ATRA therapy

Charles KS, Kanaa M, Winfield DA, Reilly JT. Scrotal ulceration during all-trans retinoic (ATRA) therapy for acute promyelocytic leukaemia. Clin Lab Haematol 2000 22(3) 171. ... 

Several studies have reported that retinoids are effective for animal models of autoimmune diseases. Lupus nephritis is a major cause of mortality among systemic lupus erythematosus patients. ATRA inhibits IFN-y cytokine production from Thl and production and deposition to the kidneys of anti-DNA antibody IgG2a, and suppresses proteinuria and renal involvement in NZB/WFl mice, which are used as a lupus nephritis model (Nozaki et al. 2005). In an open clinical trial, seven patients with active lupus nephritis were treated with ATRA. As a result, four patients showed improvements in clinical symptoms and laboratory findings, including proteinuria and anti-dsDNA antibody levels. There were no adverse effects of ATRA therapy in any patient (Kinoshita et al. 2009). 

To date, three other APL-associated translocations of the RARa gene have been characterised at the molecular level. The t(5 17)(q35 q21) [96], t(ll 17)(q23 q21) [97, 98] and t(ll 17)(ql3 q21) [99] fuse RARa to Nucleophosmin (NPM), Promyelocytic Leukaemia Zinc Finger (PLZF), and Nuclear Mitotic Apparatus (NuMA) genes, respectively. These translocations result in the expression of chimeric RARa fusion proteins, which all retain the DNA and ligand binding domains of the receptor and gain a dimerization domain from the fusion partner (see Fig. 2 for a schematic representation). So far, the t(5 17)(q35 q21) and t(l I 17)(ql3 q21) have only been reported in index cases and, as with t(15 17)-associated APL, appeared to respond to treatment with ATRA [96,99]. In contrast, APL with t(l I 17)(q23 q21) has been reported on a recurrent basis, albeit at very low frequency, and has consistently been found unresponsive to ATRA therapy [100, 101]. 

In the first reports of ATRA therapy, CR rates of about 90% were obtained in newly-diagnosed and first relapse APL, generally with a 45 mg/m daily dose of ATRA, and it was demonstrated that response was not obtained by cytotoxicity but by differentiation of APL blasts into neutrophils, leading to progressive replacement of leukemic hematopoiesis by normal polyclonal hematopoiesis [26-31]. Rapid improvement of coagulopathy, instead of the initial worsening observed with conventional chemotherapy, was also seen. 

ATRA therapy is usually well tolerated but a few major side effects can occur, mainly the ATRA syndrome. 

In APL patients treated with ATRA alone, primary fibrinogenolysis disappears during the first five days of treatment, while DIG and leukocyte-mediated proteolysis seem to persist during the first two or three weeks of ATRA therapy [54-56]. This could lead to a transient period of hypercoagulability, which could explain the few well documented cases of thromboembolic events in APL patients treated with ATRA [57-59]. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Tretinoin, also referred to ATRA, which stands for all-trans-retinoic acid, is a retinoic acid that is not cytotoxic but promotes the maturation of early promyelocytic cells and is specific to the t(15 17) cytogenetic marker. The time to peak concentrations is 1 to 2 hours after an oral dose. The elimination half-life is 21 to 51 minutes.32 These maroon-and-gold capsules are dosed at 45 mg/m2 per day divided into two doses. The most significant side effect is the retinoic acid syndrome, which may occur anywhere from the first couple of days of therapy until the end of therapy and consists of symptoms of... 

Yate PM, Flynn PJ, Arnold RW, Weatherly BC, Simmonds RJ, Dopson T. Clinical experience and plasma laudanosine concentrations during the infusion of atra-curium in the intensive therapy unit. Br J Anaesth 1987 59(2) 211-17. 

Eenaux P, Chastang C, Chevret S, et al. A randomized comparison of all-trans-retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999 94 1192-1200. 

There is now compelling evidence from the number of retinoids in the clinic and in clinical studies (Table 12.1) that these molecules exhibit efficacy in human diseases. The use of ATRA for the treatment of acute promyelocytic leukemia is considered a successful therapy in our view. It is the hope that the application of retinoids, most probably more receptor specific retinoids/rexinoids, in combination with other chemotherapeutic agents, will lead to broad clinical utility in many diseases. We anticipate that the retinoid field will continue to expand as researchers gain more information about new levels of retinoid/rexinoid biology and their relevance to human diseases. 

Although recent years have seen an explosion of interest in the identification and development of small molecule modulators of stem cell fate, early observations in this area were made over 30 years ago describing the effects of naturally derived molecules on cell fate. In 1978, two independent reports demonstrated embryonal carcinoma (EC) cells could be differentiated towards parietal endo-derm-like cells with either all-trans-vtiinoic acid (ATRA) or hexamethylenebis-acetamide. ATRA has since been shown to exhibit pleiotropic effects and to promote differentiation to multiple cell types, and has been used in the clinic for the differentiation therapy of acute promyelogenous leukaemia. ... 

The first study with retinoic acid on humans, however, failed to show any positive effects on the emphysema, but it did show mild negative side effects (including skin changes, transient headache, hyperlipidemia, transaminitis, and musculoskeletal pains) [91]. To evaluate the feasibility of ATRA as a clinical therapy, 20 patients with severe emphysema were enrolled into a randomized, double-blind, placebo-controlled pilot study. In general, treatment was well tolerated and associated with only mild side effects including skin changes, transient headache, hyperlipidemia, transaminitis, and musculoskeletal pains. 

Tallman, M. S., Andersen, J., Schiffer, C A, Appelbaum, F R, Feusner, J E, Woods, W G, Ogden, A., Weinstein, H, Shepherd, L, Rowe, J. M., and Wiernik, P. H. (1995) Phase III randomized study of all-trans retinoic acid (ATRA) vs daunorubicin (D) and cytosine arabmoside (A) as induction therapy and ATRA vs observation as maintenance therapy for patients with previously untreated acute promyelocytic leukemia (APL). Blood 86, Suppl 1,125a. 

A 38-year-old man with acute promyelocytic leukemia who was taking itraconazole 200 mg bd was given all-trans retinoic acid and during the third course of maintenance therapy developed acute renal insufficiency and symptomatic hypercalcemia, which was treated with high-volume crystalloid infusions and furosemide. Renal function was restored, and the serum calcium concentration returned to normal within 4 days after withdrawal of ATRA. The peak serum calcium concentration was 3.67 mmoUl. Serum parathyroid hormone was undetectable, and there were no increases in the concentrations of prostaglandins or vitamin D metabolites. Hypercalcemia recurred during a fourth course of ATRA. 

Cordoba R, Ramirez E, Lei SH, LopezdeGuia A, Sanjuijo MJ, Carcas AJ, Hernandez-Navarro F. Hypercalcemia due to an interaction of all-trans retinoic acid (ATRA) and itraconazole therapy for acute promyelocytic leukemia successfully treated with zoledronic acid. Eur J Clin Pharmacol 2008 64 1031-2. 

Erythropoietin derivatives are associated with an increased frequency of thrombo-vascular events in a variety of tumor types [97 ]. However, whether patients with susceptibility factors should receive prophylactic antithrombotic treatment has not been confirmed. The adverse effects of combination therapy with epoetin beta and all-trans retinoic acid (ATRA) in 59 patients with myelodysplastic syndromes were muscle pain, raised liver enzymes without hepatic failure, fatigue, headache, dry skin, and dry mucosa [98 ]. 

In the present investigation, 73 newly diagnosed APL subjects were treated with an all-trans retinoic acid (ATRA) and arsenic trioxide (AS2O3) combination in remission induction and post-remission therapy. Tumour burden was examined with polymerase chain reaction of fhe Promyelocytic Leukemia (PML)-Retinoic Acidic Receptor (RAR) fusion transcripts, and side effects were evaluated by means of clinical examination. 

In recent years, discovery of the in vitro and in vivo differentiation of APL blasts by dX -trans retinoic acid (ATRA) has modified the therapeutic approach of APL [23-25] but also lead to important advances in the biology of APL and opened new perspectives for differentiation therapy in cancer [26]. 

However, two major drawbacks of ATRA treatment were observed. First, mainly in newly-diagnosed APL, a rapid rise in leukocytes was seen in one third to one half of the patients, accompanied by clinical signs of ATRA syndrome which proved fatal in some patients [28, 32, 33]. Low dose chemotherapy (with hydroxyurea or low dose AraC) did not succeed in lowering leukocyte counts and preventing the fatal outcome, whereas more intensive anthracycline-AraC chemotherapy was able to reduce leukocyte counts and allow most patients to enter CR [70]. The second drawback was that most of the patients who achieved CR with ATRA and received either ATRA alone or low dose chemotherapy for maintenance therapy relapsed within a few months of CR achievement [25, 34-37]. These findings prompted clinicians to administer treatment combining ATRA and intensive chemotherapy in APL. 

A first pilot study treated 26 newly-diagnosed cases of APL with ATRA until CR, followed by three courses of daunorubicin (DNR)-AraC and 25 (96%) achieved CR, as compared to 76% in a historical control group treated by chemotherapy alone (difference not significant) [38, 39]. With a minimum follow up of 38 months from CR achievement, event free survival (EPS), disease free interval (DPI) and survival were significantly higher after ATRA followed by chemotherapy. Actual survival at four years was 40% after chemotherapy alone, and 77% after ATRA + chemotherapy. The combination of ATRA and chemotherapy clearly reduced the number of relapses occurring within 18 months of CR achievement, whereas the number of late relapses was similar to that seen after chemotherapy alone [38]. This suggested that combination therapy did not just delay relapses but truly reduced their incidence. 

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