All-trans retinoic acid induced a complete remission in a case of refractory relapsed acute promyelocytic leukemia]

Forty five year old male suffering from relapsed acute promyelocytic leukemia (APL) was treated with all-trans retinoic acid (ATRA) and attained second complete remission (CR) without bone marrow hypoplasia. He was diagnosed as having APL in September 1989. The DCMP-85 regimen first induced CR in October, however the disease relapsed in September 1990. The DCMP-85 and and the MEC (MIT, ETOP, Ara-C) regimens were applied for re-induction without success. Then, 45 mg/m2/day ATRA was given orally from December 28, 1990. Laboratory data before ATRA treatment were as follows; 35.4% leukemic cells in the bone marrow, Hb 11.0 g/dl, Plt 130,000/microliters, WBC 5,100/microliters without leukemic cells, and no DIC was detected. During the treatment, his bone marrow was examined frequently. The bone marrow series showed no hypoplasia at any time and gradual reduction of leukemic cells with proliferation of mature granulocytes. CR was attained on January 21, 1991. DIC did not develop. Cytogenetic anomalies including t(14;17;15) (q24;q11.2;q22) reduced from 29/30 cells at relapse to 4/30 cells at the time of CR. Dryness of mouth and lips, irritation around eyes and the elevations of GOT, GPT and triglyceride level were seen as the side effects of ATRA, however they were tolerable.     

急性早幼粒细胞白血病经全反式维甲酸缓解后维持治疗的临床探讨

目的：探索急性早幼粒细胞白血病（APL）经全反式维甲酸（ATRA）治疗达完全缓解（CR）后理想的维持治疗方案，提高APL的长期无病生存时间.方法：将我院21例初治的APL患者均经ATRA治疗达CR后，维持治疗方法为三氧化二砷（As2O3）、ATRA及6-巯基嘌呤（6-MP）加甲氨喋呤（MTX）序贯交替治疗3年;观察治疗的效果及不良反应，监测微小残留病.结果：21例患者对上述治疗均有较好的顺从性，有11例患者维持治疗超过2年，无复发病例;PML/RARα融合基因初诊时均为阳性，12例持续转阴，其中维持治疗超过2年的11例患者均转阴;治疗相关的不良反应少见且较轻.结论：用上述维持治疗经ATRA达CR的APL初步取得了令人满意的效果，其不良反应较传统的联合化疗轻，作者认为As2O3、ATRA与6-MP加MTX序贯交替治疗可能是APL理想的维持治疗方法。     

Hematopoietic stem cell transplantation in the second or later complete remission in acute promyelocytic leukemia initially treated with all-trans retinoic acid

Despite the use of all-trans retinoic acid (ATRA) as the first-line treatment for acute promyelocytic leukemia (APL), relapse occurs in about 20% of cases. Most relapsing APL patients can achieve second remission (CR2) following ATRA combined with chemotherapy or arsenic trioxide. Stem cell transplantation (SCT) has been widely adopted in CR2, but optimal SCT (auto- or allo-SCT) remains controversial. We analyzed the outcomes for 8 APL patients initially treated using ATRA, who relapsed, achieved CR2 and underwent auto-SCT (n = 4) or allo-SCT (n = 4). The mean age of patients who underwent allo-SCT was 39 years. Minimal residual disease (MRD) just prior to SCT was positive in 1 patient and negative in 3. Engraftment was achieved in all patients, but 2 patients died of transplantation-related complications within 6 months. Complete molecular remission has been maintained in the remaining 2 patients. The mean age of patients who underwent auto-SCT was 48 years. MRD just prior to SCT was negative in all 4 patients. Complete molecular remission has been maintained in all 4 patients (mean follow-up, 3 years 9 months). The results for auto-SCT are favorable in patients with MRD-negative APL.     

A third complete remission of acute promyelocytic leukemia achieved by administering a gradual increase of all-trans retinoic acid following massive ascites due to retinoic acid syndrome

A 69-year-old man was diagnosed as having acute promyelocytic leukemia (APL) and was treated with all-trans retinoic acid (ATRA) and idarubicin plus cytarabine. He achieved cytogenetic complete remission (CCR). Relapse occurred 1 year after CCR. Treatment with Am80 gave him a second CCR. However, a second relapse occurred. Re-induction therapy with ATRA was started at 70 mg per day. On day 14, abdominal fullness rapidly increased and massive ascites appeared as a symptom of retinoic acid syndrome (RAS). We ceased the ATRA treatment and started administration of methylprednisolone. The ascites decreased, but an increase of ascites was recognized again temporarily after having re-started ATRA treatment. Thus we gradually increased ATRA administration from 40 mg/day to 70 mg/day of ATRA. RAS did not occur and the patient achieved a third CCR. This case indicates that a gradual increase in ATRA administration is beneficial for RAS occurring in APL patients.     

Adams-Stokes attack due to complete atrioventricular block in a patient with acute promyelocytic leukemia during remission induction therapy using all-trans retinoic acid

We describe a case of Adams-Stokes syncope due to complete atrioventricular block which occurred in a leukemic patient receiving all-trans retinoic acid (ATRA). Remission induction therapy was performed for a 46-year-old Japanese man with acute promyelocytic leukemia using ATRA (45 mg/m2), enocitabine (170 mg/m2, 5 days), and mitoxantrone (4 mg/m2, 3 days). On the 25th day of chemotherapy, syncope suddenly occurred. Electrocardiography revealed a complete atrioventricular block, and a temporary pacemaker was inserted on the following day. The block was persistent and the cardiac rhythm was dependent on the pacemaker. ATRA was discontinued on the 29th day because the arrhythmia was believed to be an adverse reaction to the ATRA regimen. The normal sinus rhythm was restored 15 days thereafter, and the patient eventually reached remission. He subsequently received 4 courses of consolidation therapy without any cardiovascular complications. Although ATRA sometimes induces arrhythmias, to the best of our knowledge this is the first report in the literature of such a critical ATRA-related arrhythmia.     

Induction therapy of acute promyelocytic leukemia with all-trans retinoic acid: a case, followed by conventional post-remission chemotherapy in complete remission]

A 41-year-old man with untreated acute promyelocytic leukemia (APL) was treated with all-trans retinoic acid (ATRA) 80mg/body/day per os. Complete remission was reached in 16 day without bone marrow hypoplasia and aggravated disseminated intravascular coagulation. The chromosomal abnormality, t (15;17), which presented before therapy has not been found since the 29th day of therapy. During the course of induction therapy with ATRA, there was no complication worth of mentioning. Induction therapy with ATRA is thought to be more effective and safer than conventional chemotherapy to attain complete remission in APL. The complete remission has been maintained for 11 months with conventional postremission chemotherapy.     

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.     

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.     

The "retinoic acid syndrome" in acute promyelocytic leukemia.

OBJECTIVE: To describe a novel complication of therapy with all-trans retinoic acid in patients with acute promyelocytic leukemia. DESIGN: Case series. SETTING: Comprehensive cancer center. PATIENTS: Consecutive patients with a morphologic diagnosis of acute promyelocytic leukemia who underwent remission induction treatment with all-trans retinoic acid, 45 mg/m2 body surface area per day. MEASUREMENTS AND RESULTS: Nine of 35 patients (26%; 95% CI, 9% to 52%) with acute promyelocytic leukemia who were treated with all-trans retinoic acid developed a syndrome consisting primarily of fever and respiratory distress. Additional prominent signs and symptoms included weight gain, lower-extremity edema, pleural or pericardial effusions, and episodic hypotension. The onset of this symptom complex occurred from 2 to 21 days after starting treatment. Three deaths occurred; post-mortem examinations in two patients showed pulmonary interstitial infiltration with maturing myeloid cells. Six other patients survived, each achieving complete remission (five patients with all-trans retinoic acid only; 1 patient with chemotherapy). In six of the nine cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes to a level of at least 20 x 10(9) cells/L. Certain therapeutic interventions, including leukapheresis, temporary cessation of therapy with all-trans retinoic acid, and cytotoxic chemotherapy in moderate doses were not useful after respiratory distress was established. However, the administration of high-dose corticosteroid therapy (dexamethasone, 10 mg IV intravenously every 12 hours for 3 or more days) early in the course of the syndrome resulted in prompt symptomatic improvement and full recovery in three of four patients. CONCLUSIONS: The use of all-trans retinoic acid to induce hematologic remission in patients with acute promyelocytic leukemia is associated in some patients with the development of a potentially lethal syndrome that is not uniformly accompanied by peripheral blood leukocytosis. Early recognition of the symptom complex of fever and dyspnea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome.     

Differentiation therapy of acute promyelocytic leukemia: two successful cases of remission induction by all-trans retinoic acid]

We described two pediatric patients with acute promyelocytic leukemia (APL) who were successfully induced into complete remission with all-trans retinoic acid (ATRA, 45 mg/m2 per day) after failing on conventional chemotherapy. Initial response was observed as correction of DIC within a week of treatment. Hematologically, initial increase of maturing leukocytes reached a peak peripheral WBC count on the 16th and 20th day, respectively. However, these seemingly differentiated leukocytes retained Auer body and dysplastic features and there was no concomitant recovery of erythroid and megakaryocytic lineages at this point. A sudden drop of leukocyte counts after this peak made a brief period of leukopenia before the complete remission was finally attained morphologically in 4-5 weeks. Thus, remission of APL by ATRA therapy consisted of a two-phase course. In one patient, we observed an increase of histiocytes phagocytizing leukocytes in the marrow during the recovery from leukopenia. It is, therefore, postulated that the two-phase course of recovery may reflect the differentiation of leukemic cells by ATRA and subsequent clearance of senescent cells by the reticuloendothelial system followed by regeneration and differentiation of residual normal hematopoietic stem cells.     

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.     

All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia

All-trans retinoic acid (ATRA) can induce complete remission (CR) in most patients with acute promyelocytic leukemia (APL) through in vivo differentiation of APL-blasts. However, it cannot eliminate the leukemic clone and must be used in combination with anthracycline-based chemotherapy. Experience accumulated over the last 10 years has clearly shown that the combination of ATRA and chemotherapy gave better survival than chemotherapy alone in newly diagnosed APL because of fewer relapses and a slightly higher CR rate. It is also strongly suggested that maintenance treatment with ATRA, and possibly with low-dose chemotherapy, can further reduce the incidence of relapse. Overall, more than 90% of patients with newly diagnosed APL can achieved CR, and about 75% can be cured by the combination of ATRA and chemotherapy. ATRA syndrome remains the major side effect of ATRA treatment, which should be prevented by addition of chemotherapy and/or dexamethasone in case of increasing white blood cell (WBC) counts. Current issues in the treatment of newly diagnosed APL include the role of early addition of chemotherapy to ATRA, whether or not ara-C is useful in combination with anthracycline, and a possible interest of arsenic trioxide during consolidation in patients remaining at relatively high risk of relapse.     

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.