Journal of Clinical Oncology (JCO) Podcast

JCO After Hours: A Discussion With Abby Rosenberg and Reshma Jagsi

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

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

JCO After Hours: A Discussion With Kirsten Beyer and Jennifer Griggs

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.

Is Dose-Adjusted EPOCH-R the Optimal Treatment for Children with Primary Mediastinal B-Cell Lymphoma?

This podcast discusses the study, steroid dose reduction, practice experience, and guidance changes.   TRANSCRIPT [MUSIC PLAYING] ROBIN ZON: This JCO podcast provides observations and commentary on the JCO article-- "Do Steroids Matter: A Retrospective Review of Pre-Medication for Taxane Chemotherapy and Hypersensitivity Reactions," by Lansinger et al. My name is Dr. Robin Zon. And I am the quality oncology practice initiative lead physician for Michiana Hematology Oncology, an independent community oncology practice located in Mishawaka, Indiana. My oncologic specialty is general medical oncology. And I have a strong interest in breast cancer. This article is based on the premise that there exists significant variation regarding the prescribing practices of steroids for pre-medication to minimize the known hypersensitivity reactions associated with the taxanes paclitaxel and docetaxel. In fact, the authors remind the reader that initial clinical development of paclitaxel was delayed due to the notable hypersensitivity rate of 25% to 30%, as patients did not receive pre-medication. Subsequent trials used a pre-medication strategy of dexamethasone, diphenhydramine, and H2 antagonist, with a reduction of the reaction occurrence to 2% to 3%. As a result of the improved reaction rates in clinical trials with the use of a pre-medication regimen, both paclitaxel and docetaxel, FDA approved package inserts recommend oral corticosteroid pre-medication, 20 milligrams, 12 and 6 hours prior to the taxane administration. However, there has been no dose optimization to date. In fact, the authors note that lower dose regimens are routinely used in daily practice and may lead to increased risk of hypersensitivity reactions. Furthermore, steroids can cause multiple adverse effects if taken for extended periods of time, which can range from mild to moderate in their severity. This study reviewed steroid prescribing patterns in patients receiving the first dose of paclitaxel or docetaxel at Stanford Cancer Institute between 2010 and 2020. A total of 3,181 patients met criteria for analysis, with an 8.3% rate of hypersensitivity reactions. And the adjusted multivariate analysis, the authors found no correlation between the hypersensitivity reaction rate or the severity among the variables evaluated, except for the gynecology/oncology clinic patients who had an increased risk for hypersensitivity reactions overall with a hazard ratio of 1.34 and high grade hypersensitivity reactions with a hazard ratio of 2.34, and female patients who had a higher rate of hypersensitivity reactions overall with a hazard ratio of 1.26, but not high grade hypersensitivity reactions. The conclusion of the article is that neither dexamethasone dose nor route, IV or oral, correlated with subsequent hypersensitivity reactions. And that the recommended 40 milligrams dose of dexamethasone prior to taxane administration is no better than the 10 milligrams dose for protecting against hypersensitivity reactions. Therefore, the lower doses used in clinical practice is acceptable and even preferable to higher doses. Although the study authors point out that the strength of the study is the large data set reviewed, they also point out that this study was a retrospective analysis completed on first dose dexamethasone use and not on subsequent taxane exposures Additionally, the authors also point out that since there was no external validity, the results may not be generalizable to other patient populations treated at other institutions. For the remainder of this podcast, the commentary represents my opinion only and may not represent the opinion of this journal or its editors. First, I would like to commend the authors on this analysis, which addresses a very practical question-- do steroids matter. And is it possible to safely vary from the package insert? The work dedicated to collecting this data set does not go unnoticed. As the authors acknowledge, the prescribing practice patterns for steroid pre-medication does vary considerably across and within practices. Furthermore, the common references that practices use for treatment guidance, including NCCN and UpToDate, describe differing options. For example, the NCCN order template for weekly paclitaxel refers to using pre-medication of H2 blocker plus diphenhydramine and dexamethasone 10 milligrams IV with weekly doses, one to three, then may consider dose reduction of dexamethasone to 4 milligrams with weekly dose 4, and does not elaborate on further dose reduction. For Q2 or three-week paclitaxel dosing, the NCCN template follows the package insert. UpToDate also recommends 20 milligrams of dexamethasone orally 12 and 6 hours prior to drug administration with H1 and H2 receptor antagonists as a pre-medication regimen for Q2 or three-week treatment. However, for weekly paclitaxel, UpToDate offers consideration of a dexamethasone dose of 10 milligrams IV with H1 and H2 blockers, then tapering the glucocorticoid by 2 milligrams decrements after weekly dose 3 or 4, and can even discontinue the dexamethasone in patients without infusion reactions. For docetaxel, UpToDate suggests dexamethasone 8 milligrams orally BID for three days. To further confirm the practical world of dexamethasone pre-medication variability, in a straw poll within our practice and outside our practice, many providers do utilize the 10 milligrams dexamethasone dose for the first dose of Q2 or three-week taxanes, and reduce and then eliminate dexamethasone for weekly taxanes when feasible and have done so for many years, while other providers strictly follow FDA labeling. Importantly the reason providers are willing to de-escalate the pre-treatment medications for taxanes is that patients have less side effects and are grateful to have this drug reduced or even eliminated from their treatment. So the question asked and the knowledge generated by the study becomes extremely relevant as providers consider ways to de-escalate interventions, especially if patient outcomes are not placed at risk and quality of life can be improved. The next question relates to the authors' concern of lacking external validity and generalizability to other patient populations. In my opinion, it would not be feasible to conduct this labor-intensive data set collection and analysis at a multitude of independent community and academic sites. However, this could be an opportunity to query real world data platforms, such as ASCO's CancerLinQ, to look for steroid complications such as grade 3 and grade 4 events related to change in pre-medication strategies. But even real world databases may have limits based on the specificity of the query and the inadequate capture of adverse events, especially less severe toxicities, as this structure data may not be recorded in the electronic medical record. Finally, the most relevant question is whether practice and guidelines should change as a result of this data. As I have discussed, many practices have already made this initial dose modification, and even safely dose reduced beyond the scope of this data set inquiry. Therefore, I do think that initial dosing as suggested by this study should be more widely guideline adopted and that consideration for further reduction with additional taxane doses be based on practice-specific experience and guidelines. 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.

Steroid Dose and Taxanes

Improving care in vulvar cancer via the prospective Vulvar GROINSS VII study   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients with Micrometastases in the Sentinel Node: Results of GROINSS-V II” by Oonk et al. My name is David Gaffney, and I am a professor and Vice Chair of Radiation Oncology at the University of Utah. I am also Senior Director for Clinical Research at the Huntsman Cancer Institute in Salt Lake City, Utah. My oncologic specialty is radiation oncology. I have no relevant disclosures to this study. The GROINS VII study is the successor trial of the GROINS V I trial. In the GROINSS-V I study, the authors demonstrated that omission of an inguinal femoral lymphadenectomy was safe in patients with a negative sentinel lymph node with an isolated GROIN recurrence rate of 2.3%. It also showed that with long term follow up a significant proportion of patients will recur. At 10 years local recurrence occurred in 39.5% of all patients. Although local recurrences are treated with curative intent, the disease-specific survival of these patients decreases significantly. It is important to ask if there is a dose response to radiotherapy in vulvar cancer?  GOG 101 was published in 1998 and employed a split course of radiotherapy to a dose of 47.6 Gy with concurrent cisplatin and 5-FU. The complete response rate was 46.5%. The subsequent prospective phase II randomized trial, GOG 205, was published in 2012 and employed 10 Gy more of radiotherapy with weekly cisplatin to a total dose of 57.6 Gy. This study demonstrated a 78% pathologic complete response rate. Hence, by adding 10 Gy, the complete response rate increased by 30%, indicating a steep dose response. Also, by way of background, a retrospective study from MD Anderson by Stecklein et al. published in 2018 demonstrated a 3-year actuarial groin control rate of 83% with high dose conformal radiotherapy with a median dose of 66 Gy to grossly positive nodes. These data demonstrate that radiotherapy can sterilize gross disease in select circumstances.   The GROINSS-V II study was a phase II prospective study in a rare disease, and sought to answer whether radiotherapy to 50 Gy could be an effective and less morbid alternative to inguinofemoral lymphadenctomy   Patients were accrued from 59 hospitals in 11 countries. Eligibility for this study were patients with tumors less than 4 cm, with  negative groin nodes on preoperative CT, MRI, or ultrasound. The primary endpoint was a groin recurrence rate at 24 months. A combined technique was used to evaluate the sentinel lymph node of lymphoscintigram and blue dye. Bilateral sentinel lymph node procedures were required for midline lesions. The radiotherapy was 50 Gy in 25-28 fractions with the field size to extend to the bottom of the SI joints, including the distal external iliac lymph nodes. Greater than 1700 patients were registered. One hundred sixty patients were found to have micrometastases, that is disease less than 2 mm, whereas 162 patients were found to have macrometastases. The median size vulvar lesion for patients with negative sentinel lymph node was 18 mm, 23 mm for patients with micrometastases, and 25 mm for patients with macrometastases.   Results at 2 years demonstrated an isolated groin recurrence rate occurred in 1.6% of patients that were treated per protocol with micrometastases. Whereas patients with macrometastases had an isolated groin recurrence rate at 2 years of 12.2%. For patients with macrometastases treated with radiotherapy, the groin recurrence rate was 22%. Whereas groin failure was 6.9% for patients who had macrometastases treated with inguinal femoral lymphadenectomy and radiotherapy. For patients with macrometastases, no groin recurrences were observed in 7 patients treated with chemoradiotherapy. Among the 1213 patients with a negative sentinel lymph node, an isolated groin recurrence occurred in 31 patients for a rate of 2.7% at 2 years. For the 56 patients who suffered a groin recurrence, 31 of them died of vulvar cancer for an overall survival rate of 39% at 2 years.   This trial also looked at morbidity of patients treated with inguinal femoral lymphadenectomy versus sentinel lymph node procedure plus radiotherapy. The lower extremity edema rate was 32% at 6 months versus half of that for patients treated with the sentinel lymph node procedure plus radiotherapy. It should be noted that IMRT was utilized in 19% of cases, and chemotherapy was utilized in 12% of cases.   This trial clearly demonstrated that in patients with a macrometastasis or disease greater than 2 mm within a groin node, radiotherapy is not a safe alternative to inguinal femoral lymphadenectomy due to a higher rate of groin recurrence, albeit there was no difference in disease-specific survival.   Management of patients with vulvar cancer is complex. Clinicians need to control the ipsilateral and the contralateral groin. The GROINSS-V II study gives us data on contralateral groin failures also. Overall, there was a very low rate of contralateral groin failure.   The subsequent study GROINSS-V III will evaluate patients with macrometastases and compare inguinal femoral lymphadenectomy versus chemoradiotherapy with weekly cisplatin and an elevated dose of radiotherapy to the groin with 56 Gy utilizing a simultaneous integrated boost technique. It will be quite interesting in years to come to discern if IMRT with more precise daily imaging and dose escalation together with chemotherapy will improve local regional control. Additionally, there may be select populations of node positive patients where intensification of chemotherapy, radiotherapy, or more extensive surgery may be useful. McAlpine and colleagues have demonstrated that cases of HPV-negative vulvar cancers had a markedly inferior survival rate with a hazard ratio of 0.35. It is also hoped that advance radiotherapy techniques such as IMRT will decrease longstanding morbidity such as lymphedema. The GOG prospective study 244 demonstrated no increase in lymphedema in gynecologic cancer patients where radiotherapy was added compared to surgery alone.   The study by Oonk et al. is a remarkable effort in a rare disease demonstrating that patients with micromets can be safely treated with 50 Gy and patients with macromets should be treated with an inguinal femoral lymphadenectomy. It will be very interesting to see if chemoradiotherapy with increased dose can improve local-regional control and provide a high quality of life for patients with macro mets in the GROINS VIII trial.    This concludes this JCO Podcast. Thank you for listening.

Commentary on GROINSS VII

Dr. Lindsay Morton of the National Cancer Institute at the National Institutes of Health reflects on research findings by Øvlisen et al that leverage large-scale linked registries in Denmark to suggest that improvements in both chemotherapy treatments and assisted reproductive technologies have made it possible for more survivors of Hodgkin lymphoma to become parents.   TRANSCRIPT This JCO podcast provides observations and commentary on the JCO article “Rates and Use of Assisted Reproduction Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study of 793 Patients and 3965 Matched Comparators” by Øvlisen and colleagues. My name is Lindsay Morton, and I am a Senior Investigator and Deputy Chief of the Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, at the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. I am trained in epidemiology, and my oncologic specialty is in hematologic malignancies and cancer survivorship research. I have no relevant conflicts to disclose. The adverse effects of treatment among patients with Hodgkin lymphoma have long been at the forefront of oncology research. In the late 1960s, patients with Hodgkin lymphoma were some of the first to receive combination chemotherapy with a four-drug regimen called “MOPP,” consisting of mechlorethamine, vincristine, procarbazine, and prednisone. MOPP resulted in dramatic improvements in patient outcomes following diagnosis with Hodgkin lymphoma. But in subsequent decades, the toxicities of MOPP came to be understood, including both acute toxicities – most notably myelosuppression – as well as longer-term toxicities such as second cancers and sterility, especially in males. Around the same timeframe, long-term toxicities of radiotherapy also were increasingly recognized, which set off a search for effective Hodgkin lymphoma treatment approaches with fewer short- and long-term toxicities. I often think of how research on adverse effects in patients with Hodgkin lymphoma has been at the vanguard in cancer survivorship: this focus has helped to drive development of new therapies and changes in clinical practice. This has occurred in part because Hodgkin lymphoma is frequently diagnosed in early adulthood and patients now have such a good prognosis; this means there is a longer window in which to experience any long-term effects of cancer treatments, and patients face unique issues, such as impacts on fertility, which aren’t relevant for older cancer patients. In the paper accompanying this podcast, Øvlisen and colleagues present novel data on parenthood rates and use of assisted reproduction techniques in Danish patients with Hodgkin lymphoma. Importantly, the results of this study are very relevant to current patients because all the patients in the study were treated between 2000 and 2015 using standard treatment approaches that are still frequently used today. About one-third of the study population received radiotherapy plus 2-4 cycles of the combination chemotherapy regimen called “ABVD,” which consists of doxorubicin, bleomycin, vinblastine, and dacarbazine, and is the preferred front-line therapy approach for Hodgkin lymphoma patients in the United States. Another third of the study population received 6-8 cycles of ABVD, while in the remaining third, about half received either “BEACOPP” (a seven-drug regimen, which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, and which is commonly used in Europe) or some other chemotherapy regimen. In this study, the authors compared the rates of parenthood in patients with Hodgkin lymphoma to individuals in the general population who were matched to the patients by age, sex, and parenthood status. Overall, the news was good: both male and female survivors of Hodgkin lymphoma had similar parenthood rates as the matched individuals from the general population. But the details of this bigger picture finding are really worth understanding because of their important impact on patients. In particular, a larger number of patients with Hodgkin lymphoma than the comparison individuals from the general population used assisted reproductive technology in order to become parents. Specifically, nearly 22% of male and 14% of female survivors of Hodgkin lymphoma used assisted reproductive technology compared with only about 6% of those in the general population. When the authors looked at various predictors of parenthood in subgroup analyses, one other finding stood out: male survivors of Hodgkin lymphoma who had received BEACOPP therapy had about half the rate of parenthood compared with other Hodgkin lymphoma survivors and the general population. In contrast, for female survivors, parenthood rates were similar among the different treatment groups, but the numbers of female survivors treated with BEACOPP was small, so we should be cautious about drawing conclusions for females. The results from Øvlisen and colleagues seem to reflect two important changes from previous studies, most of which included patients who were treated with older chemotherapy regimens, like MOPP. First, Hodgkin lymphoma treatments have continued to evolve, and adverse effects on fertility seem to be declining for the newer regimens. Second, of course, there also have been important advances in assisted reproductive technology, so that individuals who have trouble with conception initially can be helped by these technological advances. In addition to hearing this good news for patients with Hodgkin lymphoma, the way the authors collected the information for this study was also exciting because it was large-scale, long-term, and systematic. Most of the data on fertility in patients with Hodgkin lymphoma previously has come from clinical trials. Those data have been invaluable, and in fact, provided some of the first signs several decades ago that patients with Hodgkin lymphoma treated with MOPP could face fertility issues. But we also know that clinical trials often have incomplete information on outcomes that occur more than a few years out, which raises some questions about the validity or generalizability of the study results for those outcomes. In this report, the authors collected information on patients with Hodgkin lymphoma and the matched individuals from the general population from nationwide birth and patient registries. In countries like the United States, this study design would be virtually impossible because our healthcare system is fragmented – patients receive different types of care, like their cancer treatment and fertility treatments, in different places, and there is no easy way to link information on these different types of care for a specific individual. In this Danish study, the authors were able to leverage the centralized nature of the healthcare system in Denmark to capture not only all the information on the Hodgkin lymphoma treatments but also the birth registries and use of assisted reproductive techniques – connecting this information from different sources for all the individuals in the study. Because of the linkages that are possible among all these different sources of data, we are confident that the study provides complete, unbiased information even on longer-term outcomes. While this study demonstrates both the importance of long-term patient follow-up and the power of registries, it also highlights the need to continue efforts to reduce toxicities and improve outcomes in patients with Hodgkin lymphoma, particularly those diagnosed in childhood, adolescence, or young adulthood. Fertility is just one aspect of quality of life that may be impacted by cancer treatment, and the more high-quality data we bring to bear on cancer survivorship, the better we will be at not just treating cancer but also taking care of the whole patient for the many years they have ahead of them. This concludes this JCO Podcast. Thank you for listening.

Harnessing the Power of Registries to Understand the Impact of Treatment for Hodgkin Lymphoma on Fertility

This podcast describes the findings from a population-based retrospective decedent cohort study which suggest that palliative care involvement may be associated with a decreased need for high intensity of care during the final weeks of life in adolescents and young adults with cancer.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Impact of Palliative Care Involvement on End-of-Life Care Patterns Among Adolescents and Young Adults with Cancer: A Population-Based Cohort Study” by Kassam et al. My name is Erica Kaye, and I am Director of the Quality of Life and Palliative Care Research Division at St. Jude Children’s Research Hospital in Memphis, Tennessee, USA. My oncologic specialty is pediatric palliative oncology. In this paper, the authors aim to evaluate the prevalence and predictors of high-intensity end-of-life care in adolescents and young adults with cancer in Ontario, Canada, as well as assess the impact of palliative care involvement on intensity of care received at end of life. This topic is timely and important. Growing evidence demonstrates that adolescents and young adults with cancer, defined by the National Cancer Institute as patients diagnosed between the ages of 15 and 39, face a unique set of circumstances that may adversely impact their end-of-life experiences. Several single-institution studies in the U.S. have suggested that adolescents and young adults with advanced cancer disproportionately receive high intensity medical care in their final month of life compared to children or older adults, and these findings recently have been replicated in population-level studies in California and New York. These observations raise concerns about exposure of a vulnerable population to toxicity from high intensity care at a time when such interventions are less likely to offer meaningful benefit. However, these studies had several notable limitations: some involved only insured patients; others presented data only from inpatient end-of-life care; and none evaluated the impact of palliative care provision on the intensity of end-of-life care for adolescents and young adults with cancer. Moreover, findings from U.S.-centric data sets may not be generalizable to other countries. In this study, the authors assembled a retrospective decedent cohort of adolescents and young adults with cancer who died between 2000 and 2017 in Ontario, Canada using a provincial registry linked to population-based health-care data. Predicated on previously published validated metrics, they used a primary composite measure for high-intensity end-of-life care that included receipt of intravenous chemotherapy less than 14 days from death; more than one emergency department visit; and more than one hospitalization or intensive care unit admission less than 30 days from death. Secondary outcomes included measures of the most intensive end-of-life care, such as intensive care unit admission within 30 days of death, mechanical ventilation within 14 days of death, and death in the ICU, as well as palliative care physician involvement. Predictors of outcomes were determined using regression models. In a cohort of more than 7,000 adolescents and young adults with cancer across Ontario, authors found that approximately 44% experienced high-intensity end-of-life care – double the rate for adults and slightly higher than the rate for children in the region. This percentage is lower than that seen in single-site and population-level studies in the U.S., however lack of consistently defined high-intensity end-of-life indicators for adolescents and young adults with cancer make it challenging to compare findings across studies. Importantly, adolescents and young adults with hematologic malignancies were at highest risk for receipt of high-intensity care at the end of life in Ontario, affirming findings seen across pediatric and adult populations in different countries. Some hypothesize that unique pathologies specific to hematologic malignancies may increase the risk of experiencing higher intensity end-of-life care. For example, a patient with refractory leukemia often requires frequent blood transfusions to prolong life and optimize quality time; this can be challenging to coordinate in the outpatient setting and may necessitate inpatient hospitalizations at the end of life. In both the U.S. and Canada, continuation of transfusion support often precludes hospice enrollment, further preventing patients from receipt of subspecialty palliative care in the home. In this context, legislation to support concurrent provision of palliative and hospice care with cancer-directed therapy may have the potential to mitigate high-intensity end-of-life experiences for this vulnerable patient population. This study also found that palliative care physician involvement substantially reduced the odds of adolescents and young adults with cancer receiving high-intensity end-of-life care, including the most intensive experiences such as mechanical ventilation and dying in the intensive care unit. Palliative care physicians may lessen intensity of end-of-life care by promoting conversations about goals of care and advance care planning, coordinating complex medical care in the community, and providing real-time symptom management to decrease emergency visits or hospitalizations. However, further research is needed to explore these hypotheses. Ultimately, this study provides compelling evidence that palliative care involvement may lessen the risk of high-intensity end-of-life care in adolescents and adults with cancer. Unfortunately, universal access to subspecialty palliative care remains challenging, particularly in rural regions. Disparities in access to hospice and palliative care services for racialized communities remain deeply problematic as well. This study supports the need for institutional and regional programs and policies to provide equitable access to palliative care for adolescents and adults with cancer. Strengths of this study include its population-level design, large health services dataset, and use of relatively standardized indicators for defining high-intensity end-of-life care. Study limitations include its retrospective design, which inherently precludes causal inference. Additionally, involvement of a palliative care physician was used as a proxy for integration of subspecialty palliative care; however, subspecialty palliative care is an interdisciplinary field in which care may be provided by non-physicians, and the study did not account for this phenomenon.   Lastly, the study is predicated on certain assumptions about the negative ramifications of high-intensity end-of-life care. Notably, certain experiences categorized as high-intensity care, such as more than one hospitalization during the final month of life, may not be experienced as high-intensity or burdensome by patients or families. An adolescent patient may wish to be hospitalized on multiple occasions to optimize comfort at the end of life. Or a family may request hospitalization for respite, or to protect siblings from seeing suffering at end of life. Although technically high-intensity, these interventions also may represent goal-concordant comfort care, and further research is needed to determine best practices for optimizing care that aligns with the goals of adolescents and young adults at end of life. This concludes this JCO Podcast. Thank you for listening.

Subspecialty Palliative Care Involvement May Lessen the Need for High-Intensity End-of-Life Care for Adolescents and Young Adults With Cancer

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. 

Can the Incorporation of Minimal Residual Disease Detection Enhance Post-CAR T Outcomes in Patients With Large B-Cell Lymphoma?

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.

Moving Forward With Venetoclax-Based Combinations in Younger Adults With Acute Myeloid Leukemia

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. 

A Deep Dive Into HLA Typing For Unrelated Donor Hematopoietic Cell Transplantation

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.

PENELOPE-B: Exploration of CDK4/6 Inhibition in the Adjuvant Setting

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.

ctDNA in DLBCL: A Blueprint for Better Clinical Trials?

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.

How Can We Expand Eligibility Criteria for Diffuse Large B-Cell Lymphoma Clinical Trials to Serve More Patients?

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.  

The Pathologist, the Surgeon, and the Rare Phyllodes Tumor

The Journal of Clinical Oncology (JCO) serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. Usually presented in conjunction with an original report and an editorial published on www.jco.org, the JCO podcasts enable readers to stay current on the latest research while placing the results into a clinically useful context.

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Journal of Clinical Oncology (JCO) Podcast

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