Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) characterized by the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) translocation between chromosomes 15 and 17. Historically, the combination of all-trans retinoic acid (ATRA) and an anthracycline has been regarded as the standard of care in APL1,2; however, it is associated with an appreciable relapse rate and significant toxicity, such as cardiomyopathy. In recent years, arsenic trioxide (ATO) has been shown to be effective in combination regimens that are chemotherapy-free (“chemo-free”) or chemo-reduced.3,4 Most centres in Canada are moving towards a chemo-free approach, which includes ATO in the regimen.

At the 7th International Symposium on APL, various aspects of APL treatment were discussed, including long-term and “real-world” outcomes, treatment in older patients and in children, management of relapse, therapy-related APL (t-APL), and early death (ED).

Long-term outcomes and real-world data

In Canada, the chemo-free approach (i.e., ATRA plus ATO) is widely used in most centres for adult patients with non–high-risk APL (white blood cell [WBC] counts <10 x 109/L). This was based on the early and long-term results from the German-Italian study (APL0406) led by Dr. Francesco Lo-Coco, as well as a favourable recommendation by the Pan-Canadian Oncology Drug Review.3,5,6

High-risk patients (WBC >10 x 109/L) represent a minor proportion of APL in Canada (20% to 30% of APL patients). High-risk patients are often treated with ATO plus ATRA along with systemic chemotherapy. They are not receiving chemo-free approaches because there are insufficient data to support the use of these regimens in high-risk APL. Currently, most centres in Canada are using one of the two ATO-containing regimens published for high-risk APL – the approach published in the Intergroup C9710 study by Powell et al., and the Australasian protocol published by Dr. Iland’s group.4,7

At the 7th International Symposium on APL, Ravandi et al. presented the long-term follow-up (47.6 months) of a large cohort of patients with APL at the M.D. Anderson Cancer Center.8 The treatment approach they used was similar to the German-Italian APL0406 protocol for the non–high-risk patients.3 The main difference of this study from the APL0406 trial is the addition of gemtuzumab ozogamicin (GO) in the treatment for high-risk patients. Although GO is currently unavailable in Canada, the study certainly demonstrated the feasibility of a “chemo-reduced” approach for high-risk patients. Of the 187 patients, 54 were high risk and 45 of them received GO (9 mg/m2) on Day 1. GO was also used in low-risk patients when WBC rose above 10 x 109/L during induction. Compared to the recently published U.K. National Cancer Research Institute (NCRI) trial, GO was given at a slightly higher dose (in this study versus 6 mg/m2 in the NCRI study).9

Most non–high-risk patients who experienced leukocytosis during induction (51/60) were treated with GO. Specific concerns in those who develop leukocytosis during induction are APL differentiation syndrome and coagulopathy; we often treat patients with hydroxyurea or idarubicin to reduce this leukocytosis. Although the use of GO is sensible, I think there needs to be a proven advantage to using GO for physicians to shift away from using conventional cytotoxics such as hydroxyurea, with the latter being well tolerated and less costly compared to GO.

The outcomes in the long-term follow-up of this cohort were excellent. The early death (ED) rate was low (3.7%) and relapse occurred in only 7 patients. Older patients (aged ≥60 years) had poorer outcomes compared to younger patients, likely because of a combination of higher ED, treatment-related toxicities, or relapse. The five-year event-free survival (EFS) and overall survival (OS) in older versus younger patients were 74% vs. 89% and 74% vs. 93%, respectively. However, their results in older patients are better than what we have demonstrated in historical population-based outcomes in Canada (ED rate of 36% and five-year OS of 29% in patients aged ≥50 years old).10

Overall, the results from the study by Ravandi et al. reinforce previous data from the APL0406 study, which used a well-tolerated regimen in both young and older patients.3,5 The study also consolidates the NCRI data of using GO in high-risk patients9; however, although there may be an advantage to the use of GO, the current data is insufficient to adopt GO if and when it becomes available in Canada.

APL in elderly patients

The median age of patients with APL is approximately 50 years. From our Canadian experience, patients with APL who are aged >50 years had significantly poorer outcomes compared to younger patients.10 The current standard of care for older patients with APL is the same as that for younger adult patients. We treat older, low-risk patients with a chemo-free approach (ATO plus ATRA),3,5 paying very close attention to the possibility of toxicities. This is because these patients are often on other medications with attendant risks of drug-drug interactions and complications such as cardiac arrhythmias and metabolic abnormalities. For older patients with high-risk APL, we would consider the Australian approach (ATO, ATRA, and idarubicin),4 but would favour a chemotherapy-free regimen3 if concerns about tolerability of chemotherapy exist, especially that of cardiac toxicity from anthracyclines.

At the 7th International Symposium on APL, Dr. Adès presented a subgroup analysis of the APL 2006 study, which evaluated the use of ATO and ATRA with chemotherapy in elderly patients with standard-risk, newly diagnosed APL.11 This trial defined elderly patients as age >70 years.

In this study, the overall two-year OS was 82.4% and the complete response (CR) rate was 91.1%. The treatment schedule was amended to include fewer doses of idarubicin in consolidation due to the concern of high mortality rates in CR. The amendment resulted in a significantly lower post-remission death rate (20% vs. 4%; p = 0.045) and had no negative impact on relapse. There were 3% of elderly patients with resistant leukemia. The inherent weakness of this study is that it was designed in 2006, when treating physicians were not aware of the feasibility of a chemo-free approach. Thus, idarubicin was still used in induction and consolidation phases. I question the clinical significance of the approach used in this study as current treatment is moving towards a chemo-free approach. I suspect the same or better survival outcomes can be achieved without the aid of an anthracycline.

APL in pediatric patients

Since APL is predominantly seen in adults, pediatricians tend to look at the trials and outcomes in adult patients with APL when they model their approach in pediatric patients with APL. In Canada, anthracyclines have traditionally been used in the treatment of pediatric APL; however, in view of cardiotoxicity concerns, a chemo-free approach may be preferable. Recently, the Children’s Oncology Group (COG) commenced a phase III trial (AAML1331), which examines the superiority of a chemo-free approach over standard chemotherapy in treating children with non–high-risk APL.12 In this trial, pediatric patients with non–high-risk APL receive ATO and ATRA for induction and consolidation, while patients with high-risk APL receive ATO, ATRA, and idarubicin. There is no maintenance therapy in the regimen. Many pediatric oncology centres in Canada will be embracing this trial.

At the 7th International Symposium on APL, Kutny et al. presented a study in which pediatric patients with APL were treated with a regimen containing anthracyclines in induction and consolidation.13 ATO was used in the first consolidation cycles, which resulted in a reduction of anthracycline use by 38% to 45%. The survival outcomes remained high in the study (3-year EFS: 100% for young children, 96% for older children, and only 88% for adolescents; p = 0.540), and the relapse risk was similar across all age groups (0% to 4%). The three-year EFS appeared to be lower in adolescents possibly due to lower compliance rates.

Overall, the results in this study are somewhat poorer than what has been observed in young adult patients with APL. Although the study used reduced chemotherapy, the study protocol is probably outdated compared to the current COG regimen or standard of care adult protocols.

Management of relapse in APL

With the emergence of ATO, relapses in APL have become extremely rare. Most relapses now happen in patients who completed treatment with a non–ATO-based regimen. In Canada, patients with relapsed APL are generally treated with ATO plus ATRA (with an anthracycline for high-risk patients). Once these patients achieve molecular remission, they may receive an autologous stem cell transplant because it is a preferred treatment for patients who have relapsed and are responsive to second-line treatment.14 In patients who have relapsed but fail to achieve a subsequent molecular response to second-line treatment, an allogeneic transplant would be considered. Prolonged exposure to ATO and ATRA can be considered if an autologous stem cell transplant could not be offered. As relapse cases are extremely rare, individualized, case-by-case collaborative decision making is needed.

The study by Cicconi et al. presented at the 7th International Symposium on APL was conducted in a reasonably large group of patients who relapsed after receiving front-line non–ATO-based regimens (e.g., ATRA plus idarubicin).15 These patients received prolonged ATO and ATRA therapy (without stem cell transplant), and 68% achieved molecular remission. The efficacy outcomes are better than expected, and they support the use of prolonged ATO and ATRA in patients with relapsed APL who cannot undergo a stem cell transplant.

Therapy-related APL

Therapy-related APL (t-APL) is rare worldwide. At the 7th International Symposium on APL, Kayser et al. presented a study on t-APL that followed a large group of patients with t-APL (103 patients) accrued over a very long period (~25 years of accumulated data).16 In this study, patients with t-APL were treated with a mix of different regimens. ATO and ATRA therapy resulted in 100% CR, while the chemotherapy with ATO and ATRA combination resulted in 95% CR, and chemotherapy and ATRA resulted in 78% CR. EFS excluding death due to primary malignancy was higher in patients treated with ATO and ATRA or chemotherapy with ATO and ATRA when compared with chemotherapy and ATRA. The ED rate was lower if patients received an ATO-based regimen for induction. The study demonstrated that ATRA plus ATO was a vital aspect to treating these patients.

The overall take-home message from this study is that patients with t-APL should be treated in the same way as de novo APL (i.e., using ATO plus ATRA). This study has also shown that stem cell transplant is not uniformly needed. For high-risk t-APL, the use of idarubicin should be cautioned because these patients may have received anthracyclines for their primary malignancy, such as breast cancer, and the cumulative doses of anthracyclines in these patients become a concern.

Early death in APL

The definition of ED remains controversial in the treatment of APL. We are most interested in deaths occurring in the first week of induction, but it is difficult to determine which day the patient died using population-based data, as opposed to a prospective clinical trial or patient registry. Therefore, for practical purposes, ED should be defined as death occurring in the first 30 days during induction. This definition allows comparability between treatment centres and registries.

ED rates depend on the characteristics of treatment centres. From our Canadian experience, if patients with APL are treated at an experienced acute leukemia centre, ED rates are much lower than those reported in population-based cancer registry data. Recent U.S. SEER data showed that the presence of a trauma centre and an intensive care unit in the hospital where APL patients are treated is associated with improved ED rates.17 More importantly, prompt and familiar access to blood products and ATRA is a key characteristic of a successful APL treatment centre, as blood product support and ATRA are essential to rescuing patients with APL from ED. Overall, ED in APL can be largely reduced and it relies, at least in part, on the characteristics of treatment centres where APL care is delivered.

References: 1. Sanz MA, Lo-Coco F, Martín G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000;96(4):1247–53. 2. Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103(4):1237–43. 3. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369(2):111–21. 4. Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012;120(8):1570–80. 5. Platzbecker U, Avvisati G, Cicconi L, et al. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non–high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol 2017;35(6):605–12. 6. Canadian Agency for Drugs and Technologies in Health. Pan-Canadian Oncology Drug Review: Trisenox for acute promyelocytic leukemia — details. Final recommendation issued February 18, 2014. Available online at: https://www.cadth.ca/trisenox-acute-promyelocytic- leukemia-details. 7. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia; North American Leukemia Intergroup Study C9710. Blood 2010;116(19):3751–7. 8. Ravandi F, Abaza Y, Garcia-Manero G, et al. Long-term outcome of patients with acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. Intl. Symposium on APL Abstracts 2017:CO028. 9. Burnett AK, Russell NH, Hills RK, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16(13):1295–305. 10. Paulson K, Serebrin A, Lambert P, et al. Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study. Br J Haematol 2014;166(5):660–6. 11. Adès L, Thomas X, Guerci A, et al. Arsenic trioxide (ATO) and ATRA with limited chemotherapy (CT) in newly diagnosed standard risk APL in the elderly. A report by the French Belgian Swiss APL Group (APL 2006 trial). Intl. Symposium on APL Abstracts 2017:CO024. 12. Children’s Oncology Group. Tretinoin and arsenic trioxide in treating patients with untreated acute promyelocytic leukemia. Available from: https://clinicaltrials.gov/ct2/show/NCT02339740. NLM identifier: NCT02339740. Accessed November 8, 2017. 13. Kutny MA, Alonzo TA, Gerbing RB, et al. Arsenic trioxide consolidation results in excellent survival in young children as well as older children and adolescents with newly diagnosed acute promyelocytic leukemia (APL): A report from the Children’s Oncology Group study AAML0631. Intl. Symposium on APL Abstracts 2017:CO023. 14. Ganzel C, Mathews V, Alimoghaddam K, et al. Autologous transplant remains the preferred therapy for relapsed APL in CR2. Bone Marrow Transplant 2016;51(9):1180–3. 15. Cicconi L, Brecchia M, Franceschini L, et al. Prolonged ATO and ATRA therapy for relapsed acute promyelocytic leukemia. Intl. Symposium on APL Abstracts 2017:CO032. 16. Kayser S, Krzykalla J, Elliott MA, et al. Characteristics and outcome of therapy-related acute promyelocytic leukemia after different front-line therapies. Intl. Symposium on APL Abstracts 2017:CO033. 17. Park JH, Devlin S, Lynch C, et al. Impact of treatment center characteristics on early death rates in patients with newly diagnosed acute promyelocytic leukemia: Analysis of data from the SEER program. Blood 2016;128:4008.

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january2018
Contributors

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.