NE Oncology Issue – September 2013
At the Association des Médecins Hématologues et Oncologues du Québec (AMHOQ) 2013 Annual Meeting in May, Dr. Francesco Lo-Coco, Professor of Hematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biopathology, University of Tor Vergata, Rome, Italy, presented results of his study comparing the efficacy and safety of arsenic trioxide plus all-transretinoic acid (ATRA) versus the current standard of care, ATRA plus idarubicin in patients with acute promyelocytic leukemia. New Evidence has summarized Dr. Lo-Coco’s presentation.
Acute promyelocytic leukemia (APL) is a very rare disease with an annual incidence in Italy estimated at 0.6 in 1,000,000.1 APL represents 10% to 15% of acute myeloid leukemia (AML) cases, with approximately 100 to 150 cases of APL reported yearly in Italy and Germany. Of these cases, approximately 20 relapses are expected. In Canada, the age adjusted incidence of APL is 0.073 cases per 100,000.2 The median age of patients diagnosed with APL is much younger than those diagnosed with AML (40 vs. 70 years), and the incidence in males is the same as in females. Therapy-related cases in APL and AML are likely to increase due to an increase in the number of cancer survivors and an aging population. Therefore, one can expect secondary or therapy-related AML cases to become as high as 20%.
The prognosis for patients with APL has dramatically improved since its first description in 1957. However, since patients are at high risk of death from internal hemorrhaging within a few hours after presenting at the clinic, this improvement is critically dependent on prompt patient diagnosis followed by the immediate provision of antileukemic and supportive transfusion therapies. Owing to the high risk of early death, treatment initiation may be considered the first prognostic factor. Without treatment, APL is the most malignant form of AML, with a median survival of less than one month after diagnosis. With modern therapy, however, APL is associated with very high curative rates.
For patients receiving the current standard of care, all-trans retinoic acid (ATRA) plus anthracyclines, the main prognostic marker for relapse is the white blood cell count (WBC). Patients at a high risk of relapse are defined as those with a WBC of >10 x 109/L. These patients also have a higher risk of fatal hemorrhaging at presentation and during the first days following diagnosis.
Most APL cases can be diagnosed morphologically as hypergranulated promyelocytes (± Auer rods).2 However, in about 20% of cases, cells are microgranular or agranular requiring confirmation through molecular biology techniques. Patients with APL may have one of several presenting features: 1) weakness, mucocutaneous hemorrhage (epistaxis, ecchymoses), severe bleeding (cranial, pulmonary); 2) dysplastic promyelocytes in the bone marrow with low counts in the peripheral blood; and 3) an abrupt onset with rapid coagulopathy that develops into a medical emergency. Patients typically feel normal a few weeks or days before symptoms appear. Although the presenting features of APL are very well known, it is important for nonspecialists to be aware that patients presenting with the disease may either have normal or abnormal blood counts (i.e., decreased platelets, high WBCs, or low hemoglobin). Diagnostic work-up on patients suspected of having APL involves several steps.4,5 Given the rapid progression of APL, an important first step is to view the disease as a medical emergency. Treatment with ATRA and supportive care should be initiated following morphological diagnosis and this should be followed by confirming the presence of the promyelocytic leukemia (PML)/retinoic acid receptor (RAR)α translocation, t(15:17). This can be accomplished rapidly through fluorescence in situ hybridization or staining for PML, a vital step to determine a patient’s eligibility for ATRA or arsenic trioxide (ATO)-based protocols. PML detection is a rapid procedure that can be completed in as little as two hours by immunofluorescence. Cells that are positive for PML/RARα display a bespeckled or microgranular pattern, while PML/RARα-negative cells display the nuclear body pattern. In addition to these steps, a patient’s sample should then be sent to a reference laboratory to determine baseline ribonucleic acid (RNA) expression of PML/RARα by reverse transcriptase–polymerase chain reaction (RT-PCR), which is necessary for successive monitoring of patients through the duration of treatment.
Significance of the PML/RARα fusion protein
The PML/RARα fusion protein is significant in the diagnosis and management of APL for several reasons. In addition to being the hallmark of this disease, it is unique to APL as no other leukemias have this translocation. The PML/RARα fusion protein is also strongly associated with the pathogenesis of APL. Both ATRA and ATO target and degrade PML/RARα. Once the translocation has been detected, physicians can predict the response to ATRA or ATO in all cases. The prediction is so strong that if patients who have been diagnosed with APL have a primary resistance to ATRA or ATO, a wrong diagnosis may be concluded, i.e., it is safe to assume the patient does not have APL. Finally, the fusion protein is useful to monitor minimal residual disease in patients with APL during treatment.
History of progress in APL
The history of APL is one of the most fascinating stories in medicine (Figure 1). Advances in its treatment have made APL a paradigm of success in translational medicine. The disease was first described in 1957 by the Norwegian hematologist Dr. Leaf Hillestad,6 who accurately identified APL as a distinctive subtype of AML, and one that is aggressive and rapidly fatal if not correctly diagnosed and treated immediately. Approximately a decade later after its discovery, the prognosis of APL began to change dramatically. In 1973, Professor Jean Bernard in France published a seminal paper showing APL to be highly responsive to the anthracycline daunorubicin.7 Similar findings were later replicated by our Italian multicentre GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto) group with idarubicin, another anthracycline.8 These findings revealed a unique feature of APL. Unlike other leukemias, APL was highly sensitive to single anthracycline agents such as daunorubicin and idarubicin. The reason for this extreme sensitivity remains unclear and one that is an interesting area for investigation. Following the discovery of this sensitivity to anthracyclines was the identification of the translocation between chromosomes 15 and 17 [t(15;17)] by Dr. Janet Rowley in Chicago.9
Nearly a decade later, Chinese scientists made the revolutionary discovery that APL was responsive to ATRA.10 The discovery was inspired partly by emerging data from Europe that cancer could be treated by differentiating agents, and partly by the philosophical thinking of the famous Chinese philosopher Confucius who taught that there was a greater benefit to society if criminals were rehabilitated instead of punished.11 The investigators, Dr. Zhu Chen and his mentor Professor Zhen-Yi Wang, believed that perhaps malignant cells, like criminals, could be converted into normal cells. The result of their success tore down the long held dogma that cancer is an irreversible condition.
Although ATRA converts APL cells into differentiated, nonmalignant cells, patients receiving ATRA alone are destined to relapse. We and others therefore investigated the efficacy of ATRA plus chemotherapy in the treatment of APL. The AIDA (ATRA plus idarubicin) study, begun by the GIMEMA group in 1993, observed patients who had received ATRA plus idarubicin over 12 years. Among other findings, this study revealed an overall survival (OS) rate of at least 75%, an observation later confirmed by other international studies.
In 1996, the same institution in Shanghai that discovered the effects of ATRA on APL cells also discovered that the ancient Chinese remedy ATO was extremely active in APL.9 More than a decade later in 2001, the efficacy of ATO as a single agent in patients with APL was established with the publication of the U.S. multicentre ATO trial in patients with relapsed APL.12 This study showed that patients who received the single agent ATO achieved molecular remission in 78% of cases after two cycles of treatment. The success of this trial suggested that the prospect of a cure in the relapsed state was significant, and led to the registration and licencing of ATO for the treatment of patients with relapsed APL.
The pioneering work of Eli Estey et al. from the MD Anderson Cancer Center further established the role of ATO in a chemotherapy-free approach for APL, showing that patients with <10 x 109/L (low risk) or >10 x 109/L (high risk) WBC at diagnosis, and who had received ATRA plus ATO, had a greater rate of eventfree survival (EFS) than that of patients who received idarubicin plus ATRA over a five-year period. The fact that patients in this trial did not receive chemotherapy was highly significant. A minor exception was the administration of one or two doses of the anti-CD3 chemotherapy agent gemtuzumab ozogamicin to patients who had >10 x 109/L leukocytes.
Although the mechanism of action of ATO on APL cells is not fully understood, it is now known that ATO has at least two different modes of action. Similar to ATRA, ATO targets and degrades the PML/RARα fusion protein leading to activation of repressed genes. Unlike ATRA, however, ATO also leads to activation of apoptosis.
The current recommendation for patients with relapsed APL after receiving ATRA plus chemotherapy is ATO with or without ATRA. Treatment approaches for patients who achieve remission remain a matter of debate. Different strategies such as autogeneic versus allogeneic remission are difficult to compare due to the absence of randomized trials. Important factors to consider when making a decision for consolidation of second remission in patients with APL include: the age and performance status of the patient, the length of first remission, the type of first-line treatment, the availability of a human leukocyte antigen (HLA)-identical donor, and the achievement of molecular remission. With respect to molecular remission, the consensus is that patients who do not achieve PCR negativity of PML/RARα expression should not be approved for an autologous transplantation. Patients who show persistent molecular positivity after re-induction should receive an allogeneic transplant instead.
Challenges with modern APL treatment
Early death in APL and its reduction
The risk of early death in patients with APL is a critical issue in APL management. Clinical trials report a wide range of early death frequency (2%–25%) which is most likely due to a patient selection bias.1 For example, 15/792 patients with cranial hemorrhaging and four patients with pulmonary hemorrhaging were excluded from the PETHEMA (Programa de Estudio y Tratamiento de las Hemopatias Malignas) trials.13 In addition, 14/792 patients were deemed unfit for chemotherapy and were excluded from the same trial.
Population-based studies have reported a high frequency of early death (<30 days after treatment initiation), ranging from 17% in the Surveillance, Epidemiology, and End Results database (SEER)14 to 29% in a study based on a Swedish registry.15 The percent of early death occurrence before patients receive therapy remains unknown and, in my opinion, is likely to be around 20% to 30%.
Reducing the frequency of early death in patients with APL is of paramount importance in its management. Although APL is a very rare condition, promoting education and awareness of this disease in emergency units is critical to reducing early death in these patients. Physicians in emergency units need to know of the existence of APL, and that patients, even young patients, may present with sudden bleeding without clear signs of leukemia (i.e., patients may have nonleukemic blood counts). Other recommended measures to lower the rate of early death include fostering registry studies, referring patients to highly specialized centres, improving early diagnosis and ATRA availability, as well as more studies to understand factors that can predict sudden hemorrhages and coagulopathy. In APL, supportive treatments are at least as important as antileukemic treatments. Supportive measures recommended by an international panel of experts include platelet infusion to maintain platelet levels >30–50 x 109/L, and fresh frozen plasma to maintain fibrinogen levels >150 mg/dL.4 The use of heparin and antifibrinolytics was not recommended by the panel.
ATRA plus chemotherapy toxicity
In an effort to manage the toxicity of ATRA and chemotherapy, we and other investigators developed risk-adapted treatments in which patients received different intensities of postinduction treatment.16 In Italy for example, AIDA induction was followed by more or less intensified treatment based on the assigned risk of patients (low or high risk). This approach led to a significant improvement in the rate of disease-free survival (DFS) among patients who received the new risk-adapted AIDA protocol (AIDA 2000) compared with those who received the old AIDA protocol (0493).16
Breaking new ground
ATRA plus ATO as first-line treatment: rationale and study
Despite the high cure rates with ATRA plus chemotherapy, there are several challenges to overcome. These include a high rate of patient death during induction and remission,16 death from toxicity during consolidation therapy,16 and death from the development of therapy-related secondary tumours (myelodysplastic syndrome/AML) in about 2% of patients treated with ATRA plus chemotherapy.18 Given the high potential to cure patients with APL, these are, in my opinion, unacceptable statistics.
In an effort to overcome these challenges, we investigated the chemotherapy-free approach to APL treatment. Unlike studies examining ATRA plus ATO, several multicentre studies examining ATRA plus chemotherapy in patients with APL have demonstrated a high cure rate of at least 75%, and a similarly high nonrelapse rate, as determined during the observation of thousands of patients. In contrast, the quality and quantity of studies on ATRA plus ATO have been limited. These studies show that ATRA plus ATO is effective with low toxicity. However, they were also single-centre studies involving a small number of patients with a relatively short follow-up.
In 2006, we began a phase III, long-term follow-up study on patients not at high risk (low- and intermediate risk patients) with APL comparing the AIDA protocol (ATRA plus chemotherapy plus two years of maintenance therapy) with the Eli Estey protocol (ATRA plus ATO for induction and consolidation) (Figure 2).19 The trial was designed to assess noninferiority between the two groups at a margin difference of 5%. Patients were recruited from the GIMEMA (40 centres) and SAL-AMLSG (27 centres) groups, and observed for a median of 34.3 months. Patients in both groups had similar baseline clinical and biological characteristics.
The study — presented at the American Society of Hematology in December 2012 and recently published in the NEJM in July 2013 — revealed several important findings. Induction outcome between both groups was not statistically significant (complete response [CR] = 100% in ATRA plus ATO; CR = 95% in ATRA plus chemotherapy). However, there were four deaths in the ATRA plus chemotherapy group and none in the ATRA plus ATO group. The frequency of differentiation syndrome was similar between the two groups (all patients received prophylactic prednisone 0.5 mg/kg/day until CR). However, there were significant differences in toxicities between the groups. As expected, hematological toxicity increased in patients receiving ATRA plus chemotherapy during induction and consolidation phases (Figure 3). On the other hand, patients in the ATRA plus ATO group experienced a greater frequency of QTc prolongation (13% vs. 0%, p = 0.0005), a greater frequency of grade 3/4 hepatic toxicity (57% vs. 5%; p <0.0001), and increased leukocytosis (>10 x 109/L; 47% vs. 24%; p = 0.007). These were expected from previous experiences with ATO plus ATRA, and were managed with temporary discontinuation and dose modifications of ATO, which were already written into the protocol. Out the 13 patients experiencing these toxicities, there was one permanent drug discontinuation. Patients experiencing leukocytosis were managed with hydroxyurea (500 mg four times a day (qid) if WBC ≤50 x 109 and 1 g qid if >50 x 109). No significant differences in DFS or cumulative incidence of relapse were observed between the two groups (Figure 4, Figure 5).
The primary endpoint of the study, EFS, was significantly greater in the ATO plus ATRA group than in the ATRA plus chemotherapy group (Figure 6). Similarly, patients in the ATO plus ATRA group had a slight but significant increase in OS compared with the ATRA plus chemotherapy group (Figure 7). Since this trial was designed to test noninferiority only, we concluded that ATRA plus ATO was at least not inferior to ATRA plus chemotherapy when comparing EFS after two years in patients with low- or high-risk APL. The study also showed that while ATO and ATRA was associated with less hematological toxicity, it was associated with more hepatic toxicity and QTc prolongation, both of which were effectively managed by dose adjustments. It is our belief that this regimen may emerge as a new standard of care for patients with APL who are at low or intermediate risk.
Tremendous amounts of progress have been made in the treatment of APL since its first description over five decades ago. This progress has highlighted several important lessons including 1) the observation that cancer may in fact be reversed and, therefore, killing cancer cells is not the only necessary strategy to combat this disease, 2) targeted treatment is a highly successful strategy to eradicate leukemia cells, and finally, 3) eradication of leukemia stem cells leading to a cure can be achieved without chemotherapy.
References: 1. Avvisati G, Mele A, Stazi MA, Vegna ML, et al. Epidemiology of acute promyelocytic leukemia in Italy. APL Collaborating Group. Ann Oncol 1991;2:405-8. 2. Paulson C, Serebrin A, Turner D, et al. Epidemiology and outcomes of APL in a large population based Canadian cohort. Haematologica 2012: 97(s1). 3. Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood 2009;114:5126-35. 4. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875-91. 5. Stainsby D, MacLennan S, Thomas D, et al. Guidelines on the management of massive blood loss. Br J Haematol 2006;135:634-41. 6. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand 1957;159:189-94. 7. Bernard J, Weil M, Boiron M, et al. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood 1973;41:489-96. 8. Avvisati G, Petti MC, Lo-Coco F, et al. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood 2002;100:3141-6. 9. Zhou GB, Zhang J, Wang ZY, et al. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci 2007;362:959-71. 10. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988;72:567-72. 11. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008;111:2505-15. 12. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852-60. 13. de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 2008;111:3395-402. 14. Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011;118:1248-54. 15. Lehmann S, Ravn A, Carlsson L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011;25:1128-34. 16. Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010;116:3171-9. 17. Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010;115:5137-46. 18. Montesinos P, González JD, González J, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic acid and anthracycline-based chemotherapy. J Clin Oncol 2010;28:3872-9. 19. Lo-Coco F, Avvisati G, Orlando S. ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non high-risk acute promyelocytic leukemia (APL): results of the phase III, prospective, randomized, Intergroup APL0406 study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG. ASH Annual Meeting Abstracts 2012:120:6
Carolyn Owen, MD
Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.
Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.
Jaroslav F. Prchal, MD
Dr. Jaroslav F. Prchal is an Associate Professor of Oncology and Medicine at McGill University, and Chair of the Department of Oncology at St. Mary’s Hospital Center in Montreal, Quebec, Canada. Dr. Prchal attended Charles University in Prague, receiving his Doctor of Medicine degree in 1964. He trained in Medicine at Toronto General Hospital and subsequently completed a post-graduate fellowship in Hematology at the University of Toronto and a Medical Research Council fellowship in Hematology and Marrow Transplantation in Seattle, Washington, USA. In 1979, he joined the staff at McGill University and the Royal Victoria Hospital, as well as St. Mary’s Hospital Center, where he has helped to build the Cancer Care program, serving as Chief of Oncology since 1997. Dr. Prchal’s main research interests include bone marrow disorders, specifically chronic myeloproliferative neoplasms, and his work has been published in journals such as Blood, the Journal of Clinical Investigation, Nature, and the New England Journal of Medicine.
Clemens-Martin Wendtner, MD
Clemens-Martin Wendtner, M.D., is Professor of Medicine and Director of the Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine at the Klinikum Schwabing, Munich — an academic hospital of the University of Munich. He completed his M.D. at the University of Münster in 1993. Thereafter, he received postdoctoral training at the Max-Planck-Institute in Martinsried, Germany and at the National Institutes of Health (NIH) in Bethesda, USA, until 1995. After a clinical fellowship at the University of Munich, he gained his German and US licence (ECFMG) in Internal Medicine before specialising as a Hematologist and Oncologist at the same institution. Dr. Wendtner received his postdoctoral lecture qualification at the University of Munich in 2002, and since 2004, he is a full professor of Internal Medicine, Hematology, and Medical Oncology at the University of Cologne. Dr. Wendtner is a member of multiple national and international societies in the field of Medicine and has won several research awards, including first prize at the 6th International Symposium Biological Therapy of Cancer in Munich, and a merit award from the American Society of Clinical Oncology. As a founding member of the German CLL Study Group (GCLLSG), he participates on the Steering Committee and is Secretary of GCLLSG. He has been principal investigator for numerous phase I-III clinical studies, and his interests focus on the development of new therapies in the field of CLL.
Laurie H. Sehn, MD, MPH
Dr. Francesco Lo-Coco is a full Professor of Hematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biopathology, University of Rome Tor Vergata, Rome, Italy. His main research activities include genetic characterization, monitoring, and treatment of hematologic tumours, particularly acute myeloid leukemia and acute promyelocytic leukemia (APL). He has served as President of the Italian Society of Experimental Hematology, been a board member of the Italian Foundation for Cancer Research, and a member of the Committee on Health Research at the Italian Ministry of Health. He is presently chairman of the APL subcommittee of the Italian National Cooperative Group GIMEMA, chairman of the Education Committee of the European Hematology Association, and a member of the editorial board for the journals Leukemia and Haematologica.
Valentin Goede, MD
Valentin Goede, M.D. is a Hematologist/Oncologist in the Department I of Internal Medicine at the University Hospital of Cologne, Cologne, Germany. He is also a Senior Physician and Consultant at the Department of Geriatric Medicine and Research at St. Marien Hospital, University of Cologne. After obtaining his M.D. at the University of Goettingen, Dr. Goede was trained in internal medicine at the Ammerland Clinic Westerstede. His hematology and oncology training was completed at the University Hospital Munich-Großhadern and the University Hospital of Cologne. His training in geriatric medicine was completed at the St. Marien Hospital, University of Cologne. Dr. Goede’s main research interest focuses on the prediction and management of age-related vulnerability in elderly patients with leukemia, lymphoma, and other types of cancer.