Optimizing treatment for elderly patients with acute promyelocytic leukemia: is it time to replace chemotherapy with all-trans retinoic acid and arsenic trioxide?

This review focuses on the treatment of acute promyelocytic leukemia (APL) in elderly patients and offers recommendations for improving outcomes. Nineteen percent of patients with APL are ≥60 years. Rates of response and survival are lower in elderly compared with younger patients, owing to a higher incidence of early deaths or deaths in remission. However, relapse-free survival rates are similar in both groups. Ongoing trials assess the role of reduced-intensity regimens. All-trans retinoic acid (ATRA) and concurrent arsenic trioxide is associated with high rates of response and molecular remission and low rates of induction deaths. We propose this combination as the treatment of choice in patients with APL, including the elderly. Patients with elevated leukocyte counts may also benefit from gemtuzumab ozogamicin therapy, with or without leukapheresis. Monitoring major organ function and toxicity is essential. Patients should be assessed for minimal residual disease using polymerase chain reaction testing for promyelocytic leukemia-retinoic acid receptor alpha. If molecular relapse is evident, treatment with ATRA and idarubicin, with or without gemtuzumab ozogamicin, is recommended.     

Utilization of molecular phenotypes to detect relapse and optimize the management of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by a unique genetic aberration, the t(15;17) chromosome translocation. Translocation breakpoints are located within the promyelocytic leukemia (PML) locus on chromosome 15 and the retinoic acid receptor alpha (RARA) locus on chromosome 17. In the past 2 decades, critical advances have been made in understanding the molecular pathogenesis of APL. APL represents a paradigm for molecularly targeted therapy in cancer and an extraordinary model for translational research in medicine. In fact, the release of differentiation block upon treatment of APL with all-trans-retinoic acid (ATRA) has represented the first example of targeted therapy in human cancer. More recently, the advent of arsenic trioxide (ATO) has allowed further progress in the management of this disease through improved outcomes in patients receiving this agent in combination with ATRA. Finally, optimization of therapy and minimization of toxicity is feasible in this disease through careful monitoring of residual disease using polymerase chain reaction-based approaches targeting the PML-RARA fusion gene.     

Acute promyelocytic leukemia

Opinion statement The treatment of acute promyelocytic leukemia (APL) is different from other subtypes of acute myelocytic leukemia (AML). All trans-retinoic acid (ATRA) is an essential component of the standard remission induction for all newly diagnosed APL patients. Remission induction with ATRA and chemotherapy given concurrently appears to be associated with fewer relapses. With further consolidation chemotherapy without high-dose cytosine arabinoside, the disease-free survival rate can reach 70% to 80%, and many of these patients are cured, more so than in any other AML subtype. APL is especially sensitive to anthracyclines, which should be included in the chemotherapy cycles at a higher dose than in other AML subtypes. Maintenance with low-dose chemotherapy (oral daily 6-mercaptopurine with weekly methotrexate) or ATRA further improves the long-term outcome. New approaches are also available for relapsing patients, although the optimal treatment is unknown. Patients who did not receive oral ATRA in first relapse can be treated with this agent, as can first relapsing patients who have been off the drug for more than 1 year. Because of poor remission rates, ATRA should not be used in patients with second or subsequent relapses (whether ATRA was given in the past), in patients with relapses early after ATRA discontinuation, or in patients relapsing while on ATRA therapy. Arsenic trioxide can also be used, especially in patients resistant to ATRA. Because arsenic trioxide is still experimental and not yet widely available, patients who are unlikely to respond to ATRA or who unsuccessfully undergo ATRA reinduction should be treated with chemotherapy. Patients in second or subsequent remission induced with ATRA or chemotherapy should receive consolidation chemotherapy. When arsenic trioxide is used for reinduction, the drug should be continued for several cycles; however, adding consolidation chemotherapy might improve the results. Because it is unknown whether APL in second or subsequent remission is curable with salvage therapy, allogeneic hematopoietic stem cell transplantation is often considered for patients with a human leukocyte antigen (HL-A)-identical sibling and autologous transplantation when a donor does not exist. However, compared with the new treatments, the role of transplantation for relapse is unclear. In first remission, there is no role for transplantation. A new liposomal formulation of intravenous ATRA is being investigated and seems effective in late first relapses, and it may be able to induce and maintain first remissions in selected patients without chemotherapy.     

Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate.

Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.     

Treatment of acute promyelocytic leukemia without cytotoxic chemotherapy

The introduction of all-trans retinoic acid, or ATRA, in 1985, combined with anthracycline-based chemotherapy, has transformed acute promyelocytic leukemia (APL) from a fatal disease to one that is now highly curable. With appropriate contemporary therapy, more than 90% of patients achieve complete remission, and cure rates of approximately 80% and higher response and survival rates can be expected for patients at low and intermediate risk. The introduction of arsenic trioxide, or ATO, in 1994 has provided the opportunity to minimize and even eliminate standard cytotoxic chemotherapy from initial treatment regimens without compromising the excellent outcomes achieved by anthracycline-containing protocols. APL is a unique subtype of acute myeloid leukemia that is curable with targeted therapies and potentially without exposure to conventional DNA-damaging chemotherapy. The omission of conventional cytotoxic chemotherapy may reduce long-term complications such as cardiomyopathy and therapy-related myelodysplastic syndromes. Cure rates of APL may be further increased by adopting management strategies to reduce early hemorrhagic deaths, which now appear to be the major cause of treatment failure.     

Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.     

Differentiating agents in pediatric malignancies: All-trans-retinoic acid and arsenic in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is the most potentially curable type of acute myeloid leukemia. It is characterized by the chromosomal translocation t(15;17), which results in the fusion gene PML-RAR-α. The introduction of all-trans- retinoic acid (ATRA) was a major advance in treatment of this disease. This agent induces terminal differentiation of malignant myeloid cells to mature neutrophils, and its side effects are usually well tolerated in children. ATRA does not eradicate the malignant myeloid clone in APL and, eventually, resistance develops. Arsenic trioxide induces nonterminal differentiation of malignant promyelocytes and promotes apoptosis. APL patients treated with ATRA or arsenic trioxide have rapid resolution of their coagulopathy. Because both of these drugs are well tolerated in children and their synergy has been shown in animal models, the possibility of combining ATRA and arsenic trioxide in frontline therapy for children with APL is being considered.     

Contemporary Treatment of APL

Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80–90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.     

The expression of annexin II and its role in the fibrinolytic activity in acute promyelocytic leukemia

Bleeding in acute promyelocytic leukemia (APL) is mainly associated with disseminated intravascular coagulation and hyperfibrinolysis. Annexin II (Ann II) is a co-receptor for plasminogen and tissue plasminogen activator (tPA). This study demonstrates that abnormally high levels of Ann II expression in APL cells increase the production of plasmin. Hyperfibrinolysis could be corrected by all-trans retinoic acid (ATRA) or ATRA plus arsenic trioxide therapy in patients with APL. SiRNA targetting Ann II caused a decrease in tPA-dependent plasmin generation, while Ann II cDNA transfectant stimulated plasmin production. These results suggest that Ann II play an important role in hyperfibrinolysis in APL.     

Acute promyelocytic leukemia: recent advances in diagnosis and management

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by a specific genetic alteration, affecting the retinoic acid receptor-alpha (RARalpha), and leading to a blockage in the differentiation of the granulocytic cells. The accumulation of the promyelocytic blasts in the bone marrow produces intense peripheral blood cytopenias or, less commonly, hyperleucocytosis, both of which are frequently associated with a life-threatening consumptive coagulopathy. The body of available biological information on APL establishes this leukemia as a unique entity that has to be promptly recognized and clearly distinguished from all other acute leukemias, especially in light of its striking response to treatment with anthracyclines and differentiating agents such as all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). Current state-of-the-art treatments, which include simultaneous administration of ATRA and anthracycline-based chemotherapy for induction and consolidation, as well as ATRA-based maintenance, have dramatically transformed APL into the most curable acute leukemia in adults, with approximately 80% of long-term survivors. Risk-adapted strategies to modulate treatment intensity may be an effective approach to minimizing therapy-related morbidity and mortality while maintaining the potential of cure. Nonetheless, a sizeable proportion of patients will relapse after the ATRA-based upfront therapy. Given the high anti-leukemic efficacy observed with ATO in patients who relapse, this agent is currently regarded as the best treatment option in this setting. In this article, we will review the current treatment strategies in the management of newly diagnosed and relapsed APL. We also highlight other aspects that can be crucial for the outcome of individual patients, including supportive care, recognition and treatment of life-threatening complications, management of ATRA- and ATO-associated adverse events, and the role of minimal residual disease (MRD) monitoring.     

Outcome of therapy‐related acute promyelocytic leukemia with or without arsenic trioxide as a component of frontline therapy

BACKGROUND:

Patients with therapy‐related acute promyelocytic leukemia (t‐APL) have been commonly exposed to topoisomerase inhibitors and may potentially benefit from induction regimens omitting anthracyclines.

METHODS:

Retrospective analysis of the outcomes of 29 patients with t‐APL who were either treated with arsenic trioxide (ATO) and all‐trans‐retinoic acid (ATRA) or with standard ATRA plus anthracycline‐based chemotherapy was performed.

RESULTS:

Prior therapy included chemotherapy alone, radiation alone, or a combination of the 2 in 19%, 33%, and 47% of patients, respectively. The combination of ATO and ATRA (n = 19) for induction resulted in a similar remission rate compared with ATRA plus chemotherapy (n = 10) (89% vs 70%; P = .35). The median overall survival for the patients treated with ATRA plus ATO was not reached compared with that for patients treated with ATRA plus chemotherapy (161 weeks; P = .79).

CONCLUSIONS:

In this cohort of t‐APL patients, outcomes with ATO and ATRA appeared to be comparable to anthracycline‐containing induction regimens. This combination may be preferable in t‐APL patients to avoid any risk of anthracycline‐induced toxicities. Cancer 2011. © 2010 American Cancer Society.     

Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non‐t(15;17) subtype

Aims: The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all‐trans retinoic acid (ATRA) improves overall survival (OS) or disease‐free survival (DFS) is still debated. Methods: A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French – American – British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m²/day p.o., mercaptopurine 60 mg/m²/day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m²/d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients). Results: In all patients the rates of CR, 3‐year OS and 5‐year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5‐year OS and 5‐year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively. Conclusion: Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.     

全反式维甲酸联合化疗治疗小儿急性早幼粒细胞白血病

目的观察全反式维甲酸（ATRA）联合化疗治疗小儿急性早幼粒细胞白血病（APL）的疗效。方法22例初治患儿用ATRA诱导治疗;当患儿获完全缓解（CR）后,给予DA方案或IDA方案或HA方案或AA方案巩固治疗3个疗程;以后再用ATRA、化疗交替巩固治疗36个月。结果2例在诱导治疗前死于弥散性血管内凝血（DIC）、颅内出血;22例获CR,CR率100％（20／20）。1、3、5年无病生存（DFS）率分别为100％（20／20）、93．3％（14／15）、84．7％（11／13）。ATRA常见毒副作用依次为皮肤和口唇干燥、头痛、恶心、呕吐、肝功能损害及维甲酸综合征。结论ATRA联合化疗治疗小儿APLCR率高、远期疗效好;在诱导治疗前,DIC、颅内出血仍是APL患儿死亡的主要原因;ATRA毒副作用可耐受。     

Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG)

All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.     

Treatment of acute promyelocytic leukemia for older patients

Acute promyelocytic leukemia (APL) represents a remarkable disease in which leukemogenesis is driven by the PML-RARα oncogene and for which targeted treatment with all-trans retinoic acid (ATRA)-based therapy allows substantial chance of cure. APL is seen in a small subset of older patients, with age representing one of the most important prognostic factors for outcome of treatment. Unlike other acute leukemias, the inferior outcomes for APL in older patients relates less to changes in disease biology and more to the increased toxicity of ATRA and the chemotherapy combination regimens used to induce hematologic and molecular responses. Risk-adapted strategies that use less-toxic agents, such as arsenic trioxide, allow treatment of older patients, with greater efficiency and better chances of cure.     

Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia.

Acute promyelocytic leukemia (APL) is characterized by a number of features that underpin the need for rapid and accurate diagnosis and demand a highly specific treatment approach. These include the potentially devastating coagulopathy, sensitivity to anthracycline-based chemotherapy regimens, as well as unique responses to all-trans retinoic acid and arsenic trioxide that have revolutionized therapy over the last decade. The chromosomal translocation t(15;17) which generates the PML-RARalpha fusion gene has long been considered the diagnostic hallmark of APL; however, this abnormality is not detected in approximately 10% cases with successful karyotype analysis. In the majority of these cases, the PML-RARalpha fusion gene is still formed, resulting from insertion events or more complex rearrangements. These cases share the beneficial response to retinoids and favorable prognosis of those with documented t(15;17), underscoring the clinical relevance of molecular analyses in diagnostic refinement. In other cases of t(15;17) negative APL, various chromosomal rearrangements involving 17q21 have been documented leading to fusion of RARalpha to alternative partners, namely PLZF, NPM, NuMA and STAT5b. The nature of the fusion partner has a significant bearing upon disease characteristics, including sensitivity to retinoids and arsenic trioxide. APL has provided an exciting treatment model for other forms of AML whereby therapeutic approach is directed towards cytogenetically and molecularly defined subgroups and further modified according to response as determined by minimal residual disease (MRD) monitoring. Recent studies suggest that rigorous MRD monitoring, coupled with pre-emptive therapy at the point of molecular relapse improves survival in the relatively small subgroup of PML-RARalpha positive patients with 'poor risk' disease. Advent of 'real-time' quantitative RT-PCR technology seems set to yield further improvements in the predictive value of MRD assessment, achieve more rapid sample throughput and facilitate inter- and intra-laboratory standardization, thereby enabling more reliable comparison of data between international trial groups.     

Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene.     

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.