In this interview, Aldoss discusses the challenges associated with implementing asparaginase-based regimens in AYA patients with ALL and shares recommendations to overcome them, which were recently established and published by a US consensus panel.

This educational resource is independently supported by Jazz Pharmaceuticals. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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In this interview, Maese discussed the main challenges faced when treating AYA patients with ALL and the difficulties associated with facilitating the implementation of asparaginase-based regimens to treat this patient population.

This educational resource is independently supported by Jazz Pharmaceuticals. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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In this interview, Stock reviews the clinical evidence and key considerations supporting this treatment approach in the AYA patient population.

This educational resource is independently supported by Jazz Pharmaceuticals. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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During his presentation, Aldoss highlighted that despite advances in multi-agent chemotherapy and novel immunotherapies allowing an increased number of patients to undergo allogeneic (allo) HSCT – a potentially curative approach in B-ALL – post-transplant relapse, as well as relapse following CAR T-cell therapy, remains a major cause of treatment failure. He discussed several studies exploring relapse-preventive measures post transplantation, including established strategies such as tyrosine kinase (TKI) maintenance in patients with Philadelphia-chromosome positive (Ph+) ALL, and newer strategies, such as the use of blinatumomab, inotuzumab ozogamicin, or prophylactic donor-derived CAR T-cell therapy, which have shown promising initial activity in patients with B-ALL. He also outlined the major considerations that influence the decision to initiate maintenance therapy after allo-HSCT or salvage therapy post-CAR T-cell therapy.

This educational resource is independently supported by Pfizer. All content was developed independently by the steering committee in collaboration with SES. Funders were allowed no influence on the content of the discussion.

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This educational resource is independently supported by Servier. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

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This educational resource is independently supported by Jazz Pharmaceuticals. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.

Hosted on Acast. See acast.com/privacy for more information.

Hosted on Acast. See acast.com/privacy for more information.

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The discussion topics included: 

• Key considerations when selecting patients: stable disease, degree of antigen expression, burden of bone marrow disease, and number of circulating tumor blasts 
• Bridging therapy and lymphodepletion considerations 
• The impact of prior exposure to blinatumomab and inotuzumab on CAR T-cell outcomes 
• Indications for the use of tisagenlecleucel in pediatric ALL  
• Indications for the use of brexucabtagene autoleucel in adult ALL

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·       What are the toxicities you encountered while treating patients with ALL and how did you manage them?

·       What are the barriers contributing to poor toxicity management?

Chapchap and Antillion discussed socioeconomic disparities in ALL across high middle-income countries (HMIC), low middle-income countries (LMIC), and within adult and pediatric populations.

Chapchap mentioned common toxicities such as infections and neutropenia, which are becoming easier to manage considering the increased access to antifungal medications, antibiotics, and preventative measures. Early and long-term neurological toxicities are also common and, although these are more challenging to manage, there are preventative measures in place, such as reducing the dose of cytarabine and methotrexate, reducing the dose in older patients, omitting the use of cranial radiation, and supportive care measures. Other adverse effects, include asparaginase-related toxicities such as thrombosis in adult patients, are generally treated with prophylactic heparins and/or avoiding fibrinogen replacement. Hypertriglyceridemia and liver toxicities are common asparaginase toxicities that are often managed by dose reductions in patients who are overweight.

Antillion discussed that febrile neutropenia and septic shock are often related to chemotherapy induction. Infection management involves the use of different types of prophylactic measures. Bleeding events also occur, which are related to a low platelet count. While patients can face asparaginase-related toxicities, the most common toxicities are severe cases of acute pancreatitis. Anthracycline-based medication can cause medium and long-term cardiac toxicities in pediatric ALL, which can impact quality of life. 

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•         Do treatment outcomes differ among race and ethnicity? Why do you think this is?

•         What are the obstacles to treatment adherence?

•         How do you sequence treatment in relapsed/refractory (R/R) B-ALL?

Chapchap and Antillion discussed socioeconomic disparities in ALL across high middle-income countries (HMIC), low middle-income countries (LMIC), and within adult and pediatric populations.

Chapchap highlighted that treatment adherence is more of a challenge in childhood versus adult ALL. Factors impacting adherence include concern among patients about the short and long-term adverse effects of treatment. Additionally, some patients misunderstand the importance of treatment adherence, and thus communication should be increased between patients and their physicians. Psychological issues amongst adolescent patients in particular can affect adherence to treatment. Social and economic barriers, such as distance from the centers and familial issues, can also cause low adherence to treatment.

Antillion mentioned the educational level of the family and language barriers as the main obstacles to treatment adherence. Treatment adherence remains particularly challenging in the adolescent population.

Across the public systems in Brazil, there is currently no access to immunotherapies for R/R B-cell ALL, though blinatumomab could be approved for early marrow relapses for children in the near future. In the private settings, there is access to blinatumomab, inotuzumab ogamacin (InO), and CD19-directed chimeric antigen receptors (CAR) T-cell therapies. Important factors in deciding the sequencing of immunotherapies include tumor burden, timing of relapse, CD19/CD20 expression, and prior regimens.

For patients who are minimal residual disease-positive with bone marrow relapses, blinatumomab could be an ideal option. For those with high tumor burden with early and/or primary refractory disease, InO would be a suitable option followed by blinatumomab or stem cell transplantation consolidation. For late relapse, cytoreductive therapy with pediatric-inspired regimens followed by blinatumomab consolidation could be an option. CAR T-cell therapies are generally reserved for post stem cell transplantation.

In Guatemala, sequencing of treatment depends on the timing of relapse, tumor burden, and whether there are new or different translocations. For standard or intermediate-risk patients with late relapse conventional chemotherapy is given. High-risk patients with early relapse are directed to other treatment options outside of Guatemala, as there is currently no access to blinatumomab, InO or CAR T-cell therapy, and in some cases patients will receive palliative and supportive care.

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•         What are the barriers to understanding the genetics of ALL? 

•         Is there a lack of MRD, cytogenetic, and molecular testing in the real-world setting?

•         Does this affect your approaches to managing patients?

Chapchap and Antillion discussed socioeconomic disparities in ALL across high middle-income countries (HMIC), low middle-income countries (LMIC), and within adult and pediatric populations.

Chapchap highlighted the lack of resources and genetic tests in Brazil, with some centers only having access to karyotyping and BCR::ABL testing. Also, the clonal heterogeneity of ALL presents challenges in diagnosis, and the literature is divided on the best molecular testing methods for assessing genetic alterations. Given that fewer cases of ALL are seen in adults, most of the genetic testing is restricted to research settings. The timing of results, which can sometimes take some months, also presents a challenge and possibly delays the timing of therapy.

Antillion echoed that there is limited access to molecular diagnostics in Guatemala, with testing only currently available for BCR::ABL, ETV::RUNX1, 4:11 and 1:11 translocations. Similarly, there is also no access to cytogenetics, though access to MRD testing has been recently available in a limited capacity. Overall, the limited access to resources and state of the art techniques as well as delays in receiving results can affect the management of patients with ALL. 

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Felice shared that the extensive diagnostic landscape in Argentina, including 25 centers focused on performing flow cytometry and flow minimal residual disease (MRD) assessments, and another 15 centers with a focus on genetic analyses presents a challenge. She highlighted the lack of human resources and training, particularly in genetic analyses, the logistical challenges in the shipping of samples, the disparities in access to diagnostic tests across the centers, and the persuasion of others about the relevance of different diagnostic testing.

Fleming echoed that convincing others about the value of specific diagnostic tests has been difficult across adult centers in Australia and has followed a sequential process over the years, first with genetic testing and more recently with the acceptance of MRD testing across all centers; although variation in diagnostic procedure exists. Overall, larger centers have widely accepted and adopted these diagnostic techniques though smaller and regional centers, with fewer cases of ALL, are gradually getting to a wider stage of acceptance. Public funding for diagnostic testing is often more difficult to acquire than funding for therapeutics and this impacts diagnosis overall.

Felice and Fleming both commented on how access to diagnostic procedures affects the management of patients locally. Felice highlighted that convincing private hospitals on accreditation of MRD testing is a difficult process compared with public hospitals due to there being fewer cases of ALL, economic issues, and lack of quality of control which affects the survival rates of patients. Smaller centers with fewer cases and/or specific regions with less access to medications and lower management of complications and toxicities in both LMICs and HMICs also affects survival rates. 

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Felice mentioned that diagnosis of non-frequent adverse events such as thrombosis, the management of infections given the differential access or incorrect use of antibiotics, and lack of nutritional care are some of the toxicity challenges faced in Argentina. A forum is underway for hematologists to discuss the best way to diagnose and treat complications of ALL.  

Fleming outlines that the management of toxicities in elderly patients is quite challenging, given higher rates of toxicity and lower tolerability; therefore, novel therapies are needed in Australia. Moreover, toxicities differ across populations, such as liver toxicities, pancreatitis, and thrombosis which are common in adults but rare in children; the literature and future protocols should recognize the key differences. Infections represent a major issue in HMICs, particularly among adult patients.  

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Felice explained that regions with a lower human development index and fewer resources for the management of diagnosis and treatment in Argentina have lower survival outcomes. In Australia, many indigenous populations may have to travel long distances for treatment, which affects survival outcomes. Fleming suggests one way to overcome these barriers and drive better outcomes is to increase communication with patients, such as employing interpreters to educate patients about the importance of adhering to therapies.

Felice talked about limited access to stem cell transplantation as a key problem in Argentina, with protocols now aiming to reduce the number of patients undergoing this procedure. Similarly, Fleming discussed ongoing efforts to reduce the need for stem cell transplantation in patients with ALL.

Globally, inequities in access to CAR T-cell therapies are common. Fleming highlighted that patients with relapsed/refractory ALL aged <25 years have access to CAR T-cell therapies in Australia but those aged >25 years have no access outside of clinical trials. Conversely, Felice mentions no active CAR T-cell studies in Argentina.

Patients in Argentina have access to blinatumomab in the frontline setting, but no access to inotuzumab ozogamicin as yet; whereas, in Australia patients have access to both blinatumomab and inotuzumab ozogamicin. 

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Cools begins by discussing his current research into the genetic components of ALL development in adults. He outlines the accumulation of mutations in patients, including heterogeneity amongst patients and developments of leukemic cell mutations post-diagnosis. Cools goes on to discuss research into the cell-of-origin and how single-cell sequencing can provide further clarity. Finally, Cools highlights some insights on the genetic profile of T-cell ALL, particularly the order in which mutations occur in disease development.

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Mullighan begins by highlighting the impact advances in genomics have had on ALL diagnosis and treatment, such as RNA sequencing. He goes into more detail about subtypes and the shortcomings of a gene panel approach for ALL. Mullighan discusses the benefits for patients, such as improved risk stratification, and optimization of novel and conventional therapies. Finally, he highlights the value in tracking clonal mutations and outlines the role of genomics in T-ALL.

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Rau begins by outlining the two main modalities with which MRD is measured, multiple parameter flow cytometry or PCR. Rau goes on to explain when to test MRD and the correlation between a poor prognosis and a higher MRD. She discusses high risk patients in ALL and the possible treatment options for patients who are still MRD positive after consolidation. Finally, Rau highlights that the future may hold further investigation into more sensitive assays, to further risk stratify patients, such as the clonoSEQ assay.

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While acute myeloid leukemia (AML) is more common than ALL in adult patients, the latter carries a much poorer prognosis with recent studies showing a 5-year overall survival rate of only 7–8% in patients with relapsed or refractory disease. Therefore, novel agents and methods for managing these patients are desperately needed.

In this podcast, Arnon Nagler discusses the results from recent clinical trials and the use of bispecific T-cell engager (BiTE) antibodies, such as blinatumomab. He also speaks about how to manage the common side effects of CAR T-cells such as neurotoxicity and cytokine release syndrome.

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In this podcast, Luskin discusses novel agent pairing with mini-hyper-CVD combinations which yield promising results and improved outcomes for older adults with ALL. She comments on studies looking at different treatment regiments with low-dose chemotherapy. For the future, Luskin anticipates another wave of novel agents that will further reduce toxicity and chemotherapy dosage in this patient group.

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Pediatric T-ALL accounts for 15% of total pediatric ALL cases. During the last 10 years, studies have focused on the deep analysis of genomic heterogeneities of T-ALL. In this podcast, Biondi discusses assessing molecular response as a predictive parameter for identifying the subgroup of patients with T-ALL with a dismal prognosis, and the constitutively active signaling pathways in pediatric T-ALL.

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In this podcast, Stutterheim discusses the prognostic value of MRD for survival outcomes at the end of consolidation in infants with ALL. She also discusses the predictive value of MRD status at the end of induction of therapy for selecting different consolidation therapies. Finally, she reports the relationship of MRD status at the end of induction with myeloid markers in the context of selecting myeloid-style therapy.

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Muffly begins by defining what a molecular relapse is, and how it can be monitored and evaluated. She goes on to discuss therapy options for molecular relapse post allogeneic stem cell transplantation, such as tyrosine kinase inhibitors, CAR T-cells, and bispecific antibodies according to Philadelphia chromosome (Ph) status and ALL lineages. Finally, Muffly talks about a recent publication looking at outcomes of secondary transplants.

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In this podcast, Schmiegelow gives an overview of the challenges clinicians face when treating AYAs with asparaginase for ALL. He elaborates on the five main toxicities related to the drug, liver dysfunction-associated parameters, hypersensitivity reactions, and clinical intolerance symptoms like vomiting, asparaginase-associated pancreatitis, pulmonary/CNS thromboembolism, and osteonecrosis. Finally, Schmiegelow discusses the findings of a study about preventing the risks and occurrence of these toxicities.

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To begin with, Curran discusses the approval of several novel agents such as CAR T-cell therapy, alemtuzumab, and blinatumomab, which have changed the treatment landscape in this field. She expands on what to consider when choosing the appropriate therapy for patients in the relapse setting, including efficacy, disease burden, toxicity, and whether the patient is a stem cell transplant candidate. Curran believes these are exciting times, with the field moving quickly forward which will lead to a better utilisation of novel agents in the future.

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Jabbour starts by outlining the reasons why older patient with ALL are challenging to treat. He then goes on to discuss two newly available antibody drugs, blinatumomab and alemtuzumab, which are more tolerable in older patient populations.

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