At the 7th International Symposium on APL, New Evidence spoke with Dr. Anand Jillella, Chief of the Division of Hematology and Director of Oncology and Bone Marrow Transplant at the Medical College of Georgia at Augusta University, Georgia.

New Evidence: What is the true definition of early death (ED)?

Dr. Jillella: Literature defines ED as occurring in the first 30 days after diagnosis; however, this definition is debated in the field. I disagree with this definition and believe that a more accurate definition of ED would be death occurring during the induction period, also known as induction mortality. I believe the entire length of induction should be included in this definition as induction therapy can last up to six weeks, and there are instances where complications that develop within the first 30 days could result in death after the 30-day mark.

New Evidence: Why is ED an important topic in the treatment of acute promyelocytic leukemia (APL)?

Dr. Jillella: ED is an important topic because it is currently the most common cause of treatment failure in APL; however, these deaths may all be preventable with appropriate and timely care decisions. In our experience with an all-comers population, the cure rate for patients who survive the induction phase of therapy is high (>90%), which highlights the importance of getting patients through this stage of treatment.

New Evidence: What was the rationale for the APL trial in Georgia and South Carolina?

Dr. Jillella: Almost 10 years ago, we began to notice the high percentage of patients with APL in our institution who died during induction therapy, with the main causes of death being bleeding, infection, and differentiation syndrome. We learned that we were not managing these patients appropriately and wanted to create a treatment algorithm to better care for these patients. At the time, the current treatment algorithm for APL consisted of a 15-page guideline, which was not sufficient for a rarely seen disease that requires quick reaction times. This was the rationale for developing a program using a two-page treatment algorithm for APL that could be implemented quickly. The program allowed us to do a quality control at our own institution and allowed us to gain experience and knowledge that could be shared with surrounding hospitals. After treating 10 patients with no deaths, we sought after and received funding to start a trial in Georgia and South Carolina that involved dissemination of the algorithm to several hospitals in the area and acting as an experienced resource for them to contact with patient management inquiries. The aim of the study was to reduce induction mortality from an estimated 30% to less than 15% in these two states with a population of approximately 15 million people.

New Evidence: How different are the ED rates in clinical trials versus population-based/real-world studies? Why is this difference important?

Dr. Jillella: In clinical trials the induction mortality rate is about 3%–8%, whereas in population-based studies, such as the Swedish registry trial, induction mortality is approximately 30%. This discrepancy is due to several factors, such as trial exclusion criteria, which lead to the exclusion of older patients with multiple comorbidities. For example, the average median age in trials is approximately 40–45 years, which does not reflect the median age of approximately 55 years reported in real-world studies. Another reason for this discrepancy is that compared to population-based studies, patients in clinical trials are treated on a specific protocol with strict guidelines for supportive care, and generally in experienced centres. This difference tells us that clinical trial results are not translating into the real world, and as not every patient will have the opportunity to enroll in a clinical trial, improving ED rate in the general population is very important.

New Evidence: Could you please briefly describe the simplified treatment algorithm used in your study?

Dr. Jillella: This treatment algorithm was developed by faculty members with diverse specialties, including bleeding and clotting. Together we reviewed the APL literature to form a best practice guideline that includes treatment and supportive care. As we wanted the algorithm to be simple and used to implement therapy quickly, it began as a 1.5-page, checklist-style document that outlined how to treat a patient with APL and what measures could be taken to prevent fatal complications such as bleeding, differentiation syndrome, and infection. To further simplify the algorithm, referring physicians would call our centre to share their patient details, and we would send them an email outlining 12–15 recommendations specific to their patient. The algorithm has since undergone multiple amendments to accommodate the evolving literature and impracticalities observed during implementation. The most current iteration of the algorithm is now being used in the EA9131 Eastern Cooperative Oncology Group (ECOG) study which started on September 1, 2017.

New Evidence: What were some of the difficulties encountered when the algorithm was implemented in the centres in Georgia and South Carolina?

Dr. Jillella: Although there were generally few difficulties implementing the algorithm in centres in Georgia and South Carolina due to the strong relationships we have built with physicians over the years, there were some centres who did not feel the need to seek advice in managing their patients with APL. In most cases, the availability of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) at the different centres was not a problem; however, there were three centres who did not have access to ATRA. These centres would send their patients to larger institutions to be treated. In cases where pharmacists and nurses did not have experience administering ATO, we had pharmacists and nurses available at our centre to discuss these details with them.

New Evidence: Could you please describe the patient population in your study?

Dr. Jillella: As this study had no exclusion criteria, it represents a real-world population. All patients diagnosed with APL were included, even patients who were older, had multiple comorbidities, or who came to a treatment centre in critical condition with significant bleeding. The median age of patients in this trial was 54 years, which is what you would expect in the general population.

New Evidence: The overall survival was 89% and there were 11 EDs. In your opinion, had this study met its objectives?

Dr. Jillella: The objective of this study was to reduce ED rate from an estimated 30% to less than 15%. As the ED rate of this study was 6.7%, we can conclude that the study objective was met. However, I believe all EDs are preventable and that we could still do better.

New Evidence: For elderly patients with APL, how was the algorithm modified and what was the rationale for the modification?

Dr. Jillella: It appears that most of the problems with ED occur in older patients, mainly due to differentiation syndrome. After analyzing the data in the first half of the study, we found that five of six patients who died early in induction were older than 60 years. Since the algorithm was created based on studies where dosing and schedules were developed for a patient population with a median age of approximately 40 years, this dosing and schedule would not be appropriate for a patient who is aged 70 years or older. For this reason, treatment doses were reduced to 50% for older patients in the second half of the study, which helped to reduce the number of EDs in these patients.

New Evidence: What are the key takeaways of the study? In your opinion, how will your algorithm impact future practice in APL?

Dr. Jillella: The key takeaway of this study is that by following this simplified algorithm and discussing patient cases with experts in APL, the rate of EDs can be reduced in the general population. It is important to note that although the algorithm is a tool that will improve outcomes, it is equally important to discuss patient management with an expert who treats patients with APL on a more regular basis. There are small details, such as remembering to give steroids on the first day of treatment, that can be forgotten by physicians who treat APL infrequently, and this can have fatal consequences.

By decreasing the frequency of EDs, this study was able to make an impact on the lives of patients and their families. The success of this program is the result of a whole team of people including physicians, pharmacists, nurses, and trainees who are very dedicated to the APL patients. In particular, I would like to acknowledge the significant contributions made by Dr. Vamsi Kota at the Emory Winship Cancer Institute in Georgia, as he played an integral role in the development and implementation of this program. The hope is that in time, this program will become the global paradigm for treatment of patients with APL.

New Evidence: In your opinion, how can your algorithm be adapted for use in other countries such as Canada?

Dr. Jillella: For this program to be implemented in other countries, it will be important to have a champion who has genuine interest in pushing the program forward. This person would be dedicated to visiting many practices to educate them on the program and fielding calls from multiple centres. This physician may not have the needed experience level at the beginning of implementation, but this could be acquired over time. One of the biggest challenges for implementing this program in any country will be getting the physicians in rural areas who may see a patient with APL infrequently to call an expert and discuss patient management.

New Evidence: With the experience in Georgia and South Carolina, what are the next steps in the implementation of your algorithm?

Dr. Jillella: The next step is to implement this algorithm at a national level, which is currently underway through the EA9131 ECOG trial, with the same objective of reducing the induction mortality rate to less than 15%. This trial has currently enrolled seven patients with the plan to recruit 200 patients over the next four years. If we meet our objective, the next goal would be to have the algorithm included in the National Comprehensive Cancer Network guidelines for acute myeloid leukemia, with a recommended list of ten physicians to contact for patient management advice.

Reference: 1. Jillella A, Arellano M, Karkhanis P, et al. A multi-center prospective study using a simplified treatment algorithm along with expert support decreased induction mortality and improved survival in acute promyelocytic leukemia (APL). Results of the APL trial in Georgia, South Carolina, and neighboring states. Intl. Symposium on APL Abstracts 2017:PO020.

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Dr. Abla
Oussama Abla, MD
Dr. Oussama Abla is a staff oncologist at the Division of Hematology/ Oncology in The Hospital for Sick Children in Toronto, where he has been on faculty since the year 2000. He is also an Associate Professor in the Department of Pediatrics at the University of Toronto. He received his medical degree from the University of Genoa, Italy in 1989. His post-graduate training included a pediatric residency at the Gaslini Children’s Hospital in Genoa and a pediatric hematology/oncology fellowship at the Hospital for Sick Children.

Dr. Abla’s clinical and research interests include pediatric leukemias and lymphomas with a special focus on acute promyelocytic leukemia (APL), pediatric primary central nervous system lymphoma and other rare pediatric lymphomas, as well as Langerhans cell histiocytosis (LCH) and rare histiocytic disorders. He is the chair of the Histiocyte Society “Rare Histiocytoses Steering Committee” and the primary investigator for the International Registry for Rare Histiocytic Disorders, as well as the Canadian Coordinator of the LCH-IV trial. He is also the co-editor of an upcoming textbook on Histiocytic Disorders. In addition, Dr. Abla is a member of the Children’s Oncology Group-APL study committee and co-editor of an upcoming textbook on APL. He is also a member of the international- BFM study group committees on non-Hodgkin lymphoma and acute myeloid leukemia. Dr. Abla has more than 80 scientific publications and book chapters in the fields of supportive care, leukemias, lymphomas, and histiocytic disorders.

Dr. Jillella
Anand Prasad Jillella, MBBS
Dr. Anand Jillella is currently Director of the Georgia Cancer Center (GCC) Clinic, Ambulatory Services, Network and Outreach, GCC Associate Director of Medical Oncology Services, and Chief of the Division of Hematology/ Oncology and Bone Marrow Transplant (BMT). He has also been appointed to the first J. Harold Harrison, MD Distinguished Chair in Medical Oncology.

Dr. Jillella’s professional training included a fellowship in hematology/oncology at Yale University School of Medicine and intensive training in Bone Marrow Transplantation at Johns Hopkins Oncology Center. In 1996, he was appointed Assistant and then Associate Professor and Director of the BMT Program at Medical College of Georgia (MCG). He then became Associate Professor at Temple University and Associate Director of the Fox Chase-Temple BMT Program in 2002. Dr. Jillella returned to MCG at Georgia Health Sciences University in 2005 as Professor of Medicine and Chief of the Division of Hematology/Oncology and BMT, and Director of the Bone Marrow/Stem Cell Transplant Program, and then became Associate Director for Clinical Affairs of the Georgia Regents University (GRU) Cancer Center Service Line. In 2013, Dr. Jillella left GRU to become Associate Director for Community Affairs and Outreach at the Winship Cancer Institute of Emory University in Atlanta.

Dr. Seftel
Matthew Seftel, MD, MPH, MRCP, FRCPC
Dr. Matthew Seftel is the Department Head of Hematology and Oncology at CancerCare Manitoba and the Section of Hematology/Oncology, Department of Internal Medicine at the University of Manitoba in Winnipeg, Manitoba. He is also an Associate Professor at the University of Manitoba. Dr. Seftel’s research interests include leukemia epidemiology and clinical trials in leukemia and lymphoma (including blood and marrow transplantation). He is an investigator with the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Centre for International Blood and Marrow Transplant Research (CIBMTR).

Dr. Ong
Michael Ong, MD
Dr. Ong is a medical oncologist who specializes in genitourinary malignancies, malignant melanoma, and experimental therapeutics. His training has included an undergraduate medicine degree in Ottawa, as well as an internal medicine and medical oncology residency at Western University, and further fellowship training in experimental therapeutics at the Royal Marsden Hospital in London, U.K., before being recruited to The Ottawa Hospital Cancer Centre.

Dr. Ong’s research interests primarily include development of anticancer drug combination strategies including immunotherapy and targeted therapies, dose-optimization and sequencing-optimization of currently developed therapeutics, and development of non-invasive biomarker strategies. Dr. Ong is the lead investigator for a number of clinical trials for bladder and prostate cancers, and the main investigator for novel experimental therapeutics for genitourinary cancers and melanoma, in Ottawa.