CAR T-cells in Pediatric ALL

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CAR T-cells in Pediatric ALL

ASCO eLearning Podcasts

Dr. Stephen Hunger is a Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. In today's ASCO eLearning Podcast, Dr. Hunger will discuss two patient cases related to CAR T-cell therapy. While the two cases are similar, the recommended treatments can be different. We hope you enjoy this episode. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts or Google Play. We truly value your feedback, so please leave a review. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org.

Transcription: 

The purpose of this podcast is to educate and inform. This is not a substitute for 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.

Hi, my name is Stephen Hunger. I'm a professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania, and chief of the Division of Oncology and director of the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia. My career has focused on clinical, translational, and basic research regarding childhood Acute Lymphoblastic Leukemia, or ALL.

One of the most exciting recent advances in cancer medicine is the development of Chimeric Antigen Receptor-redirected, or CAR-T cell therapy for relapsed in refractory pediatric B cell ALL. Today, I will present two cases that have similarities, but also important differences that highlight key questions and uncertainties regarding when and how to use CAR T cells in pediatric ALL.

Currently the only CAR T cell product FDA approved for treatment of children and young adults up to age 25 with relapsed refractory ALL is tisagenlecleucel, trade name Kymriah. Additional CAR T cell products are in the late stages of testing, and will likely become FDA approved soon. My discussion today will focus on tisagenlecleucel, which can persist for years following therapy. Indeed, the first child treated at CHOP for ALL with CAR T cells in 2012 still has detectable CAR T cells over eight years later.

Our first patient is Sue, who is currently 15 years old and has B-ALL that relapsed for the second time. She was first diagnosed at age 7, at which time she had an 80,000 white blood cell count. She was treated with standard chemotherapy with an excellent response, but relapsed during maintenance therapy 22 months following her diagnosis. Because this relapse occurred on therapy, she was considered high risk, and allogeneic transplant was considered the therapy of choice.

She entered a second remission and became MRD negative after two cycles of consolidation therapy. Her brother was HLA identical, and she underwent a matched sibling transplant in MRD negative second remission following a cyclophosphamide mind plus total body radiation preparative regimen. She engrafted rapidly, had no GBHD, and was weaned off immunosuppression by six months post-transplant. One year post-transplant, she presented with bone pain and was found to have a second bone marrow relapse of B-ALL. Her leukemia cells were CD19 positive.

Our second patient is 15-year-old Damian, who was diagnosed with CD19 positive B cell ALL four months ago. His initial white blood cell count was 80,000, and the cytogenetic and molecular studies did not show any known high or low-risk features or targetable lesions. He was treated with standard chemotherapy, but did not enter remission with 50% blasts at the end of four weeks of induction therapy. He received one month of consolidation chemotherapy with a Children's Oncology Group augmented BFM regimen, but still had 35% blasts after that therapy.

He then received a four-week course of the CD3/CD19 BiTE blinatumomab, but again had 30% blasts at the end of that therapy. The blasts remained strongly CD19 positive. His 17-year-old sister is fully HLA matched.

Both of these patients have relapsed refractory ALL, and meet the FDA approved indication for tisagenlecleucel, which is patients up to 25 years of age with B cell precursor ALL that is refractory or in second or later relapse. Sue is in her second relapse, and thus qualifies. Refractory is not defined precisely in the indication, but I think all would classify Damian as having refractory ALL, given that he has failed to enter remission with three different regimens.

The pivotal trial that led to the approval of tisagenlecleucel was called ELIANA, and the results were published in the New England Journal of Medicine in 2018, with my colleague Shannon Maude being the first author. Of note, that study prohibited patients who had received prior CD19-directed therapy, so Damian would not have been eligible to enroll. However, the FDA label does not mention this, and many patients have been treated with tisagenlecleucel following earlier blinatumomab therapy.

Thus, Sue and Damian are good candidates for tisagenlecleucel. Both are also medically in good condition without active infection or end organ dysfunction. There are also important differences between Sue and Damien. Sue has relapsed post-transplant while Damien has an HLA-matched sibling, but has never undergone transplant because he has never entered remission. Transplant with high level marrow disease, as he has currently, 30% blasts, is generally viewed futile, and the best transplant outcomes occur when patients are MRD negative immediately pre-transplant.

A key current question in therapy of relapsed refractory ALL is whether CAR T cells should be used as a definitive therapy with responders receiving no subsequent antileukemia treatment, or as a so-called bridge to transplant, a means to get patients to an MRD negative state so that they can then undergo transplant as definitive therapy. There is no current definitive answer to this question, and these two cases help to highlight the issues to consider.

Both Sue and Damian undergo T cell apheresis with a good collection. Cells are sent to the manufacturer to make the CAR T cells, a process that takes about four weeks. They receive low-intensity maintenance therapy for two weeks with adequate disease control, and then no therapy is given for two weeks. Both have adequate manufacture of CAR T cells, and then receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR T cell infusion. Both patients have mild signs of cytokine release syndrome not requiring intervention.

At day 30 post-infusion, both Sue and Damian are in an MRD negative complete remission and have no detectable circulating B cells. What should happen next? While some feel that the long-term efficacy of CAR T cells have not yet been established, and that transplant should be used as a consolidative therapy in almost all cases, many others believe that a long-lasting CAR T cell product such as tisagenlecleucel can be used as definitive therapy in some cases.

In the initial ELIANA publication, 81% of the 75 relapsed refractory ALL patients infused with tisagenlecleucel obtained in MRD negative complete remission within three months, usually after one month. And the 12-month event-free survival and overall survival rates were 50% and 76%. More mature survival data from ELIANA shows a two-year relapse-free survival rate of 61% among those achieving remission. Like Sue and Damian, the patients in this trial were heavily pretreated with a median of three prior regimens and 61% had previously undergone transplant.

Knowing that many patients can survive long term with no further therapy post-CAR T cell infusion, there is limited enthusiasm for a second transplant among physicians, patients, or their parents if a good response is obtained and maintained. So for Sue, I would recommend close monitoring, but no additional therapy as long as she showed continued evidence of response for 6 to 12 months.

I would repeat bone marrow MRD testing at 60 and 90 days and every three months thereafter, and measure peripheral blood B cell numbers monthly for at least six months. B cell depletion is a good surrogate for CAR T cell activity, as normal CD19 positive cells are also killed. If Sue remains MRD negative and has no circulating CD19 positive B cells for at least six months, then there is a good hope that no more therapy is needed.

Damian is a more complicated case, as he has never undergone transplant and has an HLA-identical donor, and now has excellent disease control and is in good medical condition to undergo a transplant. There are short-term risks of transplant with a 100-day mortality risk of 5% to 10% for a teenager. And there are also long-term risks related to the transplant procedure and/or graft versus host disease.

The long-term risks of tisagenlecleucel appear limited other than the persistent B cell depletion, but the longest followup is only eight years, and few patients have more than five years of followup. So we have no idea about the efficacy and potential risks 10 to 20 or more years post-infusion.

Damian failed three induction attempts. If his leukemia comes back, one may never be able to get him back into a healthy MRD negative remission. So there is a good argument that his best chance for definitive therapy is with transplant. Given this, many would strongly recommend transplant as consolidative chemotherapy for Damian. However, it's also possible that Damian has now received curative therapy and will never relapse.

Highlighting the uncertainty surrounding this question, our group at CHOP, which has treated over 300 patients with relapsed refractory ALL with CAR T cells, does not have a clear consensus on what to do for patients like Damian. It's our practice to summarize the potential advantages and disadvantages of transplant versus no further therapy, and help the patient and their family decide what is the best course for them.

To summarize, tisagenlecleucel is an exciting therapy that provides new opportunities for children and young adults with relapsed and refractory ALL. However, the field of cellular immunotherapy is young, and there are many uncertainties, particularly surrounding the issue of definitive therapy versus bridge to transplant. Today, we lack the followup data needed to make definitive statements, and patients and families need to understand that and be full partners in these complicated decisions. Thank you very much for listening.

Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

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Dr. Stephen Hunger is a Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. In today's ASCO eLearning Podcast, Dr. Hunger will discuss two patient cases related to CAR T-cell therapy. While the two cases are similar, the recommended treatments can be different. We hope you enjoy this episode. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts or Google Play. We truly value your feedback, so please leave a review. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org.

Transcription: 

The purpose of this podcast is to educate and inform. This is not a substitute for 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.

Hi, my name is Stephen Hunger. I'm a professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania, and chief of the Division of Oncology and director of the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia. My career has focused on clinical, translational, and basic research regarding childhood Acute Lymphoblastic Leukemia, or ALL.

One of the most exciting recent advances in cancer medicine is the development of Chimeric Antigen Receptor-redirected, or CAR-T cell therapy for relapsed in refractory pediatric B cell ALL. Today, I will present two cases that have similarities, but also important differences that highlight key questions and uncertainties regarding when and how to use CAR T cells in pediatric ALL.

Currently the only CAR T cell product FDA approved for treatment of children and young adults up to age 25 with relapsed refractory ALL is tisagenlecleucel, trade name Kymriah. Additional CAR T cell products are in the late stages of testing, and will likely become FDA approved soon. My discussion today will focus on tisagenlecleucel, which can persist for years following therapy. Indeed, the first child treated at CHOP for ALL with CAR T cells in 2012 still has detectable CAR T cells over eight years later.

Our first patient is Sue, who is currently 15 years old and has B-ALL that relapsed for the second time. She was first diagnosed at age 7, at which time she had an 80,000 white blood cell count. She was treated with standard chemotherapy with an excellent response, but relapsed during maintenance therapy 22 months following her diagnosis. Because this relapse occurred on therapy, she was considered high risk, and allogeneic transplant was considered the therapy of choice.

She entered a second remission and became MRD negative after two cycles of consolidation therapy. Her brother was HLA identical, and she underwent a matched sibling transplant in MRD negative second remission following a cyclophosphamide mind plus total body radiation preparative regimen. She engrafted rapidly, had no GBHD, and was weaned off immunosuppression by six months post-transplant. One year post-transplant, she presented with bone pain and was found to have a second bone marrow relapse of B-ALL. Her leukemia cells were CD19 positive.

Our second patient is 15-year-old Damian, who was diagnosed with CD19 positive B cell ALL four months ago. His initial white blood cell count was 80,000, and the cytogenetic and molecular studies did not show any known high or low-risk features or targetable lesions. He was treated with standard chemotherapy, but did not enter remission with 50% blasts at the end of four weeks of induction therapy. He received one month of consolidation chemotherapy with a Children's Oncology Group augmented BFM regimen, but still had 35% blasts after that therapy.

He then received a four-week course of the CD3/CD19 BiTE blinatumomab, but again had 30% blasts at the end of that therapy. The blasts remained strongly CD19 positive. His 17-year-old sister is fully HLA matched.

Both of these patients have relapsed refractory ALL, and meet the FDA approved indication for tisagenlecleucel, which is patients up to 25 years of age with B cell precursor ALL that is refractory or in second or later relapse. Sue is in her second relapse, and thus qualifies. Refractory is not defined precisely in the indication, but I think all would classify Damian as having refractory ALL, given that he has failed to enter remission with three different regimens.

The pivotal trial that led to the approval of tisagenlecleucel was called ELIANA, and the results were published in the New England Journal of Medicine in 2018, with my colleague Shannon Maude being the first author. Of note, that study prohibited patients who had received prior CD19-directed therapy, so Damian would not have been eligible to enroll. However, the FDA label does not mention this, and many patients have been treated with tisagenlecleucel following earlier blinatumomab therapy.

Thus, Sue and Damian are good candidates for tisagenlecleucel. Both are also medically in good condition without active infection or end organ dysfunction. There are also important differences between Sue and Damien. Sue has relapsed post-transplant while Damien has an HLA-matched sibling, but has never undergone transplant because he has never entered remission. Transplant with high level marrow disease, as he has currently, 30% blasts, is generally viewed futile, and the best transplant outcomes occur when patients are MRD negative immediately pre-transplant.

A key current question in therapy of relapsed refractory ALL is whether CAR T cells should be used as a definitive therapy with responders receiving no subsequent antileukemia treatment, or as a so-called bridge to transplant, a means to get patients to an MRD negative state so that they can then undergo transplant as definitive therapy. There is no current definitive answer to this question, and these two cases help to highlight the issues to consider.

Both Sue and Damian undergo T cell apheresis with a good collection. Cells are sent to the manufacturer to make the CAR T cells, a process that takes about four weeks. They receive low-intensity maintenance therapy for two weeks with adequate disease control, and then no therapy is given for two weeks. Both have adequate manufacture of CAR T cells, and then receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR T cell infusion. Both patients have mild signs of cytokine release syndrome not requiring intervention.

At day 30 post-infusion, both Sue and Damian are in an MRD negative complete remission and have no detectable circulating B cells. What should happen next? While some feel that the long-term efficacy of CAR T cells have not yet been established, and that transplant should be used as a consolidative therapy in almost all cases, many others believe that a long-lasting CAR T cell product such as tisagenlecleucel can be used as definitive therapy in some cases.

In the initial ELIANA publication, 81% of the 75 relapsed refractory ALL patients infused with tisagenlecleucel obtained in MRD negative complete remission within three months, usually after one month. And the 12-month event-free survival and overall survival rates were 50% and 76%. More mature survival data from ELIANA shows a two-year relapse-free survival rate of 61% among those achieving remission. Like Sue and Damian, the patients in this trial were heavily pretreated with a median of three prior regimens and 61% had previously undergone transplant.

Knowing that many patients can survive long term with no further therapy post-CAR T cell infusion, there is limited enthusiasm for a second transplant among physicians, patients, or their parents if a good response is obtained and maintained. So for Sue, I would recommend close monitoring, but no additional therapy as long as she showed continued evidence of response for 6 to 12 months.

I would repeat bone marrow MRD testing at 60 and 90 days and every three months thereafter, and measure peripheral blood B cell numbers monthly for at least six months. B cell depletion is a good surrogate for CAR T cell activity, as normal CD19 positive cells are also killed. If Sue remains MRD negative and has no circulating CD19 positive B cells for at least six months, then there is a good hope that no more therapy is needed.

Damian is a more complicated case, as he has never undergone transplant and has an HLA-identical donor, and now has excellent disease control and is in good medical condition to undergo a transplant. There are short-term risks of transplant with a 100-day mortality risk of 5% to 10% for a teenager. And there are also long-term risks related to the transplant procedure and/or graft versus host disease.

The long-term risks of tisagenlecleucel appear limited other than the persistent B cell depletion, but the longest followup is only eight years, and few patients have more than five years of followup. So we have no idea about the efficacy and potential risks 10 to 20 or more years post-infusion.

Damian failed three induction attempts. If his leukemia comes back, one may never be able to get him back into a healthy MRD negative remission. So there is a good argument that his best chance for definitive therapy is with transplant. Given this, many would strongly recommend transplant as consolidative chemotherapy for Damian. However, it's also possible that Damian has now received curative therapy and will never relapse.

Highlighting the uncertainty surrounding this question, our group at CHOP, which has treated over 300 patients with relapsed refractory ALL with CAR T cells, does not have a clear consensus on what to do for patients like Damian. It's our practice to summarize the potential advantages and disadvantages of transplant versus no further therapy, and help the patient and their family decide what is the best course for them.

To summarize, tisagenlecleucel is an exciting therapy that provides new opportunities for children and young adults with relapsed and refractory ALL. However, the field of cellular immunotherapy is young, and there are many uncertainties, particularly surrounding the issue of definitive therapy versus bridge to transplant. Today, we lack the followup data needed to make definitive statements, and patients and families need to understand that and be full partners in these complicated decisions. Thank you very much for listening.

Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

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