荧光原位杂交检测维A酸受体α基因重排对急性早幼粒细胞白血病的诊断价值

目的:研究荧光原位杂交(fluorescence in situhybridization,FISH)检测维A酸受体α(RARα)基因重排对于急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)的诊断价值。方法:对骨髓形态学检查呈典型的APL改变而常规染色体R显带核型分析t(15;17)及RT-PCR检测RARα基因重排两者皆为阴性的4例急性白血病患者采用双色荧光原位杂交检测RARα基因的重排。结果:2例FISH检测为阴性,1例80%的细胞中显示早幼粒白血病基因(PML)/RARα融合信号,1例PML/RARα融合基因信号阴性,但99.8%的细胞显示RARα基因17q21断裂点以下基因的复制及重排。结论:应用FISH技术可以在部分APL患者中检出核型及RT-PCR技术无法检出的RARα基因重排,有助于APL的确诊。     

Rapid improvement of coagulopathy by all-trans retinoic acid in acute promyelocytic leukemia

Treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment-E), cross-linked fibrin degradation product (D-dimer fragment), thrombin-antithrombin III complex and plasmin-α2-plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (A TIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near-normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low-dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells. © 1994 Wiley-Liss, Inc.     

Overexpression of BP1, a homeobox gene,is associated with resistance to all-trans retinoic acid in acute promyelocytic leukemia cells

BP1, a homeobox gene, is overexpressed in the bone marrow of 63% of acute myeloid leukemia patients. In this study, we compared the growth-inhibitory and cyto-differentiating activities of all-trans retinoic acid (ATRA) in NB4 (ATRA-responsive) and R4 (ATRA-resistant) acute promyelocytic leukemia (APL) cells relative to BP1 levels. Expression of two oncogenes, bcl-2 and c-myc, was also assessed. NB4 and R4 cells express BP1, bcl-2, and c-myc; the expression of all three genes was repressed after ATRA treatment of NB4 cells but not R4 cells. To determine whether BP1 overexpression affects sensitivity to ATRA, NB4 cells were transfected with a BP1-expressing plasmid and treated with ATRA. In cells overexpressing BP1: (1) proliferation was no longer inhibited; (2) differentiation was reduced two- to threefold; (3) c-myc was no longer repressed. These and other data suggest that BP1 may regulate bcl-2 and c-myc expression. Clinically, BP1 levels were elevated in all pretreatment APL patients tested, while BP1 expression was decreased in 91% of patients after combined ATRA and chemotherapy treatment. Two patients underwent disease relapse during follow-up; one patient exhibited a 42-fold increase in BP1 expression, while the other showed no change. This suggests that BP1 may be part of a pathway involved in resistance to therapy. Taken together, our data suggest that BP1 is a potential therapeutic target in APL. Rania T. Awwad and Khanh Do contributed equally to the present study.     

Bone marrow necrosis in two patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid

All-trans retinoic acid has been used for the treatment of acute promyelocytic leukemia (APL) with encouraging results. However, it has recently been associated with a number of potentially serious complications including the retinoic acid syndrome. We describe two patients with APL who were begun on all-trans retinoic acid therapy (45 mg/m²), but who developed leukocytosis which was treated with hydroxyurea. Both patients demonstrated clinical and laboratory findings of disseminated intravascular coagulation, massive cell lysis manifested by marked increases in serum lactic dehydrogenase, and rapid clinical deterioration. Both patients developed bone marrow necrosis within viable, non-infarcted bone trabeculae. We postulate that the development of bone marrow necrosis in these two patients was not a chance occurrence. Rather, the specific combination of cytotoxic and differentiating agents used in these patients (hydroxyurea with all-trans retinoic acid) caused massive cell lysis and death. The absence of bone marrow necrosis in the setting of induction therapy for APL both with and without all-trans retinoic acid therapy suggests that the addition of hydroxyurea was critical to the development of marrow necrosis. We, therefore, recommend caution in the use of hydroxyurea and all-trans retinoic acid in the treatment of APL. © 1994 Wiley-Liss, Inc.     

Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukemia

A 56-year-old woman with an acute promyelocytic leukemia (APL) developed a severe all-trans-retinoic (ATRA) syndrome on day 17 of treatment. Shortly after, she presented a picture of pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome (HPS) were negative. A diagnosis of HPS was made. Treatment with dexamethasone and high-dose immunoglobulins was unsuccessful. Consolidation chemotherapy with idarubicin and ATRA rapidly reversed the HPS. The HPS in this patient could be related to the release of macrophage-stimulating cytokines by APL cells during ATRA syndrome.     

All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.     

Thrombocytosis in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment

In 26 acute promyelocytic leukaemia (APL) patients treated with all- trans retinoic acid (ATRA), 23% had platelet counts between 459 and 800 ×10⁹/l during treatment. These values, observed between days 28 and 45 of ATRA treatment, were transient and asymptomatic. We report two APL cases with platelet counts >1000 × 10⁹/l during ATRA therapy who were treated with recombinant interferon alpha. In both cases ATRA doses were not modified, no complications secondary to thrombocytosis were seen, and they subsequently achieved complete remission. It is suggested that IL-6 may play an important role in the pathogenesis of the thrombocytosis induced by ATRA. To our knowledge, this is the first report of thrombocytosis occurring during ATRA treatment.     

Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

Background

Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established.

Design and Methods

We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and anthracycline-based chemotherapy enrolled in two subsequent trials of the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) and Hemato-Oncologie voor Volwassenen Nederland (HOVON) groups between 1996 and 2005.

Results

FLT3-internal tandem duplication and FLT3-D835 mutation status was available for 306 (41%) and 213 (29%) patients, respectively. Sixty-eight (22%) and 20 (9%) patients had internal tandem duplication and D835 mutations, respectively. Internal tandem duplication was correlated with higher white blood cell and blast counts, lactate dehydrogenase, relapse-risk score, fever, hemorrhage, coagulopathy, BCR3 isoform, M3 variant subtype, and expression of CD2, CD34, human leukocyte antigen-DR, and CD11b surface antigens. The FLT3-D835 mutation was not significantly associated with any clinical or biological characteristic. Univariate analysis showed higher relapse and lower survival rates in patients with a FLT3-internal tandem duplication, while no impact was observed in relation to FLT3-D835. The prognostic value of the FLT3-internal tandem duplication was not retained in the multivariate analysis.

Conclusions

FLT3-internal tandem duplication mutations are associated with several hematologic features in acute promyelocytic leukemia, in particular with high white blood cell counts, but we were unable to demonstrate an independent prognostic value in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens.     

Alterations of the retinoic acid receptor alpha (RAR alpha) gene in myeloid and lymphoid malignancies

The retinoic acid receptor alpha (RAR alpha) protein plays a central role in myeloid differentiation, and chromosomal translocations disrupting the RAR alpha gene are implicated in the development of acute myeloid leukaemia (AML). To identify haemopoietic malignant disorders which may also be linked to RAR alpha abnormalities, Southern blot analysis was performed in DNA from 153 patients with haematological malignancies other than AML FAB type M3 using RAR alpha cDNA probes. Alterations of RAR alpha were detected in 1/42 myelodysplastic syndromes (MDS), 2/24 AML, 3/47 B-chronic lymphocytic leukaemias (B-CLL), 0/40 lymphomas and 0/60 normal individuals. These data strongly suggest that alterations of RAR alpha might predispose for myeloid and lymphoid disorders.     

All-trans retinoic acid in acute promyelocytic leukemia: Preliminary results in Cuba

Summary Seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Five (71.4%) achieved complete remission (CR). Most side effects were transient and well tolerated. Hyperleukocytosis was the major adverse effect. These observations confirm the efficacy of ATRA for inducing CR in APL.     

Dexamethasone does not counteract the response of acute promyelocytic leukaemia cells to all-trans retinoic acid

Retinoic acid syndrome is a serious condition that may complicate the treatment of acute promyelocytic leukaemia patients. This syndrome may be treated effectively with high-dose corticosteroid therapy and, as a result, many patients with acute promyelocytic leukaemia receive dexamethasone at some point during treatment. We investigated whether dexamethasone would also antagonize the beneficial effects of retinoic acid. In t(15;17)-positive NB4 cells, dexamethasone did not affect the retinoic acid induced differentiation, normalization of PML-nuclear bodies or the induction of thrombomodulin mRNA. Finally, dexamethasone did not inhibit the anti-proliferative effect of retinoic acid but rather showed anti-proliferative activity itself.     

Meta-analysis of all-trans retinoic acid-linked arsenic trioxide treatment for acute promyelocytic leukemia

Objectives

To explore the combination therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO, As₂O₃) on acute promyelocytic leukemia (APL).

Methods

A meta-analysis of six studies was performed. Among 415 included cases, 165 cases were in the ATRA + ATO group, 129 cases in the ATRA-alone group, and 121 cases in the ATO-alone group. The complete remission (CR) rate and incidences of three groups were compared, respectively, between the therapies of ATRA + ATO with ATRA-alone, ATRA + ATO with ATO-alone, and ATRA with ATO.

Results

The assessment results showed that ATRA + ATO therapy significantly improved the CR rate and decreased the incidences of cutaneous reaction compared with ATRA-alone (P < 0.05). However, incidence of liver injury was higher in the ATRA + ATO and ATO-alone groups than that in ATRA-alone group (P < 0.05). Difference in the complications between ATRA + ATO therapy and ATO-alone was not significant (P > 0.05).

Conclusions

In conclusion, we suggest low-dose ATRA and ATO combination therapy may be more effective for the treatment of APL.     

Successful treatment of acute promyelocytic leukemia in a 92-year-old man using all-trans retinoic acid combined with oral arsenic: A case report

RationaleAcute promyelocytic leukemia is a special subtype of acute myeloid leukemia. The incidence of early death and complications is high. An oral regimen of all-trans retinoic acid combined with the realgar-indigo naturalis formula (RIF) without chemotherapy has provided a new strategy for the treatment of these patients.Patient concernsA 92-year-old male patient was admitted to the hospital due to fatigue and oral bleeding. He had no fever or lung infection. Routine blood test showed white blood cell count 1.0 ×109/L, hemoglobin 100 g/L, and platelets 21 × 10⁹/L. Coagulation function indicated fibrinogen 1.02 g/L and D-dimer 2360 ng/mL. And 28% abnormal promyelocytes were observed in peripheral blood.DiagnosisA bone marrow morphologic, immunophenotypic, cytogenetic, and molecular examination was performed. Routine bone marrow examination showed active proliferation of nucleated cells, with promyelocytes accounting for 91%; immunophenotyping revealed an early myeloid cell population, accounting for approximately 82.4% of all cells.InterventionsFrom February 15, 2020, 25 mg/m² all-trans retinoic acid was orally administered daily. After the fusion gene result was obtained, oral administration of 60 mg/kg RIF daily began since February 18, 2020. The combination of the 2 agents was given until March 16, 2020. Oral administration of 25 mg/m² retinoic acid daily began from March 20, 2020 for 2 weeks, and oral administration of 60 mg/kg RIF daily lasted for 4 weeks as the consolidation therapy. During the treatment, the proportion of promyelocytes in peripheral blood, white blood cell count, platelets, coagulation function, liver function, and QT interval were monitored.OutcomesOral retinoic acid and oral RIF were given without chemotherapy and the patient achieved bone marrow remission after 1 month, and molecular remission was achieved 2 months later. In the early stage of acute promyelocytic leukemia, combined thrombocytopenia and disseminated intravascular coagulation may develop. Platelet and fresh frozen plasma infusion were proactively given until platelets were stabilized above 30 × 10⁹/L, and the coagulation function returned to normal.LessonsThe regimen was safe and effective, and subsequent treatment did not require hospitalization, which helped to improve the patient''s quality of life.     

Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis

Background

The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter.

Design and Methods

Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given.

Results

Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse.

Conclusions

This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.     

全反式维甲酸治疗急性早幼粒细胞性白血病致Sweet综合征--病例报告及文献复习

目的:提高对全反式维甲酸(ATRA)治疗急性早幼粒细胞性白血病(APL)少见副作用的认识。方法:报告1例ATRA治疗APL致Sweet综合征的病例及治疗过程,并对相关文献进行复习总结。结果:ATRA治疗APL可以导致Sweet's综合征,采用糖皮质激素治疗有效。结论:Sweet综合征是维甲酸的少见副作用,临床上应提高对该综合征的早期诊断。     

Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA

All-trans-Retinoic acid (ATRA) has been shown to improve survival in patients with acute promyelocytic leukemia (APML). It is a well-tolerated drug except for the serious side effect of ATRA syndrome. Dryness of the skin, cheilitis, and xerostomia are the common mucocutaneous side effects. Occurrence of scrotal ulceration is very rare. We report a 13-year-old boy who had scrotal ulceration caused by ATRA during the induction therapy of APML.     

Serum thrombopoietin and erythropoietin levels in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment

Endogenous serum thrombopoietin (TPO) and various cytokines including erythropoietin (EPO), interleukin (IL)-3, IL-6, IL-11, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF) and stem cell factor (SCF) levels were measured in five patients with acute promyelocytic leukaemia (APL) during all-trans retinoic acid (RA) treatment. During differentiation-inducing therapy, platelet counts slowly increased and reached a peak between days 29 and 46 (median day 35). Serum TPO levels increased parallel to the increasing platelet counts and reached a maximum level during the first 10-20 d of all-trans RA treatment. The circulating TPO levels then decreased in inverse correlation to the platelet counts. These unique changes in serum TPO levels revealed that TPO levels were not regulated by platelet or megakaryocyte mass in patients with APL during differentiation-inducing therapy, and it would appear that TPO levels are directly regulated by all-trans RA during the first 10-20 d of treatment. In addition, the change in circulating EPO levels and reticulocyte counts were similar to that of the TPO levels and platelet counts during all-trans RA treatment, suggesting a close relationship between TPO and EPO signalling.     

all-trans-Retinoic acid-induced expression and regulation of retinoic acid 4-hydroxylase (CYP26) in human promyelocytic leukemia

all-trans-Retinoic acid (ATRA) induces complete remission in majority of patients with acute promyelocytic leukemia (APL). However, accelerated metabolism of ATRA that is induced by chronic daily administration of oral ATRA has been implicated as one of the mechanisms leading to a reduced sensitivity or resistance to ATRA therapy. We investigated the expression and regulation of CYP26, a novel p450 enzyme, which is highly specific for ATRA, in promyelocytic leukemia cells (NB4 and HL-60). We found that treatment of NB4 cells with a pharmacological concentration of ATRA (1 microM) induced rapid and dose-dependent expression of CYP26 mRNA. The CYP26 expression returned to pretreatment levels in both cells after ATRA was removed from the media. Retinoic acid receptor-alpha (RARalpha) specific antagonist (CD2503) totally abolished the ATRA-induced expression of CYP26 mRNA in HL-60 and NB4 cells. Furthermore, HL-60R, a HL-60 subclone expressing nonfunctional RAR because of a point mutation in the ligand-binding domain of RARalpha, failed to show CYP26 mRNA expression in response to ATRA. ATRA-induced expression of CYP26 was restored in HL-60R cells retrovirally transduced with RARalpha, but not in those cells transduced with the other retinoid receptors. In conclusion, ATRA induces expression of CYP26 in myeloid and promyelocytic leukemia cells and this expression is modulated by RARalpha. The induction of CYP26 expression by ATRA treatment might be related to a substrate-driven feedback mechanism to regulate intracellular concentrations of ATRA and its over expression in some clones may be partly responsible for reduced sensitivity or resistance to ATRA therapy.