located within one of the most gene rich regions of the human genome, are highly polymorphic, and encode proteins that critically modulate the body's immune responses against a variety of stimuli. When selecting an unrelated bone marrow or peripheral blood stem cell donor, we typically try to identify donors who are matched at HLA genes where polymorphism is predominantly present, namely, class I genes HLA-A, -B, -C, and class II genes HLA-DRB1, -DQB1 and –DPB1. Guidelines recommend using a donor who is matched at least at HLA-A, -B, -C, and –DRB1, and preferentially at -DPB1 and -DQB1 as well.

    Graft-versus-host disease or GVHD is an immune-mediated complication that continues to be a major threat to successful patient outcomes after hematopoietic cell transplantation. Better matching between the donor and the recipient lowers risk of GVHD, and guidelines recommend use of an HLA 8/8 matched unrelated donor, though in clinical practice we prefer an HLA 10/10 and even a 12/12 matched donor if one is available. In the past, HLA typing methods used 'antigen-level' serological testing. However, with advances in technology, the field has moved on to 'allele-level' or high-resolution typing which can discriminate among HLA genes that encode cell-surface proteins that ultimately constitute the antigen recognition domain, which is the functionally active portion of the HLA molecule that ultimately interacts with T-cell and NK-cell receptors. Research has shown that matching at allele-level is associated with lower risks of GVHD and better survival compared to historical serotyping-based methods, and DNA-based HLA-typing is the current standard of care.

    Further advances in technology to next-generation sequencing or ultra-high-resolution typing can now allow characterization of the full HLA gene sequence. This has raised the question of the clinical significance of HLA polymorphisms in regions outside the antigen recognition domain. Prior studies in smaller cohorts of patients have raised the possibility that transplants using ultra-high-resolution matched donors may be associated with better survival and lower risks of acute GVHD. To definitively validate these findings, Mayor et al conducted a study in a cohort of >5,000 allogeneic transplant recipients from the Center for International Blood and Marrow Transplant Research. Patients had received a matched unrelated donor transplant for acute leukemia or MDS between 2008 and 2017. The manuscript that accompanies this podcast provides details of their study population, but overall their cohort was fairly representative of unrelated bone marrow and peripheral blood stem cell transplant recipients.

    To summarize some key findings of their study, first, among donor-recipient pairs deemed HLA 10/10 match using high-resolution typing, 18% were found to not be a 10/10 match on ultra-high-resolution typing. Overall, only 12% of patients had a 12/12 ultra-high-resolution matched donor. Second, overall survival was comparable between patients receiving 12/12 ultra-high-resolution matched and mismatched transplants. Furthermore, there was no association of survival with the degree of ultra-high-resolution mis-match, that is, the number of loci where there was a mismatch. Similarly, when considering a subgroup of patients who were ultra-high-resolution matched at 10/10 loci, there was no difference in survival between patients who were 12/12 matched, that is, matched at DPB1, and those permissively or non-permissively mis-matched at DPB1. The authors did report an association of ultra-high-resolution matching with acute GVHD for their whole cohort, and associations with GVHD and transplant-related mortality in some subgroups, and I refer you to their JCO manuscript for details.

    There are some caveats to consider in applying their findings to clinical practice, and a good study always leads to more questions. The probability of finding an adult HLA 8/8 high-resolution matched unrelated donor varies from 16% to 75% depending on recipients race and ethnicity – the chances of finding a 10/10 or 12/12 donor who is ultra-high-resolution matched is going to be significantly lower. How do we factor in the role of other known non-HLA unrelated donor selection factors such as donor age, donor sex, CMV status, ABO type, and graft source vis-à-vis ultra-high-resolution matching? Even in this highly selected cohort of patients who were actually able to get a transplant, nearly 90% did not have a 12/12 ultra-high-resolution matched donor – in this setting, how do mismatches at different loci compare with respect to outcomes? Do we change our transplant conditioning and GVHD prophylaxis regimens in ultra-high-resolution mis-matched unrelated donor transplants to reduce the risk of GVHD? Several studies have indicated comparable survival between matched unrelated donor and haploidentical related donor transplants – does the use of an ultra-high-resolution 10/10 or 12/12 HLA matched donor offer any outcome advantage compared to the haploidentical transplantation? Taken together and at this time, their findings are primarily applicable to patients who have the luxury of choosing from several young 10/10 HLA matched unrelated donors. Cost of HLA typing using next-generation sequencing is also a factor that needs to be considered.

    Notwithstanding these 'yet to be answered' questions, there are advantages to ultra-high-resolution typing, and current technology does allow for rapid and unambiguous characterization of HLA genes with a rapid turnaround time. Many HLA labs are already implementing third-generation typing methods, and with increasing use and demand, it is expected to become cheaper and will no longer be cost-prohibitive.

    Overall, with HLA-identical sibling, matched unrelated, haploidentical related, mis-matched unrelated, and umbilical cord blood, nearly all patients who need a transplant have a donor. It is heartening to see that our research has pivoted from "Is there a donor available?" to "What is the best donor?" for a given patient.

    This concludes this JCO podcast. Thank you for listening.


    PENELOPE-B: Exploration of CDK4/6 Inhibition in the Adjuvant Setting May 10, 2021
    Show notes

    The PENELOPE-B phase III trial did not show a benefit to the addition of one year of the CDK4/6 inhibitor palbociclib to adjuvant endocrine therapy in patients with hormone receptor-positive/HER2-negative breast cancer and residual disease after neoadjuvant chemotherapy.

    TRANSCRIPT

    This JCO podcast provides observations and commentary on the JCO article "Palbociclib for Residual High-Risk Invasive Hormone Receptor-positive, HER2 negative Early Breast Cancer – The PENELOPE-B Trial," by Sybille Loibl and colleagues. My name is Erica Mayer, and I am a clinical investigator at the Dana-Farber Cancer Institute in Boston, MA who specializes in breast cancer.

    Since the initial approval of the CDK4/6 inhibitor palbociclib in 2015, this class of agents has become a standard part of management for most patients with hormone receptor positive HER2 negative advanced breast cancer. Use of one of the available CDK4/6 inhibitors - palbociclib, abemaciclib, or ribociclib - in combination with endocrine therapy, improves progression-free, and even overall survival, in the advanced disease setting, as shown in the respective trial series PALOMA, MONARCH, or MONALEESA. Although differentiated by their toxicity profiles, with palbociclib and ribociclib contributing more neutropenia and abemaciclib more diarrhea, across-the-board the benefit gained from use of these agents is remarkably preserved between trials, without apparent differential drug activity.

    Following the observation of benefit from use of CDK 4/6 inhibitors in the advanced setting, clinical trials evaluating the three available agents were subsequently launched to evaluate these agents in the adjuvant setting, after prior treatment with surgery, chemotherapy, and radiation if necessary. The first two trials to report in 2020, PALLAS and MONARCH-E, enrolled patients with early hormone receptor positive HER2- breast cancer, randomizing them to receive a CDK 4/6 inhibitor, palbociclib or abemaciclib respectively, for a planned 2-year duration, in addition to ongoing adjuvant endocrine therapy, versus ongoing adjuvant endocrine therapy alone. Notably, PALLAS enrolled patients with stage II and III breast cancer, whereas MONARCH-E targeted a high-risk group identified by tumor size, nodes, and Ki67 status. Initial reports from these trials were presented at an interim follow-up of about 20-24 months, a time when many were still receiving the combination therapy. The MONARCH-E analysis demonstrated a benefit from the addition of abemaciclib to endocrine therapy in prolonging invasive disease-free survival. This benefit was not observed with the addition of palbociclib in the PALLAS trial. The ongoing NATALEE trial, offering 3-years of reduced dose ribociclib in a similar setting, continues accrual.

    It is within this context that we place the PENELOPE-B trial. This trial enrolled the highest risk patients with early HR+/HER2- breast cancer: those with residual disease after preoperative chemotherapy and a high CPS-EG score, which is a calculation of anatomic stage and tumor biology meant to identify patients at highest risk of cancer recurrence. A total of 1250 patients were randomized to receive either one year of adjuvant palbociclib with ongoing adjuvant endocrine therapy, or placebo with endocrine therapy, and followed for a primary endpoint of invasive disease-free survival. As expected, the study enrolled a very high-risk population, with many patients having at least T2 disease and 4 involved lymph nodes at time of surgery. At a median follow-up of 43 months, no difference in invasive disease-free survival was observed, with a 4-year iDFS of 73% in the intervention arm, versus 72.4% in the placebo arm. No clinicopathologic subgroup appeared to derive benefit from the research intervention. The toxicity experience was similar to that seen in the metastatic setting, with notable and expected hematologic toxicity, but no significant difference in overall non-hematologic adverse events. Overall, drug exposure was satisfactory, with about 17% of patients unable to complete the planned 1-year duration of therapy.

    The PENELOPE-B study makes its mark in the adjuvant CDK4/6 landscape in several important ways. First, PENELOPE-B has the greatest duration of follow-up, allowing analysis of mature data and outcomes during and following adjuvant CDK4/6 inhibition. Although it is tempting to interpret a slight visual divergence of the Kaplan Meyer curves during the palbociclib exposure, where there is an absolute difference in iDFS of 4.3% at 2 years, there is no statistical evidence that the 2-year iDFS estimates are different between the two arms, and therefore no evidence of time-dependent efficacy. Importantly, in regard to experiences within the other CDK4/6 inhibitor trials, which have reported at an earlier time point, longer-term follow-up of those trials will be necessary to determine stability and maturity of the observed results. Additionally, PENELOPE-B is the only placebo-controlled trial presented to date. For that reason, the toxicity data presented represents the purest description of the experience of receiving a CDK4/6 inhibitor in the adjuvant setting in a population with prior chemotherapy exposure. Finally, when discriminating among the CDK4/6 inhibitors study populations, it is important to remember that PENELOPE-B enrolled a population of greatest established risk, suggesting any apparent differential outcome among the trials is unlikely related to differing baseline risk of accrued patients.

    Overall, PENELOPE-B represents a significant contribution to the breast cancer field, and substantially adds depth and dimension to the exploration of CDK4/6 inhibitors in the adjuvant setting. At the time of publication, it is unclear if an approved role will emerge for a CDK4/6 inhibitor in adjuvant therapy for our early breast cancer patients. Many questions remain regarding patient/tumor selection, agent differentiation, duration of therapy, and potential biomarkers. Importantly, the correlative analyses planned for all of the CDK4/6 inhibitor trials and molecular exploration of patient samples will substantially improve our understanding of the impact of these drugs in the early setting, and our overall ability to treat this subset of breast cancer. While waiting for these data, we should continue our focus on providing the best possible care for our patients with hormone receptor-positive, HER2-negative breast cancer who are being treated with endocrine therapy.

    This concludes this JCO podcast. Thank you for listening.


    ctDNA in DLBCL: A Blueprint for Better Clinical Trials? Apr 10, 2021
    Show notes

    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.


    How Can We Expand Eligibility Criteria for Diffuse Large B-Cell Lymphoma Clinical Trials to Serve More Patients? Mar 10, 2021
    Show notes

    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.


    The Pathologist, the Surgeon, and the Rare Phyllodes Tumor Dec 20, 2020
    Show notes

    This multi-institutional study highlights the heterogeneity of Phyllodes tumors of the breast and the importance of accurate pathology assessment and individualized surgical approaches.

    LEE WILKE: This JCO podcast provides observations and commentary on the JCO article, Contemporary Multi-institutional Cohort of 550 Cases of Phyllodes Tumors from 2007 to 2017 Demonstrates a Need For More Individualized Margin Guidelines by Rosenberger, et al. My name Lee Wilke and I am a professor of surgery and the Hendrix chair in breast surgery research at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. My oncologist specialty is breast surgical oncology. I have no relationships to disclose related to these studies.

    As medical students we are asked to adopt an expanded vocabulary to describe a multitude of diseases. The word phyllodes is frequently one of those memorable medical school terms whose origin is Greek and describes a leaf-like growth. Phyllodes are rare tumors accounting for less than 1% of breast malignancies, with just over 2,000 patients diagnosed annually in the United States.

    Originally, the phyllodes tumor was described as cyst like and, therefore, the historic term cystosarcoma phyllodes was applied. Though these tumors are of connective tissue and fibroepithelial origin, they are infrequently cystic and not a true sarcoma. And therefore, the World Health Organization now classifies them as simply phyllodes tumors. They are importantly, for treatment approaches, sub-categorized into benign, borderline, and malignant based on detailed pathologic review of celularity, atypia, overgrowth, mitotic rate, and the borders of the tumor.

    Phyllodes tumors are listed in the National Institute of Health's genetic and rare diseases program. On the center's website, surgery is described as the primary treatment for these rare malignancies and 1 centimeter margins or greater are recommended for all subtypes of phyllodes tumors, with a note that these tumors are quote, "often treated with mastectomy", unquote. As specialists caring for patients with breast malignancies, we are rapidly learning that the one-size-fits-all approach is not appropriate, and the same is true for those individuals with phyllodes tumors.

    In the article that accompanies this podcast, to support a shift towards more individualized treatment, Dr. Laura Rosenberger from Duke University in North Carolina assembled a group of key collaborators from 11 US academic cancer centers to pool and evaluate their treatment approaches and outcomes for patients with phyllodes tumors. The investigators identified a total cohort of 550 patients with phyllodes tumors treated between 2007 and 2017.

    Consistent with systematic reviews of phyllodes tumor data sets, such as that by Lu et al in Annals of Surgical Oncology, with this JCO publication being the largest, the patients have a median age of 44. The malignant cohort is approximately 10%. And median tumor size is three centimeters, with a range to as high as 29 centimeters. Key facts found within this analysis are that 2% of patients underwent nodal evaluation, all with negative nodes.

    The addition of either a sentinel node or axillary surgery is not without risks to the patient. And unless the pre-surgical diagnosis raises the question of a simultaneous adenocarcinoma, patients undergoing surgery for a phyllodes tumor should not undergo nodal mapping or axillary surgery as these tumors are primarily local malignancies and do not metastasize via the lymphatic network. This is the first key takeaway from this paper, supporting the work of others that nodal surgery in phyllodes tumors is unnecessary.

    The second notable finding is the heterogeneity, even among academic medical centers, regarding the surgical approach. Approximately 38% of patients, or 209, proceeded to a second surgical intervention. 51 of these patients, or nearly 10% of the entire cohort, had negative margins at their first surgery. Of the group that underwent a second surgery, only six patients, or 3% of those proceeding to a second intervention, had residual disease.

    On the opposite end of the spectrum, of those patients with a positive surgical margin, which was 42% of the entire group, 74, or 32% of those with positive margins, did not proceed with a second surgery. These outcomes highlight that even among patients being treated at centers that one would assume would function similarly, patients could have everything from positive margins to additional surgery in the setting of negative margins.

    What is vital to note at this point, however, is that the recurrence rate for this cohort was only 3.3% or 18 patients-- 15 with a local recurrence and three with a distant recurrence. The recurrences were differentially associated with the phyllodes subtypes, with 1.3% in benign, 5.6% in borderline, and 6.9% in malignant phyllodes. In univariate logistic regression analysis, however, margin status and margin width did not predict for a recurrence and neither did type of surgery or patient age.

    Clearly, a one centimeter margin for a phyllodes tumor is not needed, just as we are likely finding is true for our adenocarcinomas of the breast. The authors don't go so far as to state that a positive margin is acceptable, but highlight the need for a national registry to evaluate an individualized surgical approach in this rare patient population.

    A final and third key point from this retrospective but important pooled patient analysis is the primary role the pathologist plays in determining the patient outcome. As I frequently comment to my cancer patients, the pathologist is the most important doctor you never meet. In Dr. Rosenberger's analysis, factors that were influential for local recurrence were all pathological variables-- grade, extent of atypia and overgrowth and tumor size.

    Currently, there are no College of American Pathologists guidelines for reporting phyllodes tumors. With this and other patient data sets highlighting the importance of these pathologic factors in patient outcomes, perhaps a standardization and education program for identifying each of these key findings within a phyllodes tumor should be developed. Without a good pathologist or team of pathologists, oncologic surgeons lack the tools they need to advise the patient on additional surgery and potentially adjuvant therapy.

    As the use of adjuvant therapy was small in this data set, conclusions could not be provided for or against radiation therapy. Thus, as with all rare tumors, a collaborative and team approach with development of a national registry is needed across community and academic institutions to standardize and evaluate the outcomes for these patients with the eventual goal of providing a more tailored treatment approach. This concludes this JCO podcast. Thank you for listening.


    Cancer Surgery in COVID-19-Free Facilities Sep 29, 2020
    Show notes

    In this study of cancer operations conducted during the COVID-19 pandemic, rates of pulmonary complications and SARS-COV-2 nosocomial infections were compared between patients operated on in COVID-19-free facilities and those operated on in non-segregated facilities. Because lower rates of pulmonary complications and nosocomial SARS-COV-2 infection were observed in COVID-free facilities, the authors propose a restructuring of surgical facilities and pathways for cancer patients during the COVID-19 pandemic.

    This JCO podcast provides observations and commentary on the JCO article "Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International Multicenter Comparative Cohort Study, " by Bhangu et al. My name is Ken Tanabe, and I serve as Chief of Surgical Oncology at Massachusetts General Hospital, Professor of Surgery at Harvard Medical School, and Deputy Clinical Director of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts. My oncologic specialty is surgical oncology.

    The devastation and destruction brought about by the SARS-CoV-2 pandemic is difficult to fully comprehend. At time of this podcast there are more than 28 million infections worldwide and nearly 200,000 deaths in the United States alone. Hospitals and healthcare networks have been uniformly challenged to provide care and safety for patients and providers. In response to this initial wave, elective operations were cancelled as a strategy to increase critical care resources, preserve Personal Protective Equipment – or PPE, and re-deploy surgical team members to support care for COVID-19 patients. On a worldwide basis, this amounted to cancelation of a substantial number of operations. And a significant fraction of these backlogged operations was for cancer. Once hospitals recognized they could handle the size and peak of the initial wave, they resumed elective cancer operations. Some hospitals had the capacity to create COVID-19 free surgical units for these operations, as a strategy to reduce the risk of cross-infection of patients. Subsets of cancer patients are known to be at higher risk from COVID-19 morbidity and mortality, including those with lung cancer. However, creation of parallel pathways for COVID and non-COVID cancer patients diverts resources and is associated with significant costs. The relative value of this maneuver is not known, but is of critical importance, particularly in light of catastrophic hospital finances created by the pandemic.

    In the article that accompanies this podcast, the authors studied the impact of creation of COVID-19-free surgical facilities. Specifically, they gathered data from 445 hospitals in which patients underwent operation either in a COVID-19-free surgical pathway, or alternatively underwent operation in a hospital that did not have separate, COVID-free surgical units. The study included over 9,000 patients that underwent cancer operations during the pandemic. Hospitals in 54 countries are included, though the United Kingdom, Italy, Spain and United States accounted collectively for over 60% of the patients. A surgical facility was defined COVID-19 free if it had a policy of segregation of COVID-19 patients in three specific areas of the hospital: the operating rooms, the ICUs, and the inpatient units. Conversely, a surgical facility was not considered COVID-19 free if this segregation was absent in any of these three areas.

    There are several key findings.

    • First and foremost, patients who underwent surgery within COVID-free units were younger and had fewer comorbidities compared to patients operated on in non-segregated surgical units.
    • After adjustment for these differences, pulmonary complication rates were lower amongst patients operated on in COVID-free units compared to those operated on in non-segregated surgical units.
    • The post-operative SARS-COV-2 infection rate was lower in COVID-free surgical units – 2.1% compared to the 3.6% observed in non-segregated units.
    • The preoperative COVID testing rate was higher in the COVID-19-free surgical units. Specifically, the testing rate was 39% in the COVID-19-free surgical units and only 23% in the non-segregated facilities. However, in a sensitivity analysis for patients with a negative preoperative swab test, the benefit of COVID-19 free pathways remained apparent.
    • The authors conclude it is likely that differences in SARS-CoV2 transmission rates are responsible for the lower pulmonary complication rates in those operated on in COVID-19-free surgical units.

    The authors cite these observations as the basis for their recommendation for, quote, "major international redesign of surgical services -- based on local available resources -- to provide elective cancer surgery in COVID-19-free surgical pathways." End quote. Of note, there are many hospitals and healthcare networks in the U.S., let alone worldwide, that don't have the resources required to create COVID-19-free operating rooms, ICUs and in-patient wards amidst a devastating pandemic. And thus, it's imperative to understand if that is really the lesson learned here.

    It is relevant to point out that COVID-19-free surgical units – whether they cause a lower rate of post-operative complications or are merely associated with these outcomes – are sought out by patients. In my own surgical practice, once we resumed operations after the initial COVID-19 wave, some patients declined or further delayed vital cancer operations for fear of SARS-COV-2 at the hospital, despite my assurances of the strict infection control policies in place.

    There are certainly limitations to this study. The first is that selection bias was present: patients that underwent operation in COVID-19-free surgical facilities were significantly younger and healthier. Although statisticians have developed strategies to adjust risk in scenarios like this, these approaches do not always completely remove bias. The second limitation is that this study took place at a time during which relatively few patients were COVID-19 tested prior to operation. Some of the observed effect in this study may be related to unknown SARS-COV-2 infection in asymptomatic patients. Only 27% of patients underwent preoperative SARS-CoV-2 testing in this study. Going forward, all patients are tested prior to surgical procedures. The current study suggests an effect even when the analysis is limited to patients that were tested preoperatively, but a more robust analysis of post-operative transmission of infection in non-segregated facilities can be performed when all patients are tested preoperatively.

    Another important limitation of the study is that the definition of COVID-19 free surgical pathway was arbitrary in the degree of completeness. In the context of this retrospective, multi-institutional international study, the definition was relatively broad for purposes of inclusion, but simultaneously lacks some common sense, requiring only complete segregation of operating rooms, surgical ICUs, and inpatient wards to separate COVID-19 infected patients from those without infection.

    To be designated as a COVID-19 free facility for purposes of this study, it was not required to have segregated facilities for preoperative check-in, separate recovery rooms, separate emergency rooms for patients presenting with post-operative complications, or even separate equipment and staff. What is the impact of sharing with COVID-19 areas patient transporters, EKG and X-Ray machines, food service racks, language translators, or use of common elevators and corridors, or even common pneumatic tube cannisters in a pneumatic tube system that runs throughout the facility? If the best performing hospitals that don't have COVID-19 free pathways perform better than the worst performing hospitals that do have COVID-19 free pathways, what is it that these hospitals are doing that makes the difference?

    In short, it seems more than just plausible that establishing infection control Standard Operating Procedures – or SOPs, staff training, and staff adherence to these SOPs are key to controlling spread of infection. These are likely as important as segregation of just three parts of perioperative care. In other words, this study demonstrates an association between having separate peri-operative facilities and a reduction in pulmonary complications. But this type of study is unable to address whether a causal link exists. Perhaps hospitals with the capability of achieving this segregation through duplicate facilities simply have more resources. Perhaps they have more capable hospital administration and support that can more quickly implement the newest infection control policies. Perhaps they have more PPE for hospital staff. Given that many hospitals and health care networks do not have sufficient resources to create parallel, segregated COVID-19-free facilities for operations, drilling down on these important operational aspects for control of disease transmission is key.

    The time period involved in the current report was one during which hospitals were struggling to cope with several challenges. Of note, between May 14 and July 14 CDC data reveal that an average of 120 patients a day became infected with SARS-COV-2 inside U.S. hospitals. During this time hospitals were managing gaps in testing – as were evident in the current report – and shortages of PPE required to protect staff and patients. CDC data suggests hospitals have improved at controlling nosocomial SARS-COV-2 infections since then, with the risk dropping from 2% in mid-May to 1.2% as of mid-July. These promising results are likely the result of better infection-control methods employed over time. The impact of this downward trend was exemplified in a study from Brigham and Women's Hospital that demonstrated only 1 case of nosocomial SARS-COV2 transmission over 12 weeks of the pandemic in which 9,149 patients were hospitalized and 8,656 days of COVID-19-related care were provided. The infection-control strategies they implemented were thorough, improved over time, and did not involve a COVID-19-free surgical pathway. The most recent changes implemented in the Brigham and Women's study included enhanced eye protection for employees, universal testing on admission, daily nursing screening for COVID-19 symptoms, and a hospital-wide shift to N95 masks for routine COVID-19 care.

    The current study focused on cancer operations, but does control of SARS-COV-2 transmission inside hospital surgical units have as much impact on other kinds of operations? Yes, the observations are relevant more broadly. Cancer patients are at greater risk for developing severe complications from COVID-19. But a large segment of the adult population has at least one underlying risk factor for increased susceptibility to infection, as well as increased likelihood of severe complication or mortality. Razzaghi et all have determined that the prevalence of any of five underlying, non-cancer conditions associated with increased risk for severe COVID-19–associated illness among U.S. adults is 47.2%. Moreover, particular races have significant higher risk of infection and higher risk of severe complications.

    Some health care systems have the resources to create separate surgical units to control nosocomial transmission. But going forward, it appears that reducing in-hospital transmission of SARS-COV-2 to cancer surgery patients will rely primarily on rigorous implementation of aggressive and widely accepted infection control policies.

    This concludes this JCO Podcast. Thank you for listening.


    Finding a Needle in a Haystack of Mutations: Using Whole Genome Sequencing to Identify Patients with Low-Risk Myeloma Jul 20, 2020
    Show notes

    This podcast reviews the results of the whole genome sequencing study by Samur and colleagues that identified a genomic signature associated with superior survival in patients with newly diagnosed multiple myeloma.

    Disclosures: SAH has served on advisory boards or as a consultant for Adaptive Biotechnologies, Amgen, Celgene, Genentech, GSK, Oncopeptides, Sorrento; Takeda; has received research funding from Oncopeptides.

    This JCO Podcast provides observations and commentary on the JCO article "Genome-Wide Somatic Alterations in Multiple Myeloma Reveals a Superior Outcome Group" by Samur et al. My name is Sarah Holstein, and I am an Associate Professor at the University of Nebraska Medical Center in Omaha, Nebraska in the United States. My oncologic specialty is plasma cell dyscrasias. I do not have any relationships to disclose related to these studies.

    The clinical heterogeneity of myeloma has long been appreciated as it is clear there is a broad range of disease behavior, with some patients having indolent disease and others having very aggressive disease. As a result, there has been significant interest in developing risk stratification systems that classify patients into different risk groups, thus providing some information about prognosis and potentially inform treatment decisions. Historically, staging systems were based on factors related to tumor burden. However, it is increasingly evident that the underlying disease biology is a key modulator of risk. Our ability to detect disturbances in the myeloma genome has changed dramatically over time. Metaphase karyotyping represents our lowest "power of magnification". These studies led to the recognition that in general, hyperdiploidy involving odd-numbered chromosomes is associated with lower-risk disease while high-risk disease can involve translocations of chromosome 14, monosomy 13 and monosomy 17. Use of fluorescent in-situ hybridization (FISH) allowed for a higher power of magnification and identification of more subtle chromosomal abnormalities. Next, gene expression profiling studies utilizing small panels of genes, enabled classification of patients into different risk categories, although there was little concordance between the panels used in the various studies. The advent of deep whole genome sequencing technology has facilitated a much more "high-powered" view of the myeloma genome.

    In the article that accompanies this podcast, diagnostic bone marrow specimens were obtained from 183 patients enrolled in the IFM/DFCI 2009 study. This phase 3 study enrolled newly diagnosed transplant-eligible patients (up to age 65). All patients received three cycles of lenalidomide, bortezomib, dexamethasone (RVD) induction, underwent stem cell collection and then received consolidation with either 5 cycles of RVD or a single autologous stem cell transplant followed by 2 cycles of RVD. Of note, in the French portion of this study, all patients subsequently received one year of lenalidomide maintenance, while in the US portion, all patients received lenalidomide until progression. The French portion has already been published and showed a 14 month PFS benefit for the transplant arm compared to the non-transplant arm. Results from the US portion have not yet been released, but I would speculate that the PFS and OS for both arms will be superior to the French counterparts, given the existing data supporting the benefit of prolonged lenalidomide maintenance.

    Deep whole genome sequencing, with a median tumor depth of 75X, was used to interrogate the myeloma genome. Mutational signatures were based on identified single nucleotide variants, small insertions and deletions. The genomic scar score (GSS) was calculated based on allele-specific copy number alterations. A GSS of 5 or less was the cut-off for inclusion in the low GSS group. The goals of the study were to describe mutational loads and processes in order to establish genomically-defined subgroups, gain insight into patterns of evolution from clonal to subclonal mutations, and correlate these findings with clinical outcomes and more traditional risk factors.

    There were several key findings. First, mutational load varied amongst myeloma subgroups, with hyperdiploid myeloma having the lowest mutational load and t(14;16) having the highest mutational load. Second, analysis of mutational patterns led to identification of five separate mutational processes that contributed to eight mutational signatures. These five processes included: 1) an age-related process, 2) an AID/APOBEC process, 3) somatic hypermutation, 4) DNA repair, and 5) processes with unidentified etiology including the clock-like signature. Samur et al., found that these various processes contributed to different myeloma subgroups in different ways. For example, the age-related process was high in hyperdiploid myeloma, the APOBEC-related process was high in t(14;16) myeloma, the clock-like signature was high in t(4;14) myeloma and the DNA repair process was high in del(17p) and t(11;14) myeloma. Furthermore, analysis of these mutational patterns from a clonal vs subclonal perspective enabled insight into mutational development patterns of different subgroups of myeloma.

    Next, the GSS was correlated with mutational signature and clinical outcome data. The authors found that the frequency of a low GSS was higher in t(11;14) myeloma and lower in del17p, gain1q21, del1p and del13 subgroups. Patients in the low GSS group had a trend towards a longer median PFS and a statistically significant longer 4-year OS rate than other patients. In particular, patients with both low GSS and gain of chromosome 9 had a superior outcome compared to all other subgroups, with an OS probability of 100%. Patients with either low GSS and no gain(9) or with high GSS and gain(9) had intermediate outcome while those with high GSS and t(4;14), gain(1q) or no gain(9) had the worst OS. Although the numbers are quite small, an interesting finding was that for patients in the low-risk group (low GSS + gain(9)), there was a significantly superior PFS in favor of those patients in the transplant arm compared to the non-transplant arm. Overall, no statistically significant differences were found between the four subgroups and factors such as ISS stage, response, or achievement of MRD negativity. The numbers in each subgroup were quite small though. Finally, the authors demonstrated that the low GSS could separate hyperdiploid myeloma into low-risk and high-risk subgroups.

    Overall, these studies are interesting because they provide insight into the mutational processes that drive different subgroups of myeloma and offer a potential method by which to differentiate low-risk hyperdiploid myeloma from high-risk hyperdiploid myeloma. The finding that there was a difference in PFS for patients who underwent transplant vs no transplant in the low-risk group (low GSS, gain(9)) is very intriguing. There has been much discussion centered around whether low-risk patients really "need" to go through a stem cell transplant since in general their outcomes are good. The present study, aside from highlighting the fact that our traditional methods of identifying low-risk disease are likely inadequate, raises the hypothesis that patients with low-risk disease may benefit even more from transplant than other risk groups. However, it is noted that this subgroup consisted of only 28 patients. In addition, it is not clear from the manuscript whether patients were in the US vs French portion of the study, thus differences in study design (i.e., lenalidomide maintenance duration) could impact PFS findings. Clearly, this type of whole genome sequencing analysis will need to be applied to additional prospective studies in order to validate the novel risk stratification system.

    For now, these results are not practice-changing. However, they provide a potential glimpse into the future, where whole genome sequencing analysis is performed as readily as FISH analysis, and where enrichment strategies using genomic markers are used to design clinical trials. Aside from studies evaluating the use of venetoclax in t(11;14)-positive myeloma and other studies focused on high-risk disease that encompass a variety of high-risk chromosomal abnormalities, the field of myeloma has not yet moved into an era of precision medicine. Whether whole genome sequencing can finally usher us into that era remains to be determined. While this plasma cell-centric analysis is certainly revealing, it is likely that in order to maximally target myeloma, the genomics analysis must be coupled with an equally in-depth understanding of the host's immune system.

    This concludes this JCO Podcast. Thank you for listening.


    Advancing Knowledge on the Use of Dexrazoxane in Children With Acute Myeloid Leukemia and Other Childhood Cancers Jun 11, 2020
    Show notes

    This podcast describes a study addressing the use of dexrazoxane as a cardioprotectant in a cohort of more than 1,000 pediatric acute myeloid leukemia patients.

    Transcript

    This JCO Podcast provides observations and commentary on the JCO article "Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients with Acute Myeloid Leukemia: A Report From the Children's Oncology Group" by Getz et al. My name is Elvira van Dalen, and I am an epidemiologist at the Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands and a Coordinating Editor of Cochrane Childhood Cancer. My oncologic specialties are cardiotoxicity and systematic reviews and guidelines in the field of pediatric oncology. I have nothing to disclose.

    Anthracyclines are widely used in pediatric oncology. Unfortunately, one of their most serious adverse effects is cardiotoxicity, which can occur during or shortly after treatment, but also decades later. In the Dutch LATER Childhood Cancer study, we found a 10.5% cumulative incidence of symptomatic heart failure 40 years after cancer diagnosis in survivors treated with cardiotoxic chemotherapy. The Childhood Cancer Survivor Study and St Jude LIFE show similar results. Siblings report significantly less congestive heart failure than survivors. These are high risks, especially in this young patient population. Cardiotoxicity impairs quality of life and can lead to premature death. Prevention is thus very important.

    Extensive research has been devoted to the identification of possible cardioprotective interventions, like liposomal anthracyclines, increasing the anthracycline infusion duration and reducing the cumulative anthracycline dose. Concerning the cumulative anthracycline dose, it should be kept in mind that there is no safe dose. Another option is the use of cardioprotective agents like dexrazoxane.

    As shown in our Cochrane systematic review published in 2011 which is currently being updated, it prevents cardiac damage. But unfortunately, the majority of the evidence comes from studies addressing adult patients with breast cancer and these data cannot be extrapolated to children. In children as of yet only a few randomized trials have been performed, none including acute myeloid leukemia patients. In these pediatric studies, for clinical heart failure there were no significant differences between dexrazoxane and control groups, while results for asymptomatic cardiotoxicity varied with the outcome definition used. All studies were relatively short-term, and we don't know how longer follow-up will influence these results.

    Thus far only a few small non-randomized studies including 50 children or less evaluated dexrazoxane in pediatric acute myeloid leukemia, all with limitations. The article by Getz and colleagues that accompanies this podcast adds important new information to the current knowledge of the use of dexrazoxane in pediatric acute myeloid leukemia patients and pediatric patients in general. It presents the results from the Children's Oncology Group AAML1031 trial investigating the use of dexrazoxane during frontline treatment of pediatric acute myeloid leukemia. Between 2011 and 2016, patients younger than 30 years at diagnosis were enrolled. Almost 98% were younger than 21 years. The analyses included 1014 patients, of which 10% received dexrazoxane consistently at every anthracycline course and 90% were never exposed to dexrazoxane. Anthracycline treatment involved both daunorubicin and mitoxantrone. Low risk patients received a cumulative anthracycline dose of 444 mg/m2, while high risk patients received 294 mg/m2 assuming the daunorubicin equivalency conversion employed by the Children's Oncology Group at the time of this protocol. Patients were followed for a median of 3.5 years, with an interquartile range of 2.5 to 4.7 years. Cardiac function was assessed using either echocardiography or multigated acquisition scans which were performed at regular intervals. Compliance with cardiac monitoring was more than 90% on-protocol, but less than 60% off-protocol. Left ventricular systolic dysfunction was primarily defined as a shortening fraction of less than 28% or an ejection fraction of less than 55%.

    In the report by Getz and colleagues that accompanies this podcast, 26.5% of patients consistently treated with dexrazoxane and 42.2% of patients that never received any dexrazoxane developed left ventricular systolic dysfunction. The hazard ratio was 0.55 with a 95% confidence interval of 0.36 to 0.86. There was a trend towards a worse grade of left ventricular systolic dysfunction without dexrazoxane. Some evidence pointed to recovery of systolic function, but as this was based on mean values instead of number of patients below the cut-off value it is possible that patients with good and bad values balanced each other out resulting in an adequate mean value. This can give the impression that there is no problem, while for some patients this might not be true.

    It is important to note that this was not a randomized trial, which would have provided the highest level of evidence to answer this type of question. Dexrazoxane was administered at the discretion of treating physicians. However, characteristics like sex, age, risk group, treatment arm, compliance with cardiac monitoring and follow-up were similar in both groups. Unfortunately, cumulative anthracycline dose was not reported for both groups, but it was stated that patients completed a median of 4 courses regardless of dexrazoxane exposure.

    An important question regarding any cardioprotective intervention is whether it can reduce cardiotoxicity without negative effects on anti-tumor efficacy and non-cardiac toxicities. At the moment, despite its clear cardioprotective effects, at least in adults, dexrazoxane is not routinely used in clinical practice. This might be explained by the suspicion of interference with anti-tumor efficacy and the occurrence of secondary malignancies. However, as shown in our Cochrane systematic review no significant differences between treatment groups were identified, which is in line with more recently published randomized trials.

    Studies often do not report data on anti-tumor efficacy and non-cardiac toxicities, but fortunately Getz and colleagues did. This is important as extrapolation of many of these data to other types of malignancies is difficult. Survival and relapse risk were comparable between groups. And even though this study did report on only a few non-cardiac toxicities, those that were reported were similar. Despite the relatively short follow-up period, four secondary malignancies occurred, three in the non-dexrazoxane group. This was not statistically significant different. None of the secondary malignancies was acute myeloid leukemia, but it might have been difficult to distinguish a secondary malignancy from a relapse.

    In summary, although this is not a randomized trial, this large study provides new knowledge on the use of dexrazoxane in pediatric acute myeloid leukemia patients with regard to cardiac function, anti-tumor efficacy and non-cardiac toxicities. Overall, dexrazoxane seems to be cardioprotective, at least within the relatively short follow-up period of maximal 4 years, without negative effects on anti-tumor efficacy and non-cardiac toxicities including secondary malignancies. Hopefully the authors will continue to follow these patients for long-term results. Even though this study does have limitations, it definitely adds to the knowledge of the use of dexrazoxane in children. It can help to inform the development of a much-needed evidence-based clinical practice guideline that is currently being developed by the International Late Effects of Childhood Cancer Guideline Harmonization Group.

    This concludes this JCO Podcast. Thank you for listening.


    Better Diet – Fewer Side Effects? Apr 30, 2020
    Show notes

    This podcast reviews the results of the observational study by Ladas and colleagues that found protective associations between dietary antioxidant intake and the occurrence of bacterial infections and mucositis.

    TRANSCRIPT

    This JCO podcast provides observations and commentary from the JCO article "The Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia, A Report From the DALLT Cohort" by Ladas et al.

    My name is Wendy Demark-Wahnefried, and I am Webb Endowed Chair and Professor of Nutrition Sciences at the University of Alabama at Birmingham, as well as the Associate Director for Cancer Prevention and Control at the O'Neal Comprehensive Cancer Center at UAB in Birmingham, Alabama in the United States. I do not have any relationships to disclose regarding these studies, and my review is grounded by the fact that I am a nutrition scientist with particular expertise in cancer survivorship.

    The topic of nutrition and cancer generates a great deal of interest, especially once individuals are diagnosed with cancer. This is particularly germane with regard to antioxidants, since some scientists hypothesize that high levels of antioxidants may be beneficial for cancer control while others speculate that high levels may prevent apoptosis of cancer cells and actually impede the effectiveness of cancer therapy. However data are sparse, and there are very few studies of high quality, therefore the paper by Ladas and colleagues is both timely and important.

    The study enrolled 794 children ages 1 through 18 who were diagnosed with acute lymphoblastic leukemia. These children were enrolled from 10 institutions across the continental United States, Puerto Rico, and Canada. The children or their guardians completed age appropriate food frequency questionnaires that assessed dietary intake over the previous month and did so at two time points, soon after diagnosis and after the induction phase of treatment, or roughly a month after the first questionnaire.

    The nutrients that were studied were vitamins A, C, and E, as well as alpha, beta and total carotenoids-- these are the substances in plant foods that give the food its color-- and zinc. It should be noted that the antioxidant selenium was not studied.

    Nutrient intake was statistically analyzed in relation to bacterial infection and higher grade mucositis or inflammation of the digestive tract resulting in mouth sores or ulceration of the esophagus. Nutrient intake also was studied in relation to disease-free survival and minimal residual disease. Children were followed for up to 10 years.

    Of the 513 participants who completed the dietary surveys at both time points, 23% experienced a bacterial infection, and 16% experienced higher grade mucositis. Only 9% had higher levels of minimal residual disease, and 2% did not achieve complete remission.

    Results showed that children having diets with higher levels of antioxidants had a significantly lower risk of bacterial infection, with risk lowered by 10% to 27%, depending upon the antioxidant. Similarly, children having diets with higher levels of antioxidants had a significantly lower risk of higher grade mucositis, with risk lowered by 17% to 67%, again, depending upon the antioxidant.

    Importantly, evidence of protection was only observed for nutrients obtained through the diet and not nutritional supplements. In addition, no significant associations were observed between antioxidant intake, either through diet or supplements, and disease-free survival.

    This study has several strengths, in that it involved the participation of a diverse and ample sample of several children and their parents across several sites. Furthermore, data were collected at two time points.

    As always, there are limitations, and when relying on self-reported data there is always the risk of inaccurate reporting and misclassification. In addition, and thankfully, the number of children who had higher levels of minimal residual disease or who had not experienced complete remission was very small. And therefore, the study was likely under power to detect any associations between nutrient intake and these outcomes.

    Finally, because these results emanate from an observational study, cause and effect cannot be inferred. Thus the title of this manuscript, which begins with "The Protective Effects" in quotations, may be a bit of an overstatement. So what are the implications of this study?

    As noted previously, there are few data in this area, therefore more studies are needed to either confirm or refute these results. And such research is necessary in other cancer populations, such as among adults with other cancers who receive different therapies. Until such time, these data reinforce that a healthy diet may associate with lower risk of common treatment-related toxicities.

    It is noteworthy that investigators were only able to detect protective associations from antioxidants from dietary sources and not from supplements. These data reinforce both the American Institute of Cancer Research and the American Cancer Society guidelines that recommend that nutrients be obtained from foods rather than from supplements.

    As such, both clinicians and patients may have an interest in the dietary sources of antioxidants that were studied. Many people already know that citrus fruits are rich sources of vitamin C, but there are also other fruits and vegetables, such as strawberries, cantaloupe, and mangoes, as well as tomatoes, peppers and vegetables in the cabbage family, which also contain high levels of this nutrient. Foods that are high in vitamin E include plant oils, nuts, and seeds.

    Dark green and orange vegetables, and fruits, such as spinach, broccoli, sweet potatoes, apricots, and peaches are rich sources of carotenoids, which ultimately can be converted to vitamin A. Alternatively, preformed vitamin A in the diet can be obtained from animal products such as dairy products and eggs. Finally, foods rich in zinc include shellfish, poultry, legumes-- meaning dried beans, peas, and peanuts-- and red meat.

    In sum, these data reinforce current guidelines that encourage consumption of a well-balanced plant-based diet that has ample amounts of vegetables and fruit, at least 2 and 1/2 cups a day, as well as whole grains, nuts, seeds, and legumes. Such a diet may be beneficial in preventing common treatment-related toxicities, and larger studies may be able to discern potential associations with cancer-related outcomes such as disease-free survival. However, more study is required.

    This concludes this JCO podcast. Thank you for listening.

    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.


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