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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute promyelocytic leukaemia (APL) with M3 (or M3v) morphology is the only AML subtype to date for which morphology and immunophenotype agree. In other words, FAB M3 is interchangeable with a unique marker profile. More precisely, we have finally recognized a surrogate marker profile for leukaemia derived from the (15;17) translocation and expressing PML/RARalpha transcripts. To present this as a new development may come as a surprise to many. After all, the antigen expression pattern of AML-M3 was well recognized for many years: absence or weak expression of HLA-DR, CD117, CD15, CD11b and CD34 in the context of a myeloid phenotype (CD33 and CD13 expression) and frequently associated with moderate to high side-scatter appearance upon flow cytometric evaluation, depending upon the degree of granularity of the leukaemic cells. While partially correct, this established APL phenotype is both flawed and limited in its ability to distinguish APL from other AML subtypes, such as natural-killer-cell AML. Given the availability of phenotype-specific therapy for APL, such as all-trans retinoic acid or arsenic trioxide, failing to diagnose APL or misdiagnosing a case of AML with an APL-like phenotype will result in serious clinical consequences. Faced with this dilemma, we have recently performed a comprehensive immunophenotypic analysis of APL patients entered on Eastern Cooperative Oncology Group trials. Our results give diagnostic power to only three antigens, HLA-DR, CD11a and CD18, all of which are characteristically expressed at low levels by APL cells. Despite some significant antigenic differences (e.g. in CD34 expression), this surrogate marker profile for t(15;17) APL applies to both the M3 and the M3v FAB phenotypes and to all three isoforms of the PML/RARalpha transcript.
Best Pract Res Clin Haematol 2003 Sep
PMID:Expression of cell-surface antigens in acute promyelocytic leukaemia. 1293 57

It has been 12 years since the simultaneous discovery of the unique sensitivity of acute promyelocytic leukaemia (APL) to differentiation therapy with all-trans retinoic acid (ATRA) and the discovery that the retinoic acid receptor alpha (RARalpha) gene was rearranged in APL. Nearly 98% of cases of APL are associated with t(15;17) chromosomal translocation and fusion of the PML gene to that encoding RARalpha to yield an abnormal receptor with the capability of de-regulating gene expression in the haematopoietic cell, causing differentiation block and eventually the development of leukaemia. Since this original discovery, four other translocations were described in APL. In each of these the RARalpha gene is fused to different partner genes, all yielding aberrant nuclear receptors. These fusion proteins share in common the ability to repress rather than activate retinoic acid targets, one so strongly that the result is an ATRA-resistant form of the disease. In addition each of the partner proteins is important for normal cell growth and development. In this chapter we explore the biology of the RARalpha, the fusion proteins created in APL and the normal forms of the partner proteins. Through continued study of this disease it is hoped that novel treatments, potentially more applicable to other forms of leukaemia, may arise.
Best Pract Res Clin Haematol 2003 Sep
PMID:Molecular pathogenesis of acute promyelocytic leukaemia and APL variants. 1293 58

Our understanding of the genetic basis of acute myeloid leukaemias has been enhanced through cloning of recurring chromosomal translocation breakpoints. However, the remarkable observation, more than a decade ago, that all-trans retinoic acid (ATRA) induced remission in patients with t(15;17) acute promyelocytic leukaemia (APL) was a driving force in the subsequent cloning and characterization of the PML-RARalpha fusion that is causally implicated in the pathogenesis of this disease. Major improvements in treatment and outcome of APL patients have been made since that time by incorporating ATRA in conventional chemotherapy but 30% of APL patients still succumb to complications of their disease or their therapy. Recent information that the haematopoietic receptor tyrosine kinase FLT3 is mutated in about 30% of APL patients suggests strategies for further improving treatment and outcome in this subset of APL patients using small-molecule inhibitors of FLT3. The role of FLT3 mutations in APL and other AML will be discussed.
Best Pract Res Clin Haematol 2003 Sep
PMID:FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors. 1293 59

The vitamin A derivative, all-trans retinoic acid (ATRA), induces differentiation of leukaemic promyelocytes in patients with acute promyelocytic leukaemia (APL). As a result, the majority of patients achieve complete remission either with ATRA alone or with combined ATRA and chemotherapy. The most important complication is the retinoic acid syndrome, which is usually successfully treated with the early administration of dexamethasone. Prospective randomized trials have shown that ATRA is better than conventional chemotherapy in newly diagnosed patients, that ATRA combined with chemotherapy confers an advantage with respect to relapse rate, compared to ATRA alone for induction followed by chemotherapy for consolidation, and that maintenance therapy with ATRA or ATRA plus low-dose chemotherapy is beneficial. The presence of adverse prognostic factors, including older age, presenting white blood cell count and platelet count, expression of CD56 and presence of mutations in the FLT3 gene, identify patients at risk for relapse for whom new strategies are needed.
Best Pract Res Clin Haematol 2003 Sep
PMID:All-trans retinoic acid in acute promyelocytic leukaemia. 1293 60

Cure of acute promyelocytic leukaemia (APL) is now a reality for most patients through the use of combined all-trans retinoic acid (ATRA) and chemotherapy. The simultaneous administration of ATRA and anthracycline-based chemotherapy is currently considered the most appropriate induction therapy. However, no consensus has been reached on the consolidation strategy. Therapeutic efficacy apparently did not differ according to the number of cycles and types of drug combined with anthracyclines. Encouraging results have been reported recently using less-intensive chemotherapy with anthracyclines alone, leading to a significant reduction in treatment-related toxicity during the consolidation phase and a high degree of compliance. Some ongoing risk-adapted protocols are now exploring the potential synergistic effect of ATRA and chemotherapy given simultaneously in consolidation. Preliminary data suggest that higher molecular remission rates post-consolidation and improved outcome may be obtained through this strategy. Persistence or recurrence of molecular disease at the end of consolidation is strongly associated with impending relapse and poor prognosis, indicating the need for further aggressive therapy. As for maintenance therapy, once demonstrated, the advantage of using ATRA with or without low-dose methotrexate and 6-mercaptopurine has encouraged most groups to incorporate such treatment into their protocols for APL.
Best Pract Res Clin Haematol 2003 Sep
PMID:Choice of chemotherapy in induction, consolidation and maintenance in acute promyelocytic leukaemia. 1293 61

All-trans retinoic acid (ATRA) is a potent differentiation agent that is effective therapy in acute promyelocytic leukaemia. Although ATRA is generally well tolerated, some patients develop retinoic acid syndrome. This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure. However, if identified early enough, effective therapy can be administered. This chapter discusses the clinical aspects and pathogenesis of retinoic acid syndrome.
Best Pract Res Clin Haematol 2003 Sep
PMID:Retinoic acid syndrome: manifestations, pathogenesis, and treatment. 1293 62

Life-threatening bleeding, which remains a challenging complication of acute leukaemia, is particularly characteristic of the subtype, acute promyelocytic leukaemia (APL). The clinical picture and laboratory abnormalities are most compatible with the diagnosis of disseminated intravascular coagulation (DIC). Evidence for diffuse activation of the coagulation system, hyperfibrinolysis and systemic elaboration of non-specific protease activity can usually be demonstrated and occurs most commonly during induction chemotherapy. While both host- and tumour-associated mechanisms can be implicated in the pathogenesis of the coagulopathy, leukaemic cell properties appear to be the proximate cause of activation of the haemostatic mechanisms. In this chapter we summarize the current state of knowledge of the pathogenesis of the coagulopathy of APL and the therapeutic approaches that have proved most useful for the management of this complication. Special attention is devoted to the use of all-trans-retinoic acid (ATRA), which has revolutionized the treatment of APL and markedly ameliorated the APL-related coagulopathy.
Best Pract Res Clin Haematol 2003 Sep
PMID:Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia. 1293 63

Only 15 to 20% of acute promyelocytic leukaemia (APL) patients are older than 60 years, and the characteristics and outcome of APL in that age range are not well known. Published studies show that APL in elderly patients has haematological features similar to those of APL in younger patients. However, using the current combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, the outcome for these patients, although it has much improved, remains less favourable than that for younger patients. This is due to a higher incidence of early deaths and deaths in complete remission (CR), during consolidation chemotherapy courses, whereas the relapse rate appears similar in older and younger adults. Treatment approaches with more limited myelosuppression, especially consolidation chemotherapy with an anthracycline alone (without Ara-C), low-dose maintenance treatment with 6-mercaptopurine, methotrexate and ATRA, and consolidation with arsenic trioxide, should be tested especially in elderly patients in order to replace more toxic 'classical' anthracycline-Ara-C consolidation treatment, after achieving CR with ATRA.
Best Pract Res Clin Haematol 2003 Sep
PMID:Treatment of older adults with acute promyelocytic leukaemia. 1293 65

Modern molecular technology makes it possible to detect minimal residual acute promyelocytic leukaemia (APL) when the marrow remains in complete remission (CR). Thus, an important question, and the first to be discussed, is whether patients should be treated at molecular relapse, rather than only at haematological relapse. The second question to be addressed is when the various options for treatment of relapsed APL-i.e. all-trans retinoic acid (ATRA) and anthracyclines, arsenic trioxide (ATO), gemtuzumab ozogamycin (GO, 'mylotarg'), and allogeneic or autologous stem cell transplant-should be used. We suggest that patients with relapsed APL have different prognoses and that, accordingly, they should not all be treated identically. We note the significance of extramedullary relapse. We conclude with a summary of treatment recommendations and a discussion of new therapies that might be useful in the future.
Best Pract Res Clin Haematol 2003 Sep
PMID:Treatment options for relapsed acute promyelocytic leukaemia. 1293 67

Acute promyelocytic leukaemia (APL) may be characterized simultaneously as the most potentially rapidly fatal human acute leukaemia if untreated, yet the most frequently cured acute leukaemia if promptly diagnosed and treated without delay. Co-operative group and single-institution studies which include large numbers of patients with relatively long follow-up demonstrate that, with all-trans retinoic acid (ATRA) plus anthracycline-based chemotherapy, the majority of newly-diagnosed patients appear cured of their disease. The 5-year disease-free survival rates range from 75 to 85%. Early death is still observed in approximately 10% of patients and remains a difficult obstacle to increasing the cure rate. Prognostic factors which identify patients at high risk for recurrence are becoming increasingly recognized. Older age (over age 55-60 years), elevated white blood cell count at presentation (higher than 5,000-10,000/microl), and expression of CD56 unfavourably influence outcome. The treatment of such patients remains a challenge, although it is important to note that APL is the only type of AML in which a significant proportion of older patients may be cured. Because more patients are cured of their disease, potential long-term consequences may become increasingly recognized. These include the emergence of extramedullary disease, the development of secondary myelodysplasia or acute myeloid leukaemia and the potential for late-onset cardiac toxicity.
Best Pract Res Clin Haematol 2003 Sep
PMID:Long-term follow-up and potential for cure in acute promyelocytic leukaemia. 1293 68


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