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 in acute promyelocytic leukaemia

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.     

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.     

All-trans retinoic acid-induced erythema nodosum in acute promyelocytic leukemia

A 24-year-old woman with acute promyelocytic leukemia was treated with all-trans retinoic acid (ATRA) as a remission induction therapy. After pneumonia in the neutropenic period was successfully treated with antibiotic treatment, there was recurrence of high fever alone, followed by the appearance of erythema nodosum with pain in her upper limbs on day 25 of ATRA therapy. Skin biopsy neither revealed infiltration of leukemic cells nor suggested Sweet's syndrome. We considered the eruptions to be associated with ATRA, and prednisolone (30 mg/day for 5 days) was administered. Although the administration of ATRA was continued until complete remission of the leukemia, the erythema nodosum rapidly disappeared following short-term steroid therapy and no recurrence was observed. ATRA-induced erythema nodosum is rare, however it should be recognized as a possible adverse effect in ATRA therapy.     

All-trans retinoic acid and in vitro cytokine production by acute promyelocytic eukemia cells

Abstract: Leukemic cells spontaneously secrete cytokines involved in the proliferation of the clone; in this study we evaluated the effects of all-trans retinoic acid (ATRA) on the in vitro autocrine production of cytokines by acute myeloid leukemia cells. Thirty acute nonlymphoid leukemia cases (ANLL) (10 APL and 20 ANLL of other cytotypes than APL) were studied; the in vitro secretions of IL-1α, IL-3, IL-4, IL-6, IL-10, G–CSF, GM–CSF, TNF-α were tested with and without ATRA addition. After 5 d exposure to ATRA 10^?6 m APL-treated samples showed a significant reduction of IL-6 (p = 0.008) and GM–CSF (p = 0.03) and a significant increase of IL-1α (p = 0.01) production, if compared to untreated APL samples. No difference was seen in IL-3, IL-10 and IL-4 productions; G–CSF production resulted absent in all but 3 APL cases, in which addition of ATRA determined increase in the production. Interestingly, the 3 G–CSF-producing cases did not obtain clinical remission with ATRA; GM–CSF and IL-6 were spontaneously produced by all the cases, and 7 of 10 APL patients subsequently obtained complete remission after induction. TNF-α was produced only in 1 case. No statistical difference was seen in all the productions obtained from other than promyelocytic acute leukemic cells, both with and without ATRA addition. However, it is noteworthy that the production of IL-6 was more than twice as high in ANLL non-APL than in APL cases. In conclusion, these data could thus suggest possible complementary mechanisms of the exhaustion of the leukemic clone upon treatment with ATRA.     

All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol

We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.     

All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia

Therapeutic results in elderly patients with acute promyelocytic leukemia (APL) have been generally reported as less effective than for younger patients. Patients 60 years or older with APL who were enrolled in 2 successive multicenter PETHEMA studies received induction therapy with all-trans retinoic acid (ATRA) and idarubicin, consolidation with 3 anthracycline monochemotherapy courses with or without ATRA, and maintenance with ATRA and low-dose chemotherapy. Eighty-seven of 104 patients achieved complete remission (84%). Eighty-six proceeded to consolidation therapy (2 withdrew after the first and second courses). Deaths in remission occurred during consolidation and maintenance therapy in 3 and 4 patients, respectively. One patient showed molecular persistence after consolidation and 5 had a relapse. The 6-year cumulative incidence of relapse, leukemia-free survival, and disease-free survival were 8.5%, 91%, and 79%, respectively. A significantly higher incidence of low-risk patients found among the elderly, as compared to younger patients, may partially account for the low relapse rate observed. This study confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of protocols using ATRA and anthracycline monochemotherapy for induction and consolidation therapy in elderly patients.      

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.     

All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases--were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.     

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.     

Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid

The recent finding that retinoic acid induces terminal granulocytic differentiation of the human promyelocytic leukemia cell line, HL-60, prompted an investigation of the sensitivity to this inducer of human myelocytic leukemia cells in primary suspension culture. Of the 21 leukemic specimens, only cells from the two patients with acute promyelocytic leukemia differentiated in response to retinoic acid. After an incubation period of 5--7 days in 1 microM retinoic acid, the cells from these two patients showed extensive morphological and functional maturation. Thus, because it appears that retinoic acid specifically induces granulocytic differentiation of leukemic promyelocytes, this compound may have therapeutic utility in the treatment of acute promyelocytic leukemia.     

Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells

Retinoic acid (RA) overcomes the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. Patients receiving RA alone invariably develop RA resistance. RA-resistant cells can serve as useful models for the development of treatments for both APL and other leukemias. Previously, we showed that RA and tumor necrosis factor (TNF) promote monocytic differentiation of the APL cell line NB4 and U937 monoblastic cells. Here, we report that combining TNF with RA leads to maturation of several RA-resistant APL cells along a monocytic pathway, whereas UF-1, a patient-derived RA-resistant cell line, showed characteristics of granulocytic differentiation. We found distinct differences in gene regulation between UF-1 cells and cells showing monocytic differentiation. Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation. Furthermore, synergistic induction of PU.1 DNA binding and macrophage colony-stimulating factor receptor (m-CSF-1R) mRNA was observed only in cells differentiating into monocytes. Using neutralizing antibodies against m-CSF-1R or its ligand, we found that inhibiting this pathway strongly reduced CD14 expression in response to RA and TNF, suggesting that this pathway is essential for their synergy in RA-resistant leukemia cells.