September 2014, Vol 3, No 6
Highlights From the 6th International Symposium on Acute Promyelocytic LeukemiaUncategorized
Recently, more than 200 scientists, researchers, and clinicians from around the globe gathered in Rome, Italy, for the 6th International Symposium on Acute Promyelocytic Leukemia (APL). Held every 4 years since 1997, this comprehensive congress reviewed recent scientific advances and clinical research in APL and related malignancies.
Two internationally recognized APL experts served as the meetingâ€™s chairs: Francesco Lo-Coco, MD, professor of hematology at University Tor Vergata, Rome, Italy, and Miguel A. Sanz, MD, PhD, head of the department of hematology and bone marrow transplant unit, University Hospital La Fe in Valencia, and professor of medicine at the University of Valencia, Spain. Dr Lo-Coco directs the APL subcommittee of the Italian Gruppo Italiano Malattie Ematologiche dellâ€™Adulto
(GIMEMA) group. Dr Sanz leads the Spanish Programa EspaĂ±ol de Tratamiento en HemotologĂa (PETHEMA) group, where he manages the working parties of APL, acute myeloid leukemia (AML), and infections in neutropenic patients.
Intensive study of the biology of APL has resulted in a remarkably thorough understanding of its pathogenesis, as well as the identification of druggable targets.1 Cure rates in newly diagnosed patients with APL, which were essentially nil in the early 1970s, now exceed 70%.2,3 This impressive achievement reflects collaborative laboratory and clinical study. Initially led by innovative investigators in China and France and then by GIMEMA, PETHEMA, and other dedicated cooperative oncology groups throughout the world, efforts to improve clinical outcomes in this rare subtype of AML have culminated in the ultimate reward for both patients and practicing physicians.4,5 Today, APL serves as a paradigm for the treatment of patients with other acute and chronic leukemias.3
In addition to clinical and research updates on unpublished work in APL, the 6th International Symposium on APL educated participants about critical issues related to early patient identification, risk stratification, therapeutic management, molecular monitoring, and supportive care. The symposium also served as a forum for international collaboration and clinical networking for practitioners in developing countries. Finally, the congress offered young investigators the opportunity to interact with global leaders in APL research, share ideas, and learn from experts.
What Is APL?
APL, the M3 subtype of AML, has distinct biologic and clinical features.1-3 Morphologically, APL is characterized by an accumulation of immature white blood cells (WBCs), called promyelocytes, in the bone marrow.6 Cytogenetically, APL is distinguished by the presence of a translocation of genetic material between 2 chromosomes (t[15;17]), specifically a fusion of the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17.7
In normal cells, PML encodes a protein that suppresses tumors and interacts with proteins that are active in cell proliferation and apoptosis. Alteration of PML in APL prohibits these important cell functions. The protein produced from the fused gene PML-RARA, known as PML-RARa, causes abnormal cell proliferation and blocks differentiation of WBCs at the promyelocyte stage. As these promyelocytes accumulate in the bone marrow, the formation of normal WBCs is hindered.6,8 Red blood cell and platelet production is also reduced.8
Because they have low levels of WBCs, red blood cells, and platelets, patients with APL commonly report bruising, petechiae, epistaxis, hematuria, fever, fatigue, pallor, anorexia, weight loss, and joint pain.8 Many patients with APL are at high risk of death from internal hemorrhaging within a few hours after presentation, such that APL is considered a medical emergency. If APL is suspected based on clinical presentation and cell morphology, targeted therapy and supportive transfusion therapies should be initiated immediately. Cytogenetic testing is then conducted to confirm the diagnosis of APL and proceed with induction therapy.
APL is relatively rare, accounting for 10% to 15% of the approximately 14,600 adults diagnosed with AML in the United States each year.9,10 In a recent analysis of a data set from the US Surveillance, Epidemiology, and End Results (SEER) registry (1992-2007), the age-adjusted annual incidence of APL was 0.23 per 100,000 persons.11 The median age at APL diagnosis was 44 years, which is younger than most patients with AML (median age at diagnosis was 66 years, based on 2006-2010 data).11,12
Evolution of APL Treatment
Once considered a highly fatal malignancy, APL has evolved into a highly curable condition with use of targeted therapy.2-4 Today, administration of the new agents, with or without cytotoxic chemotherapy, results in complete remission (CR) in the large majority of patients newly diagnosed with APL, as well as in patients with relapsed or refractory APL.
In their opening remarks at the 6th International APL Symposium, Drs Lo-Coco and Sanz outlined the fascinating history of APL, starting with its identification in 1957, usage of anthracycline-based chemotherapy in the early 1970s, the use of vitamin A derivatives first developed from Chinese herbal medicine in 1987, to new combinations of therapy evaluated in the 21st century (Figure).13
â€śAfter more than 20 years of work in APL, we win because patients are cured. We have defined the dogma of malignancy reversibilityâ€¦.There is no more need for cytotoxic drugs. We now know that we can modulate malignant cellsâ€¦.Why do we have these targeted therapies? Because of the dialogue between scientists and cliniciansâ€¦.All of us have been involved in a great success story; we fought APL and we succeeded.â€ť â€“ Dr Lo-Coco, September 29, 2013.
Clinical Questions in the Treatment of Patients With APL
Although APL is recognized as a success story for translational medicine, nuances in the diagnosis, risk stratification, treatment, and monitoring of patients with APL can be overlooked, and treatment dilemmas remain. During their introductory remarks, both Dr Sanz and Dr Francesco Grignani of the University of Perugia in Italy outlined several clinical questions that remained unanswered by the APL community:
- What is the optimal nonchemotherapeutic choice for patients with low-risk APL? For patients with intermediate-risk APL? Should these patients also receive chemotherapy during induction?
- Must patients with high-risk APL receive chemotherapy during induction? Which cytotoxic agent is most effective? Is an anthracycline always necessary?
- What is the role of cytarabine in consolidation therapy? Which patients are candidates for consolidation with cytarabine based on risk features?
- What is the role of therapeutics in maintenance therapy? Which patients are candidates for maintenance with which therapeutic agents based on their risk status?
- In what circumstances is central nervous system (CNS) prophylaxis (eg, intrathecal [IT] methotrexate) appropriate?
- In APL, the PML-RARA fusion gene can be quantitatively monitored using polymerase chain reaction (PCR) assays to document disease burden and confirm molecular remission. In whom is PCR monitoring appropriate? How often should testing occur?
- What is the ideal management of patients with newer therapies? What can be done to overcome challenges with access to these therapies?
Preventing Early Death in APL
In addition to questions regarding treatment selection, APL experts and meeting presenters highlighted the importance of optimizing early intervention and supportive care. Patients with APL often present to emergency departments or to physiciansâ€™ offices with signs and symptoms of severe coagulopathy. Hemorrhagic events are the primary cause of early death in patients with APL, particularly during the initial days of induction therapy. Despite the availability of effective targeted therapy, an analysis of 1400 patients with APL in the US SEER database (1992-2007) documented an early death rate of more than 17%, and only a modest change in the rate of early death over this 15-year time frame.11 In comparison, international APL cooperative group trials report rates of early deathâ€”typically defined as â€śdeath during or within 7 or 30 days from the start of induction chemotherapy, or as death during induction therapyâ€ťâ€”of less than 10%.14
In light of data like these, several experts presenting at the 6th International APL Symposium emphasized that early death is now the greatest contributor to treatment failure in this otherwise highly curable cancer.14 SEER data and other real-world registry data reveal a significant need for hematologists and healthcare providers (HCPs) across a wide range of medical specialties to appreciate the acute challenges associated with APL. Because they are often the first to suspect APL, emergency department specialists and other HCPs can have a major impact on early death and cure rates in APL.11
Several APL Symposium presentations verified the reality of high early death rates through analyses of patient registries and other databases. During an oral session, Dr R. Rahme of the French Belgian Swiss APL Group reported a 9% early death rate using retrospective data from APL clinical trials conducted in France.15 Using a population-based analysis of Canadian registry data, Dr Matthew Seftel of the University of Manitoba in Winnipeg, Canada, reported an early death rate of 22% among patients with APL.16
To address the need for more effective preventive approaches, Dr Anand Jillella of Georgia Regents University in Augusta, Georgia, presented his research, â€śA Successful Model to Decrease Early and Preventable Deaths in Acute Promyelocytic Leukemia Through the Use of a Simplified Algorithm and Expert Support in Experienced as Well as Smaller Leukemia Treatment Centers in the US.â€ť17 He reported that use of streamlined treatment guidelines, along with support from APL experts, effectively decreased the rate of early deaths in APL in selected Georgia hospitals. Larger-scale implementation of this strategy is now under way in an attempt to decrease early mortality in APL throughout the states of Georgia and South Carolina.
Treatment Of Patients With Newly Diagnosised APL
APL is unique among myeloid leukemias due to its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Unlike cytotoxic chemotherapies, ATRA does not directly kill malignant cells. Rather, treatment with ATRA induces terminal differentiation of malignant myeloid cells into mature neutrophils. Cancer cells develop into mature blood cells, progressing through full differentiation, and become nonmalignant.13,18
Because of the risk of early death secondary to hemorrhage, Dr Sanz and other APL experts reminded symposium participants of the importance of emergent initiation of ATRA treatment and aggressive blood product support for patients with newly diagnosed APL. When clinical findings and cell morphology (peripheral blood examination) suggest APL, ATRA should be started immediately.19
In patients with newly diagnosed APL, ATRA combined with anthracycline-based chemotherapy for induction, followed by 2 years of consolidation and then maintenance, has become the standard of care.19,20 In his lecture regarding first-line treatment of adults with APL, Dr Sanz recalled the initial trial of AIDA (ATRA plus idarubicin) by the Italian cooperative group GIMEMA, which was conducted in 1993 with more than 600 patients newly diagnosed with APL. This trial reported a CR rate of 94% and a 6-year overall survival (OS) rate of 78%.21 Since then, multiple clinical trials have established impressive long-term remission rates in patients with APL receiving ATRA and chemotherapy.21,22
Dr Sanz noted that, while receiving AIDA on protocol, 25% of patients with newly diagnosed APL experienced differentiation syndrome (DS), also known as cytokine release syndrome, a potentially fatal complication characterized by fever, peripheral edema, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, and rash.23,24 When DS is suspected, dexamethasone should be started immediately and maintained until symptoms are eliminated. In patients whose DS symptoms are severe, ATRA should be discontinued. Dr Sanz also reminded the audience that it is appropriate to reduce doses of anthracycline-based chemotherapy in both older patients and in children and adolescents diagnosed with APL in order to minimize morbidity.
In patients with APL, the PML-RARA fusion gene can be quantitatively monitored using PCR assays to document disease burden and confirm molecular remission status. Dr Sanz recommended PCR assessment upon completion of consolidation therapy. Performance of bone marrow biopsy to evaluate response after induction is â€śtoo earlyâ€ť and often provides misleading information.
After completion of consolidation, bone marrow evaluations should be performed every 3 months during the first 3 years, and then periodically depending on the patientâ€™s individual risk and clinical status.23 Dr Sanz noted that evidence establishing the optimal duration of PCR monitoring is not yet available.
The treatment of patients with newly diagnosed APL continues to evolve. Given the known activity of arsenic trioxide (ATO) in relapsed APL, Dr Sanz and colleagues have explored whether ATO-based options are viable alternatives to chemotherapy in newly diagnosed patients. He cited a recent publication by GIMEMA that reported efficacy of ATO plus ATRA in patients with low-risk APL; that is, those whose WBC count was 10 Ă— 109 per liter at diagnosis.25 Three additional studies have examined induction with â€śtriplet therapyâ€ť of ATO combined with ATRA and chemotherapy.26-28 This triplet regimen, followed by ATRA plus ATO in consolidation and ATRA plus chemotherapy as maintenance, was shown to be effective in all patients with APL regardless of risk status.26 Randomized studies comparing induction with ATO plus ATRA versus ATRA plus chemotherapy are currently under way in patients with newly diagnosed low- and intermediate-risk APL.29
Treatment of Patients with Relasped APL
In their presentations regarding the management of relapsed APL, Dr Pierre Fenaux of the French Belgian Swiss APL Group and Dr Martin Tallman of Memorial Sloan Kettering Cancer Center in New York congratulated the APL community for converting relapsed APL into an extremely rare occurrence, particularly among patients with low- and intermediate-risk APL.25
- Although rare, APL relapses occur in 1 of 3 forms30:
- Hematologic or clinical relapse is a symptomatic recurrence that typically occurs within the first 3 years of diagnosis.
- Molecular relapse is detected by rising PML-RARA transcript levels using independent bone marrow samples and PCR analysis by 2 different laboratories. These patients are often asymptomatic.
Extrahematologic relapses are rare. They often occur in the CNS and are usually correlated with molecular relapse in the marrow. Risk factors for extrahematologic relapse include high WBC count at diagnosis, CNS bleeding during induction, use of high-dose cytarabine, and use of IT infusion therapy. Because ATO is now used more frequently in induction, and because the agent crosses the bloodâ€“brain barrier, Dr Fenaux predicted that CNS relapses will occur less often in the future.
Dr Fenaux highlighted steps in the evolution of treatment for relapsed APL, starting with chemotherapy-Âbased regimens and culminating in highly effective ATO-based combinations.30 ATO, which was discovered in China, has consistently demonstrated the ability to generate sustained molecular remissions when used in patients with relapsed APL who were refractory to ATRA-containing regimens.31-33 Unlike ATRA, ATO binds the PML moiety of the PML-RAR oncoprotein, leading to its degradation and resulting in leukemia cell apoptosis.34
The efficacy of ATO in patients with relapsed and refractory APL is well established.35 In a multicenter trial of single-agent ATO, molecular CR was documented in 86% of 40 patients with APL who had relapsed after receiving ATRA-based induction.32 In light of its clear activity and favorable tolerability profile in APL, ATO is now incorporated into large-scale cooperative group studies as a component of induction.
Multiple speakers at the 6th International APL Symposium noted that the cause of relapsed and refractory APL is not fully understood. However, it has been hypothesized to be correlated with unfavorable prognostic factors, such as the presence of FLT3 mutations, the BCR3 isoform of PML-RARA, expression of CD56, and additional cytogenetic aberrations beyond translocation t(15;17).
In this context, Dr Hugues de ThĂ© of UniversitĂ© Denis Diderot, Paris, France, highlighted an example of a rare cytogenetic aberration: the presence of a promyelocyte leukemia zinc finger (PLZF)-RARA fusion gene. In approximately 1% of the cases of APL, RARA fuses with other genes. Among these variant mutations, the t(11;17)(q21;q23) translocation, which generates PLZF-RARA, is most common. PLZF-RARaâ€“positive APL is clinically distinct from PML-RARaâ€“positive APL in that ATRA-based therapy is typically ineffective.36
Like other acute leukemias, APL can occur as a primary or secondary cancer. Dr Armin Rashidi of Eastern Virginia Medical School in Norfolk, Virginia, presented data suggesting that approximately 12% of all cases of APL are therapy-related (t-APL), and about 3% to 13% of all cases of therapy-related AML are actually t-APL.37He noted that even though the incidence of t-APL appears to be rising, the APL communityâ€™s understanding of t-APL stems mainly from sporadic case reports rather than from formal study.
After a systematic review of the English literature through March 15, 2013, Dr Rashidi and colleagues identified a total of 326 t-APL cases. From their analysis of these case reports, they offered the following observations37:
- t-APL affects predominantly middle-aged adults (median age at diagnosis, 47 years; female-to-male ratio, 1.7 to 1)
- The incidence of t-APL appears to be increasing
- The 4 most common primary antecedent conditions were breast cancer, hematologic malignancies (often lymphoma), multiple sclerosis, and genitourinary malignancies
- Topoisomerase II inhibitors and radiation are the most common potential risk factors
- Radiation-related t-APL does not appear to have a longer latency interval than chemotherapy-related APL
- Despite different DNA damage â€śhot spotâ€ť sites, t-APL has no significant clinical or pathologic differences compared with de novo APL; t(15;17) is the sole cytogenetic abnormality in the vast majority of patients with t-APL
- More than one-third of patients with t-APL come to medical attention incidentally (ie, due to abnormal laboratory findings); mucocutaneous bleeding is the most common symptom; most (79%) patients with t-APL have clinical disseminated intravascular coagulation (DIC)
- The remission rate of t-APL is about 80%, which is comparable to that seen in de novo APL.
More than 40 posters were presented during the 6th International Symposium on APL, covering topics ranging from prognostic factors to management of APL in pediatrics and the elderly. Summaries of 4 posters in 3 categories are provided below. Abstracts of all 43 posters can be found at www.apl2013.com/doc/ABSTRACT_BOOK.pdf.
 Chemotherapy versus ATO in Relapsed APL
Dr Pau Montesinos of Valencia, Spain, and other researchers involved with the PETHEMA, HOVON, PALG, and GATLA cooperative research groups, presented a poster entitled â€śLong-Term Outcome of 151 Patients with Relapsed APL Receiving Second-Line with Chemotherapy- or Arsenic Trioxide-Based Regimens.â€ť38 Because long-term outcomes of salvage therapy using an ATO-based approach relative to chemotherapy-based regimens are not well understood, Dr Montesinos and colleagues analyzed the clinical outcome of 151 patients with APL who relapsed after initial therapy (ATRA plus anthracycline) and who received either second-line chemotherapy- or ATO-based regimens.
From June 1997 to May 2013, 151 patients (94 male, 57 female; median age, 42 years [range, 2-81 years]) relapsed after initial therapy in the PETHEMA trials. Patients presented with either molecular relapse (n = 47) or hematologic relapse (n = 104; 24 of which involved the CNS).
Sixty-seven of these relapsed patients received salvage therapy with chemotherapy-based regimens (ie, induction with mitoxantrone, cytarabine, and ATRA [n = 45]; etoposide, mitoxantrone, and cytarabine [n = 7]; or other regimens [n = 15]). Patients who were ineligible for stem cell transplantation (SCT) received consolidation with or without maintenance therapy.
From October 2003, 84 patients received salvage therapy with ATO-based regimens: induction with ATO alone (n = 59), ATO and ATRA (n = 19), or ATO and chemotherapy (n = 6), followed by 1 consolidation cycle of ATO plus ATRA. When the postconsolidation bone marrow PCR results were negative, autologous SCT was recommended. When postconsolidation bone marrow PCR results were still positive, allogeneic SCT was planned. Patients who were ineligible for SCT received maintenance therapy with ATO plus ATRA with or without low-dose chemotherapy.
Baseline characteristicsâ€”sex, relapse risk at primary diagnosis, morphologic and BCR subtype, age at relapse, and type of relapseâ€”were similar in both patient cohorts. Although not significant, patients rescued with chemotherapy-based regimens presented with more â€śearlyâ€ť relapses within 18 months after initial APL diagnosis than did those rescued with ATO-based regimens (55% vs 43%, respectively; P = .13). CR and molecular CR data are summarized in the Table.38 Median follow-up was 95 months (range, 24-167 months) in the chemotherapy-based group, and 33 months (range, 3-100 months) in the ATO-based group. The 5-year OS, disease-free survival (DFS), and relapse-free survival (RFS) results for both groups are also shown in the Table.
This long-term study of a large series of patients with relapsed APL documented high CR rates with both ATO-based and chemotherapy-based salvage regimens. Salvage therapy with ATO-based regimens was more likely to allow autologous SCT (per negative PCR) and resulted in improvements in 5-year OS, DFS, and RFS for patients with relapsed APL.
 Early Use of ATRA
In their poster, â€śOutcome Effects of Early All-Trans Retinoic Acid in Acute Promyelocytic Leukemia: A Multicentric Study,â€ť Dr Rashidi and colleagues noted that APL has long been considered a hematologic-oncologic emergency.39 Upfront initiation of ATRA before molecular confirmation is standard of care in all university-affiliated hospitals in the United States. In contrast, nonâ€“university-affiliated community hospitals may not always follow this standard. In this retrospective multicenter study, Dr Rashidi and colleagues investigated whether delaying ATRA until cytogenetic confirmation affects early outcomes in APL.
Three Virginia and West Virginia hospitalsâ€”University of Virginia (Charlottesville), West Virginia University (Morgantown), and Sentara Hospital (Norfolk, VA)â€”contributed consecutive patients with APL to the study. The mean age of patients was 48 (Â±17) years, and 57% were female. Bleeding (40%), anemia symptoms (29%), and infections (19%) were the most common presenting symptoms (n = 65). According to Dr Sanzâ€™s risk stratification, 23%, 43%, and 34% of patients were low, intermediate, and high risk, respectively.
More than half of the patients (60%) had DIC on admission. Another 4 of the patients (15%) who did not have DIC on admission developed it later. Approximately one-quarter of patients with APL (24%) had additional cytogenetic abnormalities. More than one-third of patients (38%) were transferred to an intensive care unit (ICU) during their hospital stay.
APL was suspected in 76% of patients within the first 2 days of admission, and in 16% between days 3 and 5. ATRA-containing chemotherapy was used in 92% of patients, with the remainder dying before treatment initiation. Twenty patients (32%) who received ATRA developed ATRA syndrome.
ATRA was administered on the day APL was morphologically suspected in 28 patients (44%); there was a delay of at least 1 day in the remainder. In 39 cases (56%), ATRA was postponed despite suspicion of APL. Early death, within the same hospitalization, occurred in 13 patients (19%), 7 of which were due to catastrophic intracranial or intrapulmonary hemorrhage. Patients were then divided into 2 groups: Group A, early death; Group B, no early death.
There were no significant differences between the groups with regard to hospital type (university-affiliated or community), age, sex, presence of additional cytogenetic abnormalities, development of ATRA syndrome, whether or not ATRA was delayed, and the number of days ATRA was delayed. However, DIC on admission and ICU care were significantly more common among Group A than Group B patients (P <.01). Also, patients in Group A had significantly higher risk scores than those in Group B (P<.01).
Researchers concluded that patients with APL in Group A had a worse prognosis, not because of different treatment strategies, but simply because they were â€śsicker.â€ť With inclusion of more data, Dr Rashidi and colleagues will continue to evaluate how delay in ATRA treatment affects early outcomes.
 Minimal Residual Disease
In their poster entitled â€śMonitoring Minimal Residual Disease (MRD) in Patients (pts) with Acute Promyelocytic Leukemia (APL) Treated with All-Trans-Retinoic Acid (ATRA) and Arsenic Trioxide (ATO),â€ť Dr Lorella Melillo and colleagues of the Department of Hematology of the Casa Sollievo della Sofferenza in San Giovanni Rotondo, Italy, reported results of a prospective study of bone marrow minimal residual disease (MRD) monitoring in patients with APL treated with ATO plus ATRA.40
Detection of the PML-RARA fusion gene using bone marrow MRD monitoring is known to be an effective predictor of outcomes in patients treated with ATRA plus chemotherapy. However, the kinetics of leukemia clearance with the use of ATO plus ATRA in induction are significantly different from those with the use of ATRA plus chemotherapy (ie, AIDA protocol). To assess the value of MRD monitoring in ATO-plus-ATRA recipients, Dr Melillo and colleagues followed 6 patients with APL who were treated with this combination, 3 of whom had newly diagnosed APL and 3 who had relapsed disease (2 with bone marrow plus CNS relapse).
MRD was monitored upon completion of induction and after consolidation, as well as every 2 months during maintenance for the first 2 years and then every 6 months thereafter. A total of 72 bone marrow samples were obtained for quantitative PCR analysis. Another 120 bone marrow samples were obtained from 12 different patients with APL who were treated with the AIDA protocol during the same period.
All 6 patients treated with ATO plus ATRA achieved molecular CR, with 4 patients alive and in molecular CR at the end of the study. Three patients with relapsed APL who were successfully retreated with ATRA plus ATO underwent allogeneic bone marrow transplants, but 2 died secondary to relapsing disease at +8 and +12 months from bone marrow transplant, respectively. In 1 of 3 patients treated at diagnosis, PCR results were transiently positive after achievement of molecular CR, but the patient had not experienced hematologic relapse after 30 months of follow-up.
Preliminary data demonstrated a strong correlation between quantitative PCR for PML-RARA values and patient outcomes. The authors concluded that serial MRD monitoring can be a predictor of RFS in patients with APL treated with ATO plus ATRA without chemotherapy.
Dr Thoraya Adbel Hamid of the National Cancer Institute at Cairo University in Egypt presented the poster â€śMinimal Residual Disease (MRD) Detection in Acute Promyelocytic Leukaemia and Its Relation to Clinical Outcome.â€ť42 Dr Hamid and colleagues studied the PML-RARA fusion gene with real-time PCR (RT-PCR) before and after therapy to assess its prognostic value and impact on therapeutic decision-making. They calculated levels of PML-RARA by different methods, including normalized copy number (NCN), which is calculated as copy number of PML-RARA divided by copy number of ABL multiplied by 10,000.
This study included 41 patients with newly diagnosed APL. RT-PCR was performed before treatment and then after consolidation. Induction and consolidation included ATRA and daunorubicin or idarubicin for 3 courses. Maintenance therapy was given with 6-mercaptopurine, methotrexate, and ATRA for 2 years.
Of the 41 patients in the study, 30 achieved hematologic remission and underwent MRD detection, 8 failed to achieve CR, and 3 died early. The decrease in expression level of PML-RARA using NCN after consolidation was highly significant.
During the observation period of 39 months (range, 1-56 months), 6 patients relapsed. The time between detection of molecular relapse and appearance of hematologic relapse ranged from 1 to 3 months, with most cases clustering in the third month. The DFS rate was 69%, while OS was 77% (mean, 50 months).
Patients with low-risk APL had significantly longer DFS and OS versus patients with high-risk APL. Researchers also demonstrated a highly significant correlation between a 2 or more log reduction of PML-RARA after consolidation and improved DFS.
Dr Hamid and colleagues concluded that MRD monitoring is essential for follow-up on patients with APL, for prediction of relapse, and for choice of therapy. The PML-RARA NCN method that was used was both simple and accurate, and enabled standardization among laboratories.
- Melnick A, Licht JD. Deconstructing a disease: RARa, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999;93:3167-3215.
- Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002;99:759-767.
- Tallman MS. Acute promyelocytic leukemia as a paradigm for targeted therapy. Semin Hematol. 2004;41(2 suppl 4):27-32.
- Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505-2515.
- Degos L, Dombret H, Chomienne C, et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood. 1995;85:2643-2653.
- Genetics Home Reference. PML. http://ghr.nlm.nih.gov/gene/PML. Published October 21, 2013. Accessed October 28, 2013.
- Grignani F, Ferrucci PF, Testa U, et al. The acute promyelocytic leukemia-specific PML-RARa fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993;74:423-431.
- Genetics Home Reference. Acute promyelocytic leukemia. http://ghr.nlm.nih.gov/condition/acute-promyelocytic-leukemia. Published October 21, 2013. Accessed October 28, 2013.
- Tallman MS, Altman JK. Curative strategies in acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 2008:391-399.
- Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.
- Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248-1254.
- Surveillance Research Program of the National Cancer Institute. Annual SEER Cancer Statistics Review 1975-2010. Bethesda, MD: NCI; 2013. http://seer.cancer.gov/csr/1975_2010/results_merged/sect_01_overview.pdf. Accessed October 31, 2013.
- Advances in the management of acute promyelocytic leukemia: summary of the presentation by Dr. Lo-Coco at AMHOQ. New Evidence in Oncology. 2013;20:46-51.
- McClellan JS, Kohrt HE, Coutre S, et al. Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica. 2012;97:133-136.
- Rahme R, Thomas X, Recher C, et al. Early deaths (ED) in APL in France: a retrospective study in 399 patients (pts). Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract C17.
- Seftel MD, Serebrin A, Lambert P, et al. Epidemiology and outcomes of acute promyelocytic leukemia: a pan-Canadian population-based analysis. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy.
- Jillella A, Kolhe R, Awan F, et al. A successful model to decrease early and preventable deaths in acute promyelocytic leukemia through the use of a simplified algorithm and expert support in experienced as well as smaller leukemia treatment centers in the US. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract C18.
- Calleja EM, Warrell RP. Differentiating agents in pediatric malignancies: all-trans-retinoic acid and arsenic in acute promyelocytic leukemia. Curr Oncol Rep. 2000;2:519-523.
- Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood. 2009;114:5126-5135.
- AdĂ¨s L, Guerci A, Raffoux E, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010;115:1690-1696.
- Lo-Coco F, Avvisati G, Vignetti M, et al; Italian GIMEMA Cooperative Group. 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;116:3171-3179.
- Sanz MA, Montesinos P, RayĂłn C, et al; PETHEMA and HOVON Groups. 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;115:5137-5146.
- Sanz MA. Front-line therapy in acute promyelocytic leukemia. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy.
- Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113:775-783.
- Lo-Coco F, Avvisati G, Vignetti G, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111-121.
- Iland HJ, Bradstock K, Supple SG, et al; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120:1570-1580.
- 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;116:3751-3757.
- Hu J, Liu YF, Wu CF, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly-diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009;106:3342-3347.
- Lo-Coco F, Avvisati G, Orlando SM, et al. 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. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 6.
- Fenaux P. Relapsing APL. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy.
- Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354-3360.
- Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852-3860.
- Breccia M, Lo-Coco F. Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother. 2012;13:1031-1043.
- Shao W, Fanelli M, Ferrara FF, et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells. J Natl Cancer Inst. 1998;90:124-133.
- Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315-3324.
- Jansen JH, LĂ¶wenberg B. Acute promyelocytic leukemia with a PLZF-RAR fusion protein. Semin Hematol. 2001;38:37-41.
- Rashidi A, Fisher SI. Therapy-related acute promyelocytic leukemia: a systematic review. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract C22.
- Montesinos P, MartĂnez-CuadrĂłn D, Rivas C, et al; on behalf of the PETHEMA, HOVON, PALG, and GATLA cooperative groups. Long-term outcome of 151 patients with relapsed APL receiving second-line with chemotherapy- or arsenic trioxide-based regimens. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P23.
- Rashidi A, Goudar R, Sayedian F, et al. Outcome effects of early all-trans retinoic acid in acute promyelocytic leukemia: a multicentric study. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P20.
- Melillo L, Minervini MM, Bodenizza C, et al. Monitoring minimal residual disease (MRD) in patients (pts) with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P07.
- Ley TJ. The APL genome. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy.
- Hamid TA, Alla FG, Garaar E, Raslan H. Minimal residual disease (MRD) detection in acute promyelocytic leukaemia and its relation to the clinical outcome. Presented at: 6th International Symposium on Acute Promyelocytic Leukemia; September 29-October 2, 2013; Rome, Italy. Abstract P11.
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