Introduction Of All-trans Retinoic Acid Research Articles

Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia

AbstractThe introduction of all-trans retinoic acid combined with anthracyclines has significantly improved the outcomes for patients diagnosed with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries in which arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly because of high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited from 2005 to 2020 in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has notably decreased to 14.6% compared with the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age of ≥40 years, Eastern Cooperative Oncology Group performance status score of 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level of ≤3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival rate is 81%, the 4-year disease-free survival rate is 80%, and the 4-year cumulative incidence of relapse rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia.

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments.

CPX-351 and allogeneic stem cell transplant for a therapy-related acute myeloid leukemia that developed after treatment of acute promyelocytic leukemia: a case report and review of the literature

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.

How to avoid early mortality in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL), a phenotypically and genotypically unique subtype of acute myeloid leukemia, has seen unprecedented advances in its management since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide. However, the phenomenal pharmacologic conversion of this once highly fatal disease to one with a long-term survival exceeding 90% among patients who survive induction remains impaired by the significant incidence of early death (ED) reaching 30% in some real-world studies. The key driver for ED in APL is catastrophic hemorrhage with a proclivity for cranial sites. Most EDs in APL are currently considered preventable. Here, we discuss the concept of early death in APL and its characteristics. Importantly, we outline implementable strategies to reduce the incidence of ED. Early recognition of APL underpins these preventive measures as significant delays in the diagnosis increase the likelihood of ED. While early administration of ATRA is often taught to all hematology trainees, this lifesaving intervention is only possible if providers, including those in emergency departments and urgent/immediate care settings, are trained to have a high index of suspicion and competence to recognize the morphologic and clinical characteristics of the disease. Other proposed strategies tackle the complications that can be present at diagnosis or arise during induction therapy and address the issues of expert consultation and protocol adherence in the management of these patients. While some of these measures appear intuitive and others aspirational, widespread adoption could bring about an era of cure for almost every patient with APL.

Hematopoietic Stem Cell Transplantation in Acute Promyelocytic Leukemia in the Era of All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO).

Acute promyelocytic leukemia (APL) currently represents one of the malignant hemopathies with the best therapeutic responses, following the introduction of all-trans retinoic acid (ATRA) and subsequently of arsenic trioxide (ATO) treatment. As a result, a large proportion of patients with APL achieve long-term responses after first-line therapy, so performing a hematopoietic stem cell transplant as consolidation of first complete remission (CR) is no longer necessary. Even in the case of relapses, most patients obtain a new remission as a result of therapy with ATO and ATRA, but an effective consolidation treatment is necessary to maintain it. The experience accumulated from studies published in the last two decades shows the effectiveness of hematopoietic stem cell transplantation (HSCT) in improving the outcome of patients who achieve a new CR. Thus, the expert groups recommend transplantation as consolidation therapy in patients with a second CR, with the indication for autologous HSCT in cases with molecular CR and for allogeneic HSCT in patients with the persistence of minimal residual disease (MRD) or with early relapse. However, there is a variety of controversial aspects related to the role of HSCT in APL, ranging from the fact that outcome data are obtained almost exclusively from retrospective studies and historical analyses to questions related to the type of transplantation, the impact of minimal residual disease, conditioning regimens, or the role of other therapeutic options. All these questions justify the need for controlled prospective studies in the following years.

The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away.

Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO). ATRA's success has deepened our understanding of the role of the RARα pathway in normal hematopoiesis and leukemogenesis, and it has influenced a generation of cancer drug development. Retinoids have also demonstrated some efficacy in a handful of other disease entities, including as a maintenance therapy for neuroblastoma and in the treatment of cutaneous T-cell lymphomas; nevertheless, the promise of retinoids as a differentiating therapy in acute myeloid leukemia (AML) more broadly, and as a cancer preventative, have largely gone unfulfilled. Recent research into the mechanisms of ATRA resistance and the biomarkers of RARα pathway dysregulation in AML have reinvigorated efforts to successfully deploy retinoid therapy in a broader subset of myeloid malignancies. Recent studies have demonstrated that the bone marrow environment is highly protected from exogenous ATRA via local homeostasis controlled by stromal cells expressing CYP26, a key enzyme responsible for ATRA inactivation. Synthetic CYP26-resistant retinoids such as tamibarotene bypass this stromal protection and have shown superior anti-leukemic effects. Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.

High Risk Acute Promyelocytic Leukemia - An Enigma for Hematologists: Optimizing Treatment with APML-4 Protocol.

Management of Acute Promyelocytic Leukemia (APML) has improved drastically after the introduction of ATRA (All-trans-retinoic acid) and Arsenic trioxide (ATO). The use of APML-4 protocol has shown its effectiveness in Australian population. We know that high-risk APML represents a subset with poor outcomes. There is scarcity of literature reporting outcomes of high-risk APML from India. We present a 5-year retrospective analysis of the safety and efficacy of APML-4 protocol in our 28 high-risk patients. Of 28 patients, there were 8(28.5%) early deaths; all 20 patients (100%) who were alive achieved hematologic complete remission post-induction and molecular complete remission post-consolidation. The 5-year disease free survival, failure free survival (FFS) and overall survival were 100%, 69% and 69% respectively. Factors affecting FFS were age > 45years (p = 0.008), baseline ECOG-PS > 1 (p < 0.0001), and grade 3-4 differentiation syndrome (p = 0.008). APML-4 protocol in high-risk patients is capable of achieving excellent disease control with less toxicities. While early induction deaths in high-risk APML still remain an issue, protocol modifications (for steroid and anthracyclines) are important considering high frequency of infections at baseline and during induction therapy in our population.

Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

Acute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all-trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death.

Acute Promyelocytic Leukemia in Children: A Model of Precision Medicine and Chemotherapy-Free Therapy.

Acute promyelocytic leukemia (APL) represents a paradigm of precision medicine. Indeed, in the last decades, the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) completely revolutionized the therapeutic approach to this previously highly fatal disorder. This entirely chemotherapy-free treatment, which provided excellent survival rates, has been initially validated in adults and, recently, translated in the pediatric setting. This review summarizes currently available data on the use of ATRA and ATO combination in pediatric APL, providing a particular focus on peculiar issues and challenges, such as the occurrence of pseudotumor cerebri and death during induction (early death), as well as the advantage offered by the ATO/ATRA combination in sparing long-term sequelae.

Early mortality and overall survival in acute promyelocytic leukemia – a single-center experience

Acute promyelocytic leukemia (APL) is a subtype of acute leukemia (AL) with distinct cytogenetics, clinical and biological characteristics. APL was considered as one of the most rapidly lethal forms of acute myeloblastic leukemia (AML), but recently, with the introduction of all-trans retinoic acid (ATRA) it has become the most curable subtype of AL. The main difficulty with APL is early death (ED), defined as death because of any cause within 30 days after diagnosis, and it has emerged as the most important cause of treatment failure. Our retrospective-prospective study was realized at the University Clinic for Hematology from January 2004 until December 2020. It included 46 patients with APL, according to FAB and WHO classification with confirmed molecular diagnosis. The following patients’ risk stratification factors were analyzed: age, Sanz risk score, WBC, PL, clinical presentation of the disease, levels of fibrinogen and D-dimers. During the study period, APL was diagnosed in 46 patients, 24 females (52.2%) and 22 males (47.8%), with mean age of 45 years. The overall survival showed that 24 patients (52.1%) were alive and 22 (47.8%) had lethal outcome. Regarding treatment, five patients (10.9%) died before starting the chemo-treatment. But, still, ED was observed in 13 patients (59%), and in 9 patients (40.9%) death occurred 30 days after establishing the diagnosis. The main reasons of mortality were also analyzed. To prevent ED prior to treatment, suspected APL patients should be immediately hospitalized and treated as medical emergency. Keywords: acute promyelocytic leukemia, early death, all-trans retinoic acid

UK Experience of an Alternative ATO Dosing Regimen in APL.

The introduction of all-trans retinoic acid (ATRA), and more recently of arsenic trioxide (ATO) in the treatment of Acute Promyelocytic Leukaemia (APL), has been instrumental in achieving the high cure rates recently reported. For the majority of patients, it is now possible to successfully treat this disease “chemo-free” without the use of cytotoxic chemotherapy as reflected in current clinical guidelines. The Sanz risk score developed by the GIMEMA and PETHEMA groups categorizes patients into three risk groups—low, intermediate, and high and correlates with relapse-free survival (RFS). Low- and intermediate-risk APL are now often considered together as ‘standard-risk’ defined by a white blood cell count (WBC) of less than 10 x 109/L. High-risk APL has a WBC greater than 10 x 109/L. In the UK our approach for patients with standard risk APL is to treat with ATRA and ATO without the use of cytotoxic chemotherapy. This approach is based on results from two large randomized clinical trials. The GIMEMA APL0406 trial showed an overall survival advantage compared to anthracycline-based chemotherapy plus ATRA. The UK NCRI AML17 trial which used an attenuated dose of ATO demonstrated a significant reduction in relapse and improved relapse-free survival. In the UK, the National Institute for Clinical Excellence approved both ATO plus ATRA regimens for re-imbursement for standard risk Acute Promyelocytic Leukaemia (APL). We use the AML17 schedule in standard-risk patients upfront and also in patients with relapsed Acute Promyelocytic Leukaemia (APL) previously treated with chemotherapy or in those with molecular persistence. The treatment of high-risk Acute Promyelocytic Leukaemia (APL) remains an area of contention as ATO is not approved for this indication. These patients have a greater risk of complications during remission induction with ATO including differentiation syndrome. The optimal approach is to incorporate chemotherapy early into the treatment schedule with either Gemtuzumab Ozogamicin (GO) as in the high-risk arm of the NCRI AML17 trial and MD Anderson Cancer Centre studies or Idarubicin as in the Australian APML4 study.

Early Mortality and Overall Survival in Acute Promyelocytic Leukemia: Do Real-World Data Match Results of the Clinical Trials?

Introduction Acute promyelocytic leukemia (APL), considered a medical emergency, requires prompt treatment at the first suspicion of the diagnosis. Treatment is initiated even before cytogenetic or molecular confirmation of diagnosis because of high early mortality with APL, mostly due to hemorrhage and disseminated intravascular coagulation. Once a cancer with dismal prognosis, APL is now considered a highly curable cancer with the introduction of all-trans retinoic acid and arsenic trioxide. In fact, recent clinical trials in APL report excellent outcomes with &amp;gt;90% OS at 3-years with &amp;lt;5% mortality in the first 4-6 weeks. Here we analyze a large National Cancer Database (NCDB) to determine one-month mortality and overall survival (OS) of patients with APL treated in real-world practices. Methods We utilized the NCDB Participant User File to identify patients of all age groups who were diagnosed between 2004 and 2015. A Chi-square test was used to determine association of different covariates with one-month mortality. Multiple logistic regression analysis was used to evaluate the effect of covariates on the probability of one-month mortality. A full model was run that included all covariates; the subsequent reduced model included covariates significant at the p&amp;lt;0.1. OS was analyzed with Kaplan Meier methods. Results Our study included a total of 7190 patients- median age was 50 years, 50% were female, 82% were white, 53% had private insurance, 82% had Charlson comorbidity index (CCI) of 0 or 1, and 57% were treated at academic centers. Ninety-seven percent of patients were treated with either multiagent (67%) or single-agent chemotherapy (30%). Patients diagnosed in 2004-2009 comprised 49% of total cohort, the remaining 51% were diagnosed in 2010-2015. One-month mortality for the entire cohort was 12%. One-month mortality varied significantly for different age groups: 6% for &amp;lt;35, 8% for 35-54, and 18% for ≥55 years. One-month mortality was not significantly different based on the year of diagnosis or CCI. In a multivariate analysis, patients &amp;lt;55 years of age (p&amp;lt;0.0001), and those with private insurance (p&amp;lt;0.0001) had lower one-month mortality (Table 1). Patients treated at comprehensive cancer centers, as compared to academic centers, had worse one-month mortality (p=0.005). Median OS at 1-, 3-, and 5-year were 81%, 75%, and 71% respectively. OS differed significantly based on age. Median OS was not reached for patients &amp;lt;55 years, compared to 6.5 years for patients ≥55 years (Figure 1). Detailed analysis will be presented. Conclusion Our large national database study demonstrates that early mortality is still high in real-world practices. OS at 1 year (81%) is worse than reported OS of &amp;gt;90% in clinical trials. Surprisingly, only 1/3rd of patients received single agent chemotherapy, which is not the standard of care. The use of suboptimal chemotherapy may not explain high early mortality rate but may explain worse OS. We also identified age as a significant predictor of outcomes with older adults ≥55 years almost at a two-fold higher risk of early and late mortality. Lower rate of enrollment of older adults may yet be another reason for higher OS seen in clinical trials. Our findings highlight the challenges associated with translating trial findings to clinical practices and provide rationale to support studies aimed at improving outcomes of APL in the real world. Disclosures Gundabolu: BioMarin: Consultancy; Bristol Myers Squibb pharmaceuticals: Consultancy. Chaulagain:Sanofi Genzyme: Honoraria. Bhatt:Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Jazz: Research Funding; Rigel: Consultancy; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy.

Advances in the management of coagulopathy in acute promyelocytic leukemia

Since the introduction of all-trans retinoic acid and, more recently, arsenic trioxide into the therapy of acute promyelocytic leukemia (APL), significant improvements in patient outcomes have been achieved, and this disease has become the most curable subtype of acute myeloid leukemia. However, while primary leukemia resistance has virtually disappeared, a sizable fraction of APL patients still die before or during induction therapy. Hemorrhagic death still remains the major problem during this early phase of treatment and, to a lesser extent, deaths due to infection, differentiation syndrome and other causes. Patients with APL typically present with a range of laboratory abnormalities consistent with the diagnosis of disseminated intravascular coagulation and hyperfibrinolysis. This APL-associated coagulopathy, as a result of a dysregulation of the hemostatic system due to the imbalance between procoagulant, anticoagulant and profibrinolytic mechanisms, may show a variety of clinical manifestations, ranging from minimal bleeding or localized thrombosis to lethal or life-threatening hemorrhages or thrombotic events that sometimes occur concomitantly. Hemorrhagic events are the most common cause of death associated with APL coagulopathy, but thrombosis, a less recognized and probably underestimated life-threatening manifestation of the thrombo-hemorrhagic syndrome, is also a non-negligible cause of morbidity and mortality in patients with APL. In this article, we aim to discuss recent advances in the knowledge of pathogenesis, predictors of thrombo-hemorrhagic events, management of coagulopathy associated with APL and the controversial issues that still persist.

Acute Promyelocytic Leukemia: A History over 60 Years-From the Most Malignant to the most Curable Form of Acute Leukemia.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARα) genes. Because patients with APL present a tendency for severe bleeding, often resulting in an early fatal course, APL was historically considered to be one of the most fatal forms of acute leukemia. However, therapeutic advances, including anthracycline- and cytarabine-based chemotherapy, have significantly improved the outcomes of APL patients. Due to the further introduction of all-trans retinoic acid (ATRA) and—more recently—the development of arsenic trioxide (ATO)-containing regimens, APL is currently the most curable form of AML in adults. Treatment with these new agents has introduced the concept of cure through targeted therapy. With the advent of revolutionary ATRA-ATO combination therapies, chemotherapy can now be safely omitted from the treatment of low-risk APL patients. In this article, we review the six-decade history of APL, from its initial characterization to the era of chemotherapy-free ATRA-ATO, a model of cancer-targeted therapy.

Intravenous arsenic trioxide and all-trans retinoic acid as front-line therapy for low-risk acute promyelocytic leukemia

ABSTRACTIntroduction: The outcome of acute promyelocytic leukemia (APL) has drastically improved following the identification of the PML-RARA oncogene as a key player in the pathogenesis of APL, and the subsequent introduction of all-trans retinoic acid (ATRA) as a therapeutic agent.Areas covered: Randomized trials have recently demonstrated the efficacy of arsenic trioxide (ATO) in combination with ATRA for the front-line treatment of standard and medium risk APL patients. This chemotherapy-free combination is associated with a decreased cumulative rate of relapse, prolonged overall survival, and reduced early death rate.Expert commentary: The most challenging issue in the management of APL remains the significant rate of early deaths in high-risk patients. The ongoing studies will clarify the possible role of ATO in this setting in combination with ATRA and other agents. The aim of this review is to report data of efficacy and safety of intravenous ATO in newly diagnosed patients and discuss on its potential role as a new standard of care for APL patients.

Acute Promyelocytic Leukemia: Clinical Outcomes, Induction Deaths and Challenges

IntroductionAcute promyelocytic leukemia (APL) was an oncologic emergency but the introduction of All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) ameliorated the treatment outcomes. A translocation of chromosomes which was once considered most fatal and patients bled till death in the course; is highly curable now, thanks to the dramatic advancement happened in the development of single/combined use of regimens.It is reported way back in 2008 that APL cases in India have a varied genetic setup. There is a significant dearth of published articles on APL cases from India. In a developing country, especially like India; where the patient pays for the cancer care ‘out of pocket’ and also where the GDP spent on health care is less than 5 percent, the management of APL is certainly challenging as the average cost of treatment runs to $2183 (Median per capita income in India is $616). In addition, clinical outcomes are highly influenced by multidrug resistant microbes and several environmental factors. They have critically increased the infection and early death rate.MethodsTo discern the clinical outcomes of APL at our center we performed a retrospective record-based study of APL patients. We went through 156 Acute myelocytic leukemia patients over the past 16 years from July 2002 to January 2018 and out of which 19 patients were diagnosed with APL in our tertiary care hospital. Our aim was to determine the clinical outcome, cause of induction death and the current challenges in APL management. We included all the fresh cases diagnosed at our center and we set exclusion criteria as those who denied the treatment due to social/financial constraints and those whom we have lost follow-up.ResultsThe patients were from the age of 10 years to 67 years (Mean age: 38.5). 31.5 percent of the patients were male and 68.4 percent were female. 47.3 percent of the patients were in the high-risk APL group and 15.7 percent of the patients belonged to the low risk group. The remaining 36.8 percent patients comprised the intermediate risk group. Promyelocytic retinoid acid receptor alpha (PML/RARX) was standard for all patients. For 18 patients we gave ATRA for 45 days and one patient expired during induction due to bleeding (ATRA syndrome). Arsenic was given for 20 days. At the end of induction, we did a bone marrow aspiration and PML/RARA. All 18 patients had complete remission. PML/RARX shows Zero for all 18 patients. 11.1 percent of the patientsexpired and16.66 percent of the patients are alive with disease. 72.2 percent of the patients are alive without disease and until the most recent follow-up; they showed no sign of recurrence.ConclusionsDespite certain noteworthy challenges which must be taken into consideration, our center presents more than 70 percent relapse free survival. In conclusion, if infection control, social support and health security improves, the survival rate can go even higher as a lot of AML patients diagnosed in our hospital and other various centers across India had denied the treatment because of the financial and social constraints. Our finding reveals a good survival rate and must open novel prospects for cost-effective targeted therapies of a much shorter duration in developing countries. DisclosuresNo relevant conflicts of interest to declare.

Cell dynamics during differentiation therapy with all-trans retinoic acid in acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.

Management of patients with acute promyelocytic leukemia.

With the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) acute promyelocytic leukemia (APL) has become from a detrimental to one of the most curable malignant diseases in humans. In particular, the chemotherapy-free regimen with ATO/ATRA has been proven to be highly effective in de novo APL and has become standard first-line therapy in younger adult, non-high-risk patients. Nevertheless, early death is still a major issue in APL, particularly in older patients, emphasizing the need of rapid diagnostics and supportive care together with immediate access to ATRA-based therapy. Despite the dramatic progress achieved in therapy of APL challenging situations occur, particularly in patients excluded from controlled studies with clinical knowledge mainly based on case reports and registries. Rapid identification and treatment of newly diagnosed patients as well as the management of toxicities and complications remain challenging. We offer up-to-date information and guidance regarding treatment of APL. Based on a literature review of existing scientific evidence we also discuss the approach to high-risk, elderly, pregnant and pediatric patients, treatment in patients with renal failure as well as of therapy-related or relapsed/refractory APL.

Novel Chemotherapeutics in AML

Over the past several decades, despite advances in understanding the biology of AML, the standard therapy for patients with this disease has changed very little with the notable exception of the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in the therapy of acute promyelocytic leukemia (APL). The combination of cytarabine and an anthracycline continues to be the basis for most induction and consolidation regimens in other types of AML. Older patients with AML, particularly the septa and octogenarians and those with comorbid conditions, are less able to tolerate the traditional cytotoxic chemotherapy and have been treated using less toxic strategies such as the use of hypomethylating agents decitabine and 5-azacytidine.

Validation of a Molecular Risk Score for Prognosis of Patients With Acute Promyelocytic Leukemia Treated With All-trans Retinoic Acid and Chemotherapy-containing Regimens.

Although treatment of acute promyelocytic leukemia (APL) has evolved dramatically during the past decades, especially with the introduction of all-trans retinoic acid, risk stratification remains an important issue. To date, relapse risk can be predicted by leukocyte and platelet counts only. In the present report, we present a validation study on 3 candidate genes and a newly developed molecular risk score for APL in 2 independent patient cohorts. An integrative risk score combining the expression levels of BAALC, ERG, and WT1 was calculated for 79 de novo APL patients from the original cohort and 76 de novo APL patients from a validation cohort. Gene expression analysis was executed the same for both cohorts, and the results regarding the effect on patient outcomes were compared. The expression levels of BAALC, ERG, and WT1 were similar in both cohorts compared with the healthy controls. The relapse and survival rates were not different between the low- and high-risk patients according to the Sanz score. However, application of the molecular risk score on the validation cohort distinctly discriminated patients according to their risk of relapse and death just as in the original APL cohort, although single gene analyses could not reproduce the negative prognostic impact. The analysis clearly validated the prognostic effect of the integrative risk score on the outcome in APL patients. The value was further empowered because the single gene analyses did not show similar results. Whether the integrative risk score retains its prognostic power in the chemotherapy-free setting should be investigated further.