Introduction Of All-trans Retinoic Acid Research Articles

PATHOGENESIS AND TREATMENT OF THROMBOHEMORRHAGIC DIATHESIS IN ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukemia (APL) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha). APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA) for the cure of APL, fatal hemorrhages due, at least in part, to the APL-associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha)], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO) also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication.

Addition of Hemoglobin Level Into the Prognostic Scoring System Together with White Blood Cell and Platelet Count Provides Better Prognostic Stratification for Overall Survival, Complete Remission Rate and Early Death, but Not for the Relapse Risk in Adult Patients with Acute Promyelocytic Leukemia

Abstract 4898 Background:Although the introduction of all-trans retinoic acid (ATRA) and combined chemotherapy improved clinical outcomes of acute promyelocytic leukemia (APL), treatment failure still occur due to early death or disease relapse. The PETHEMA study suggested that the risk adapted stratification of disease into 3 groups (low, intermediate and high risk) according to the white blood cell (WBC; 10×109/L) and platelet counts (40×109/L) could improve treatment outcomes of APL patients. However, this stratification system needs to be validated in an independent cohort of patients. The current study attempted to validate the prognostic significance of WBC count, platelet counts, hemoglobin level and PETHEMA risk stratification system in Asian population and to propose new clinical prognostic system consisting of WBC counts, platelet counts and hemoglobin level. Methods and patients:Between 2000 and 2009, total of 156 consecutive patients with APL from 7 institutes in Republic of Korea were retrospectively reviewed. The patients received Idarubicin/ATRA based combination chemotherapy during remission induction, and consolidation therapy was given with idarubicin monotherapy or Idarubicin plus cytarabine. In the new 3 score prognostic model, WBC more than 10×109/L, platelet less than 40×109/L as well as hemoglobin less than 8g/dL were separately considered as an one risk factor, and patients having “0”, “1” and “2 or 3” risk factors fall into a score “0”, “1” and “2”, respectively. Results:With median follow-up of 3.8 years, the CR rate following remission induction treatment was 81.4% in overall patients (127 out of 156), and 24 (15.4%) were considered as failures due to early death (ED) within 30 days of APL diagnosis. The 4-year OS, LFS and CIR rate was 73.8±4.1%, 85.7±3.7, and 18.7±3.8%, respectively. Compared to the single variables such as WBC count, platelet count or hemoglobin level, the combined prognostic system such as PETHEMA stratification or CBC score provided better stratification for the prognosis in APL patients. The risk stratification system by PETHEMA could predict OS (p=0.014) and ED (p=0.024), but not CR rates or relapse. However, the proposed 3 score prognostic system could provide better stratification of APL patients in term of the CR rates (p=0.004), OS (p=0.004) and ED (p=0.008), but not of relapse risk. Conclusions:This retrospective study suggested that the proposed 3 score prognostic system could provide better stratification of APL patients in term of the CR rates, OS and ED, but not of the relapse risk. Prospective study with a single protocol will be needed to reach a clean conclusion of better clinical prognostic stratification of APL patients. Disclosures:No relevant conflicts of interest to declare.

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

Coagulopathy occurs in most patients with (APML) and is life-threatening; therefore prompt diagnosis and recognition of any coagulation defect is imperative. Unfortunately haemorrhage remains a major cause of early death, preventing some from reaching treatment. The coagulopathy is caused directly or indirectly by the leukaemic cells through expression of activators of coagulation and fibrinolysis, proteases and cytokine generation, compounded by failure of platelet production due to marrow invasion. At presentation the predominant feature is usually hyperfibrinolysis. Since the introduction of all-trans retinoic acid (ATRA), patient outcome has dramatically improved; yet, haemorrhagic complications remain the most frequent cause of mortality. Thrombotic complications occur but are less well recognized and potentially underreported. Supportive measures and prompt initiation of ATRA currently represent the mainstay of treatment of the coagulopathy in patients with suspected APML, but unanswered questions remain as to the optimal approach to further decrease the associated haemorrhagic and thrombotic risks. In particular, it is unclear how to best predict and monitor the coagulopathy; whether there is a role for the early use of antifibrinolytics; the most appropriate trigger for giving fibrinogen replacement and the value of low-dose anticoagulation to suppress coagulation activation once fibrinolysis has been suppressed.

Reality of Pediatric Cancer in Iraq

This brief report displays comprehensive details of health services provided by Children's Welfare Teaching Hospital, medical city, Baghdad. In 2010; 366 children with newly diagnosed cancer were admitted for treatment, two thirds were leukemia and lymphoma cases followed by other solid tumors except brain tumors. With this large number of patients; there are shortcomings in provision of health services in many aspects including professional manpower, infrastructure, diagnostic and therapeutic facilities, supportive and palliative care. The previous wars and sanction and the current instability of the country added to the socioeconomic difficulties of the families jeopardizing the appropriate therapy and ultimately the poor treatment outcome. Since 2003 an international collaboration had a major contribution in many aspects like provision of drugs and medical supplies, attendance of scientific workshops, and updating doctor's knowledge and experience through telemedicine programs which resulted in decreasing the induction mortality in acute lymphoblastic leukemia from 24% in the year 2007% to 10% in 2010 after introduction of pre-phase steroids and in acute promyelocytic leukemia from 95% to 5% after introduction of all trans-retinoic acid. A collaborative work with Rome University resulted in changing diagnosis of 20% of pathological samples sent there for reevaluation. Iraqi pediatric oncologists still need real attempts to improve infrastructure and human resources in addition to twinning programs with internationally recognized cancer centers to face these management challenges.

A Blueprint for Advancing Genetics-Based Cancer Therapy

In the era of next-generation sequencing, there are significant challenges to harnessing cancer genome information to develop novel therapies. Key research thrusts in both academia and industry will speed this transition, and lessons learned for cancer will more broadly shape the process for genetic contributions to the therapy of disease more broadly.

Managing acute promyelocytic leukemia without conventional chemotherapy: is it possible?

The introduction of all-trans retinoic acid in 1985 combined with anthracycline-based chemotherapy has revolutionized the prognosis of acute promyelocytic leukemia (APL) with current complete response rates of more than 90% and cure rates of approximately 80%. The subsequent advent of arsenic trioxide in 1994 marked an additional milestone in APL treatment and has inspired the design of rationally targeted, chemotherapy-free front-line treatment regimens without compromising the excellent outcome achieved by anthracycline-containing protocols. APL is, therefore, a unique subtype of acute myeloid leukemia potentially curable with targeted therapies without any exposure to conventional DNA-damaging chemotherapy. Cure rates of APL can be further increased by implementing management strategies to reduce early hemorrhagic deaths, which remain the major cause of treatment failure with the current therapy.

Emerging new approaches for the treatment of acute promyelocytic leukemia

The introduction of all-trans retinoic acid (ATRA) in the late 1980s combined with anthracycline-based chemotherapy has revolutionized the prognosis of acute promyelocytic leukemia (APL) with more than 90% complete response rates and cure rates of approximately 80%. The subsequent advent of arsenic trioxide (ATO) in 1990s and progress in the treatment of APL have changed its course from a highly fatal to a highly curable disease. Despite the dramatic improvement in clinical outcome of APL, treatment failure still occurs due most often to early death. Relapse has become increasingly less frequent, most commonly occurring in patients with high-risk disease. A major focus of research for the past decade has been to develop risk-adapted and rationally targeted nonchemotherapy treatment strategies to reduce treatment-related morbidity and mortality to low- and intermediate-risk or older patients while targeting more intensive or alternative therapy to those patients at most risk of relapse. In this review, emerging new approaches to APL treatment with special emhasis on strategies to reduce early deaths, risk-adapted therapy during induction, consolidation and maintenance, as well as an overview of current and future clinical trials in APL will be discussed.

Arsenic in the treatment of newly diagnosed acute promyelocytic leukemia: current status and future research direction

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. In past decades, intensive studies on the biology and treatment of this disease have resulted in a remarkably thorough understanding of its pathogenesis and improvement of treatment outcomes. In particular, the introduction of all-trans retinoic acid to conventional chemotherapy improved dramatically the remission and survival rates of APL patients and consequently became the major treatment modality for it. In the last decade, the groundbreaking development of arsenic further improved the survival rate of APL patients. As the most active agent in APL, arsenic directly degrades the PML-RARα fusion transcript, leading to the differentiation and apoptosis of leukemia cells and the potential eradication of APL leukemiainitiating cells (LICs), thus making the disease a potentially curable type of leukemia. More notably, the recent development of oral arsenic compounds may further enhance not only clinical outcomes but also the convenience of patients, which may dramatically change the APL clinical scenario in the near future.

Arsenic-Induced Pancreatitis

The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide has brought about tremendous advancement in the treatment of acute promyelocytic myelogenous leukemia (APML). In most instances, the benefits of these treatments outweigh the risks associated with their respective safety profiles. Although acute pancreatitis is not commonly associated with arsenic toxicity, it should be considered as a possible side effect. We report a case of arsenic-induced pancreatitis in a patient with APML.

Addition of Hemoglobin Level Into the Prognostic Scoring System Together with White Blood Cell and Platelet Count Provides Better Prognostic Stratification for Treatment-Related Mortality and Overall Survival, but Not for Relapse Risk In Adult Patients with Acute Promyelocytic Leukemia

AbstractAbstract 4371 Background:Although the introduction of all-trans retinoic acid (ATRA) and combined chemotherapy improved clinical outcomes of acute promyelocytic leukemia (APL), treatment failure still occur due to early death or disease relapse. The PETHEMA study suggested that the risk adopted stratification of disease risk into 3 groups (low, intermediate and high risk) according to the white blood cell (WBC; 10×109/L) and platelet counts (40×109/L) could improve treatment outcomes of APL patients. However, this stratification system needs to be validated in an independent cohort of patients. The current study attempted to validate the prognostic system based on WBC and platelet counts, hemoglobin level, risk stratification system by PETHEMA and proposed prognostic system consisting of WBC and platelet counts and hemoglobin level. Methods and patients:Total of 164 patients was included retrospectively from 5 institutes in Republic of Korea. In patients receiving Idarubicin/ATRA based combination chemotherapy. Consolidation therapy was given with Idarubicin monotherapy in 79 patients, or Idarubicin plus cytarabine in 42 patients. Result:With median follow-up of 2.94 years, the CR rate following remission induction treatment was 83.9% in overall patients, while the 3 years OS, TRM and relapse rate was 77.6±3.5%, 20.4±3.3, and 9.6±3.1%, respectively. The combined prognostic system provided better stratification of APL patients according to their prognosis compared to single variable comparison such as WBC counts, platelet counts or hemoglobin level. In addition, the risk stratification system by PETHEMA could predict OS (p=0.06) and TRM (p=0.05), but not CR rates (p=0.1) or relapse (p=0.7). However, the proposed 3 score prognostic system could provide better stratification of APL patients in term of the CR rates (p=0.01 vs 0.1 between 3 score system vs PETHEMA risk stratification), OS (p=0.02 vs. 0.06) and TRM (p=0.006 vs 0.05), but not of relapse risk (p=0.9 vs 0.7). Conclusion:This retrospective study suggested that the proposed 3 score prognostic system could provide better stratification of APL patients in term of the CR rates, OS and TRM, but not of relapse the risk. Further study will be needed to reach a clear conclusion of better prognostic stratification of APL patients with large number of patients. Disclosures:No relevant conflicts of interest to declare.

Mobilization of PML/RAR negative peripheral blood stem cells with a combination of G-CSF and CXCR4 blockade in relapsed acute promyelocytic leukemia pre-treated with arsenic trioxide

Mobilization of PML/RAR negative peripheral blood stem cells with a combination of G-CSF and CXCR4 blockade in relapsed acute promyelocytic leukemia pre-treated with arsenic trioxide

Pediatric Acute Promyelocytic Leukemia: All-transretinoic Acid Therapy in a Brazilian Pediatric Hospital

Acute promyelocytic leukemia (APL) is an uncommon form of pediatric acute nonlymphocytic leukemia. It is characterized by clinical (refractory coagulopathy), morphologic (promyelocytic differentiation arrest), and cytogenetic t(15;17) hallmarks. The introduction of all-transretinoic acid (ATRA) or tretinoin, a biologic response modifier, in its therapy was followed by dramatic improvement in its outcome. To show the results of APL treatment in our hospital, we reviewed the information about 15 patients less than 18 years old, newly diagnosed with APL between November 2002 and November 2006. The diagnosis was made upon examination of bone marrow aspirates. The clinical charts were searched for data regarding clinical presentation, diagnosis, initial response with induction therapy, toxicity of ATRA, and antracyclic drug (daunorubicin). The median age was 10 years; the male-to-female ratio was 2:1. Fourteen patients received induction chemotherapy. Thirteen achieved complete remission. Six patients showed signs of coagulopathy. Only 1 patient was diagnosed with ATRA syndrome. There was a death owing to sepsis before the beginning of the therapy and 2 relapses with death associated with the therapy discontinuation. Preliminary results are encouraging and confirm that ATRA is safe and efficacious as first choice therapy for APL.

Acute promyelocytic leukemia: from highly fatal to highly curable

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia. Morphologically, it is identified as the M3 subtype of acute myeloid leukemia by the French-American-British classification and cytogenetically is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARalpha). It seems that the disease is the most malignant form of acute leukemia with a severe bleeding tendency and a fatal course of only weeks. Chemotherapy (CT; daunorubicin, idarubicin and cytosine arabinoside) was the front-line treatment of APL with a complete remission (CR) rate of 75% to 80% in newly diagnosed patients. Despite all these progresses, the median duration of remission ranged from 11 to 25 months and only 35% to 45% of the patients could be cured by CT. Since the introduction of all-trans retinoic acid (ATRA) in the treatment and optimization of the ATRA-based regimens, the CR rate was raised up to 90% to 95% and 5-year disease free survival (DFS) to 74%. The use of arsenic trioxide (ATO) since early 1990s further improved the clinical outcome of refractory or relapsed as well as newly diagnosed APL. In this article, we review the history of introduction of ATRA and ATO into clinical use and the mechanistic studies in understanding this model of cancer targeted therapy.

Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome

Even after the introduction of all-trans retinoic acid (ATRA), early hemorrhagic death remains a major cause of remission induction failure for acute promyelocytic leukemia (APL). To investigate severe hemorrhagic complications during remission induction therapy with respect to incidence, risk factors, and influence on outcome. Results were analyzed for 279 patients enrolled in the APL97 study conducted by the Japan Adult Leukemia Study Group (JALSG). Severe hemorrhage occurred in 18 patients (6.5%). Although most of them were receiving frequent transfusions, the targeted levels of platelet counts (30 x 10(9)/L) and plasma fibrinogen (1.5 g/L) for this study were reached at the day of bleeding in only 71% and 40%, respectively. Nine of them succumbed to an early death, while the remaining nine patients eventually achieved complete remission (CR). The 5-yr event-free survival rate was 68.1% for those who did not suffer severe hemorrhage, and 31.1% for those who did (P < 0.0001). For patients who achieved CR, on the other hand, there was no difference in disease-free survival between patients with and without severe hemorrhage (P = 0.6043). Risk factor analysis identified three pretreatment variables associated with severe hemorrhage: initial fibrinogen level, white blood cell count, and performance status. Additionally, patients with severe hemorrhage were more easily prone to develop retinoic acid syndrome or pneumonia than patients without hemorrhage. These results indicate that fatal hemorrhage represents a major obstacle in curing APL, and that patients with such high-risk features may benefit from more aggressive supportive care.

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.

CNS Relapses of Acute Promyelocytic Leukemia After All-trans Retinoic Acid

OBJECTIVE:To review the role of all-trans retinoic acid (ATRA) and arsenic trioxide in central nervous system (CNS) relapses of acute promyelocytic leukemia (APL).CASE SUMMARY:A 69-year-old white man diagnosed with APL presented with bleeding diathesis. His molecular and cytogenetic studies were positive for promyelocytic leukemia—retinoic acid receptorα (PML-RARα) and t(15;17) transformation. Complete molecular and cytogenetic remission was achieved with ATRA, daunorubicin, and cytarabine. Within 6 months, the patient was readmitted for investigation of severe global headaches and an ataxic gait. His peripheral blood and cerebral spinal fluid were positive for PML-RARα fusion protein. Intrathecal chemotherapy and radiation, as well as ATRA, were the main treatment modalities provided. Molecular and cytogenetic remission was again obtained. Three months later, a second relapse occurred in the CNS and the peripheral blood.DISCUSSION:APL is typically treated with anthacycline-based chemotherapy and ATRA. Approximately 85–95% of patients achieve complete remission (CR); however, the relapse rate has been reported to be about 30–40%. A thorough literature search (MEDLINE, EMBASE, CANCERLIT, 1966–January 2002) revealed only 54 cases of extramedullary disease, of which 35 involved the CNS.CONCLUSIONS:The introduction of ATRA has improved patient survival dramatically. APL relapse, in general, has been in part attributable to repetitive or prolonged exposure to ATRA and the possibility of additional chromosomal changes, making the disease more refractory to treat. Given the evidence, one could argue that, with repeated ATRA treatment, CR duration may be shortened. However, limited data are available to guide the appropriate management of APL relapsed to the CNS with either ATRA, chemotherapy, or arsenic trioxide. In our opinion, treatment using arsenic trioxide is an unconventional option worthy of exploring.

Rapid diagnostic approach to PML-RARalpha-positive acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a distinct entity characterized by a specific bone marrow morphology and a rearrangement of the PML- and the RARalpha-gene mostly due to a balanced translocation between the long arm of chromosome 15 with a breakpoint in 15q22 and the long arm of chromosome 17 with a breakpoint in 17q12-21. The introduction of all trans retinoic acid (ATRA) into treatment protocols has improved the outcome of APL dramatically. Therefore, it is essential to establish the diagnosis of APL as quickly and as reliably as possible. We investigated 1714 newly diagnosed AML. In 92 cases an AML M3 (n=67) or M3v (n=25) was diagnosed using cytomorphology. In all these cases chromosome banding analysis and molecular studies were performed. In 3/92 APL cases (3.2%) normal chromosomes 15 and 17 in chromosome banding analysis were observed. In these cases either an insertion of parts of the PML-gene into the RARalpha-locus or an insertion of parts of the RARalpha-gene into the PML-locus was detected by FISH analysis. In all three patients a PML-RARalpha-rearrangement was also observed by RT-PCR. A small subgroup of APL shows cryptic rearrangements of the PML- and RARalpha-gene that are undetectable by cytogenetics. This is analogous to Ph-negative, BCR-ABL-positive CML cases. FISH and RT-PCR have to be performed in all cases that show the typical characteristics of AML M3 or M3v in cytomorphology in addition to chromosome banding analysis.

Current Controversies: Which Patients With Acute Myeloid Leukaemia Should Receive A Bone Marrow Transplantation? – An Adult Treater's View

Current Controversies: Which Patients With Acute Myeloid Leukaemia Should Receive A Bone Marrow Transplantation? – An Adult Treater's View

Acute promyelocytic leukemia: Clinical and morphologic features and prognostic factors

The most impressive clinical feature of acute promyelocytic leukemia (APL) at diagnosis is the presence in 80% to 90% of patients of a severe hemorrhagic syndrome. Recent data favor a fibrinolytic/proteolytic process rather than a disseminated intravascular coagulation as the mechanism mainly responsible for the hemorrhagic diathesis in APL. Morphologically, two main cytologic variants have been identified: the classical hypergranular APL (M3), which represents the great majority of all APL, and the microgranular variant (M3v), which accounts for about 15% to 20% of all APL. A rare basophilic variant has also been described. With regard to prognosis, it has markedly changed from that of a rapidly fatal acute leukemia to that of a highly curable disease. This revolutionary progress was mainly due to the introduction during the 1990s of all- trans retinoic acid (ATRA) for the treatment of this disease. After the introduction of ATRA, in addition to clinical features such as hyperleukocytosis (white blood cell count > 10 × 10 9/L) or thrombocytopenia (platelet count < 10 × 10 3/L) at presentation, immunophenotype markers and polymerase chain reaction status for promyelocytic leukemia/retinoic acid receptor-α during follow-up also had an impact on prognosis.