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.     

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.     

复方青黛片联合全反式维甲酸治疗急性早幼粒细胞白血病的近期临床疗效观察

目的:观察复方青黛片联合全反式维甲酸治疗急性早幼粒细胞白血病(APL)的临床疗效、作用特点及不良反应。方法:将APL患者随机分22例,21例及18例3组,分别给予全反式维甲酸(ATRA),复方青黛片及ATRA联合复方青黛片治疗,观察APL的缓解率,无病生存期及药物不良反应。结果:联合治疗组可减少达缓解所需时间,较快速恢复凝血功能。结论:复方青黛片联合全反式维甲酸治疗APL是一种更为有效及合理的方法,是切实可行的,值得推广。     

急性早幼粒细胞性白血病:全反式维甲酸诱导分化治疗中出血并发症的处理

16例急性早幼粒细胞性白血病(APL)采用全反式维甲酸(RA)进行诱导分化治疗。入院时和病程中80%(13/16例)的患者发生弥散性血管内凝血(DIC),4例发生严重出血。经配合包括肝素抗凝、新鲜血及血小板输注,并用地塞米松、脱水和防治感染等积极的综合性治疗,渡过危险期,有效保障 RA 诱导分化作用的发挥,全部病例取得骨髓完全缓解.     

Long-term follow up of re-induction with a new synthetic retinoid, Am-80, for relapse of acute promyelocytic leukemia previously treated with all-trans retinoic acid: results of 7 cases from a single institute

Seven patients experiencing first (n = 5) or second (n = 2) relapse of acute promyelocytic leukemia (APL) were treated with a new synthetic retinoid, Am-80. All 7 patients were previously treated with all-trans retinoic acid (ATRA). Am-80 was orally administered at a dose of 6 mg/m2 daily. Chemotherapy was combined in 3 patients because of leukocytosis. All 7 patients achieved a complete remission (CR) during periods ranging from 36-56 days (median 52 days). Adverse effects such as hyperlipidemia and skin lesions, were tolerable. After achieving CR, 3 patients underwent allogeneic bone marrow transplantation and 4 patients received only consolidation chemotherapy. In 2 of 3 patients who received allogeneic transplantation, relapse free survival has lasted for 9.7 and 28.3 months. Furthermore, in 2 of 4 patients who received only chemotherapy, relapse free survival has lasted for 84.7 and 90.1 months. Am-80 is an active agent for APL patients who have relapsed from ATRA-induced remission.     

Acute promyelocytic leukemia after living donor partial orthotopic liver transplantation

We encountered a 12-year-old girl with acute promyelocytic leukemia (APL) that occurred 21 months after a living donor partial orthotopic liver transplantation from her father for ornithine transcarbamylase deficiency. FK-506 had been administered for prophylaxis against graft-versus-host reaction. The bone marrow specimen revealed a massive infiltration of promyelocytic blasts (M3 by FAB classification) with chromosome 46, XX, t (15; 17) (q22; q12), being the recipient origin. A PML/RAR alpha chimeric gene was detected by RT-PCR. The patient was diagnosed as having APL and successfully induced to complete remission by chemotherapy including daunorubicin (DNR), cytarabine (araC), and all-trans retinoic acid (ATRA). She has been in continuous remission for 12 months after the treatment. Leukemia after liver transplantation is generally taken as a rare complication. However, recent advances in the survival rate of patients who have undergone liver transplantation will lead to an increase of such cases.     

Two Patients with All -trans Retinoic Acid-Resistant Acute Promyelocytic Leukemia Treated Successfully with Gemtuzumab Ozogamicin as a Single Agent

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is the target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). Therefore, GO is predicted to be a successful treatment for APL. In this article, we report on the GO treatment of 2 patients with APL, who had fully relapsed after induction therapy with all-trans retinoic acid (ATRA) following chemotherapy. Both patients had relapsed 3 times and were resistant to reinduction therapy with ATRA. GO (9 mg/m2) was administered on days 1 and 15. After GO treatment, both patients achieved complete hematologic and molecular remission. GO may be another promising agent for the treatment of ATRA-resistant relapsed APL when given as salvage chemotherapy.     

Acute promyelocytic leukemia with additional chromosome abnormalities in a renal transplant case

Some cases of acute myeloid leukemia following organ transplant (PT-AML) have been published in the literature. We report the second case of acute promyelocytic leukemia (APL), which developed post-transplant and immunosuppressive treatment, in a 50-year-old male who had undergone a renal transplant. At diagnosis he presented typical t(15;17)(q12;q13) with additional abnormalities, including +8,t(13;22)(q12;q13) and an abnormal chromosome 1 which was better characterized by fluorescence in situ hybridization (FISH). He obtained cytological, karyotypic and molecular complete remission (CR) with induction treatment according to the all-trans retinoic acid + idarubican (AIDA) protocol; after 12 months, he relapsed (molecular relapse) and achieved molecular remission with all-trans retinoic acid (ATRA) plus mitoxantrone and cytosine arabinoside. After a further 14 months, he was treated with arsenic trioxide for cytological relapse and obtained a third CR; at the cytological relapse the karyotype showed 47,XY,+8, t(15;17)(q22;q21),t(13;22)(q12;q13),der(22)t(1;22)(p22;q13). He is alive 3.3 years after diagnosis of APL. Cyclosporin A (CsA) was given during all cycles of chemotherapy. We did not observe any severe infections or kidney failure during treatments. The use of conventional cytogenetic analysis plus FISH may identify complex karyotype also in transplanted patients receiving immunotherapy, and may also contribute to a better assessment of PT-AL.     

Successful treatment of relapsed and refractory acute promyelocytic leukemia with arsenic trioxide (As2O3)

It has been shown that arsenic trioxide (As2O3) may induce hematologic remissions in patients with acute promyelocytic leukemia (APL) refractory to all-trans retinoic acid (ATRA). We reported on a patient with ATRA and drug-resistant APL that was successfully treated with As2O3. The patient had been given a diagnosis of typical APL and was treated with ATRA and chemotherapy for 12 months. He achieved complete remission (CR), but leukemia relapsed with 43% APL cells in the bone marrow in the 16th month of treatment. ATRA and cytarabine plus daunorubicin were administered; however, the APL cells in the bone marrow increased to 97.2%. As2O3 was initiated intravenously, and bone marrow showed a decrease of APL cells (6.7%) and a partial differentiation after 9 days. The patient received idarubicin (IDA) and steroid pulse because of the development of ATRA-like syndrome, and achieved CR 37 days after the initiation of As2O3. He received an additional 2 courses of As2O3 with IDA, and is in CR. These results demonstrated the therapeutic efficacy of As2O3 in treating ATRA and drug-resistant APL.     

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.     

Successful All-<Emphasis Type="Italic">trans</Emphasis> Retinoic Acid Treatment of Acute Promyelocytic Leukemia in a Patient with <Emphasis Type="Italic">NPM/RAR</Emphasis> Fusion

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocation involving the gene for retinoic acid receptor alpha(RAR). Most APL patients have a t(15;17) translocation that generates the PML-RAR fusion gene, and such patients respond well to treatment with all-trans retinoic acid (ATRA). Some APL cases also involve rearrangements that fuse RAR to partner genes other than PML, including nucleophosmin (NPM), promyelocytic leukemia zinc finger (PLZF), nuclear mitotic apparatus (NUMA), and Stat5b, but the clinical characteristics of APL without PML-RAR have not been fully clarified. We describe a 64-year-old man with NPM-RAR-positive APL who was receiving hemodialysis therapy for chronic uremia. Complete remission was achieved with ATRA monotherapy and was maintained for 18 months with consolidation chemotherapy. These findings suggest that ATRA can be used to treat APL patients with NPM/RAR as well as APL with PML/RAR.     

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.     

Retinoids--"differentiation agents" for cancer treatment and prevention.

The ability of vitamin A and its derivatives to induce differentiation in certain target tissues has been appreciated for nearly a century. Recently, oral all-trans retinoic acid (ATRA), a vitamin A metabolite, has been shown to induce terminal differentiation of leukemic cells in patients with acute promyelocytic leukemia (APL). Complete remissions are obtained and normal hematopoiesis is established in an outpatient setting with minimal side effects in the majority of cases. Although remissions are not durable, disseminated intravascular coagulation, a frequent complication of remission induction in APL, is avoided by oral ATRA prior to definitive chemotherapy. The molecular basis for the efficacy of ATRA in APL appears to be the involvement of the retinoic acid receptor alpha locus in the t(15;17) translocation breakpoint characteristic of APL.     

Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation.

Chromosome 17 breakpoints in translocation t(15;17), a hallmark for acute promyelocytic leukemia (APL), have been shown to disrupt the retinoic acid receptor-alpha (RARA) gene. In this study, DNA probes around the second exon of the RARA gene showed rearrangements not previously detected. Analysis of 25 Chinese APL cases showed that RARA gene rearrangements were present in 23 cases (92%). The breakpoints were mapped unequivocally in 22 cases within the second intron of the gene. Therefore, the RARA gene rearrangement provides us with a specific marker of the disease. Simultaneous molecular and cytologic studies showed that the RARA gene rearrangements persisted during the first 2 to 3 weeks of all-trans retinoic acid (ATRA) therapy when differentiated granulocytes predominated in bone marrow, while these rearrangements disappeared after achieving complete remission. These data indicate that ATRA induces differentiation of APL cells.     

Acute promyelocytic leukemia accompanied by scrotal Fournier's gangrene during ATRA treatment and relapsed as external ear tumor

A 43-year-old man was admitted because of gingival bleeding. A diagnosis of acute promyelocytic leukemia (APL) was made. He was given combination chemotherapy including all-trans retinoic acid (ATRA). During the myelosuppression stage, the patient developed Fournier's gangrene of the scrotum. He achieved complete remission and underwent a hemicastration procedure. Seven months later, bilateral external ear tumors developed. Biopsy specimens of the tumors revealed infiltration of APL cells. A second remission was obtained by chemotherapy including ATRA. However, bilateral ear tumors developed again 5 months later despite indications of normal marrow without proliferation of leukemic blasts. Irradiation successfully reduced the ear tumors, but the patient died of cerebral hemorrhage from a left frontal extramedullary tumor. This was a rare case of APL accompanied by Fournier's gangrene of the scrotum during ATRA treatment, and by extramedullary tumors of the external ear and brain during leukemic relapse.     

9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia

9-cis retinoic acid (RA) is a high-affinity ligand for both retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). Although all- trans RA does not bind to RXRs, RAR/RXR heterodimers or RXR/RXR homodimers bind to specific DNA response elements and modulate proliferation and differentiation of normal and malignant cells. Because the development of clinical resistance to all-trans RA has been associated with a progressive decrease in plasma drug concentrations, we evaluated the ability of 9-cis RA to induce in vitro cytodifferentiation in subclones of a retinoid-sensitive and resistant APL cell line (NB4) and in short-term cultures of fresh leukemic cells aspirated from patients. We also evaluated the clinical activity and pharmacokinetics of 9-cis RA (LGD 1057) in patients with APL who were previously treated with all-trans RA. In vitro tests of both retinoid- sensitive NB4 cells, as well as samples of fresh cells from 11 patients with APL, showed relatively equivalent degrees of sensitivity to both 9- cis RA and all-trans RA at concentrations ranging from 10(-6) to 10(-8) mol/L; however, no substantial cytodifferentiation was observed using either drug alone or in combination (10(-6) mol/L of each) in retinoid- resistant NB4 cells. Seven patients with APL who had previously relapsed from a remission induced by all-trans RA were treated with 9- cis RA at daily oral doses ranging from 30 to 230 mg/m2. Pharmacokinetic studies showed that the mean terminal plasma half-life of 9-cis RA (1.3 hours) changed very little after several weeks of dosing, although the mean change per dose level in area under the plasma concentration x time curves and peak plasma concentrations showed a decrease by 49% and 45%, respectively. Peak plasma concentrations equaled or exceeded concentrations that were effective against retinoid-sensitive cells in vitro. Despite these favorable pharmacokinetic results, only one of the seven patients achieved complete remission, corroborating in vitro studies of blasts from three of the nonresponders that showed a relatively equivalent degree of resistance to both retinoids. Our results suggest that while 9-cis RA may not induce its own catabolism to the same degree as all-trans RA, this feature does not appear to overcome clinically acquired resistance to all-trans RA in APL. Nonetheless, the drug can induce complete remissions in patients with APL and may be useful for extended therapy in other diseases. Future studies should address the use of lower doses in patients who have not previously received retinoid therapy.(ABSTRACT TRUNCATED AT 400 WORDS)