Acute promyelocytic leukemia treatment

Cunningham I, Gee T, Reich L (1989) Acute promyelocytic leukemia treatment results during a decade at Memorial Hospital. Blood 73 1116-1122... 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Lu D-P, Qiu J-Y, Jiang B, Wang Q, Liu K-Y, Liu Y-R et al. Tetra-arsenic tetra-sulflde for the treatment of acute promyelocytic leukemia a pilot report. Blood 2002 99 3136-43. 

Other organoarsenicals, most notably lewisite (dichloro[2-chlorovinyl]arsine), were developed in the early twentieth century as chemical warfare agents. Arsenic trioxide was reintroduced into the United States Pharmacopeia in 2000 as an orphan drug for the treatment of relapsed acute promyelocytic leukemia and is finding expanded use in experimental cancer treatment protocols (see Chapter 54). Melarsoprol, another trivalent arsenical, is used in the treatment of advanced African trypanosomiasis (see Chapter 52). 

A unique use of arsenic, in the form of arsenic trioxide (AS2O3), is for the treatment of cancer. Relapsed or refractory cases of acute promyelocytic leukemia have been successfully treated with this arsenical. Its use in the United States was approved by the US Food and Drug Administration (FDA) in 2000 (Antman, 2001). 

Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988 72 567-572. 

Sun HD, Li H, Ma L et al (1992) Treatment of acute promyelocytic leukemia by Ailing-1 therapy (in Chinese). Chin J Integr Trad Med West Med 12 170-172... 

Soignet SL, Maslak P, Wang ZG et al (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339 1341-1348... 

Chen GQ, Zhu J, Shi XG et al (1996) In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As203) in the treatment of acute promyelocytic leukemia As203 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RARa/PML proteins. Blood 88 1052-1061... 

As an alternative to using synthetic analogs for disease treatment, the natural ligand for the retinoic acid receptor, all-irans-retinoic acid (ATRA), is used effectively in the treatment of acute promyelocytic leukemia (APL) (73). Chromosomal translocations in APL patients are responsible for the cellular transformation in this disease. The transformation results in a fusion of the retinoic acid receptor alpha (RARa) with another protein (73). Treatment of APL patients with pharmacologic doses of ATRA induces complete remission by restoring normal granulocytic differentiation (74, 75). 

Schwartz BS, Williams EC, Coulau MG, Mosher DF. Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency. Ann Intern Med 1986 105(6) 873-7. 

De Renzo A, Santoro LF, Notaro R, Pane F, Buonaiuto MR, Luciano L, Rotoli B. Acute promyelocytic leukemia after treatment for non-Hodgkin s lymphoma with drugs targeting topoisomerase 11. Am J Hematol 1999 60(4) 300. ... 

Shimamoto Y, Suga K, Yamaguchi M, Kuriyama K, Tomonaga M. Prophylaxis of symptoms of hyperhistamine-mia after the treatment of acute promyelocytic leukemia with all-trans retinoic acid. Acta Haematol 1994 92(2) 109-12. 

An increased risk of thrombotic events, especially coronary thrombosis, has been reported in elderly patients taking retinoids (33). Two patients with acute promyelocytic leukemia developed thrombus in the right ventricle during induction treatment with tretinoin plus idarubicin (34). 

A 32-year-old woman with acute promyelocytic leukemia developed severe retinoic acid syndrome after 3 days, with respiratory failure, fever, and bilateral lung infiltrates. Withdrawal of tretinoin and treatment with dexamethasone and antibiotics rapidly ameliorated the syndrome, and on day 10 tretinoin was restarted. However, routine echocardiography showed a 3 cm pedunculated mass in the right ventricle. There was consistent and stable reduction of the mass after 1 year of oral anticoagulant therapy. 

A 56-year-old woman with acute promyelocytic leukemia developed a fever of unknown origin, weight gain of 5 kg, and respiratory distress 9 days after the start of treatment with tretinoin 45 mg/m (38). Her white cell count rose to 21 x 10 /1 despite treatment with cytosine arabinoside and idarubicin. A chest X-ray showed bilateral alveolar opacities. She recovered fully after 5 days of treatment with dexamethasone 10 mg bd. 

A 24-year-old woman with acute promyelocytic leukemia took tretinoin, and 2 days later developed dyspnea and general aching (39). Her total leukocyte count was 5.04 x 10 /1, her Pa02 was 42.5 mmHg, and a chest X-ray showed bilateral parenchymal infiltration consistent with respiratory distress syndrome. She recovered within 3 days of treatment with low-dose cytarabine and glucocorticoids, without withdrawal of the retinoic acid. 

Although the retinoic acid syndrome involves the lungs, pulmonary hemorrhage has only rarely been reported. Two patients with acute promyelocytic leukemia developed severe lung hemorrhage during the first 3 weeks of treatment with tretinoin, shortly after the administration of chemotherapy (40). 

Extramedullary relapse of acute promyelocytic leukemia, which is rare after chemotherapy alone, was more common after tretinoin, but it is not clear whether it truly increases the risk of extramedullary recurrence and what the risk factors are. In a retrospective analysis of the incidence of extramedullary relapse in patients after prior treatment with tretinoin and in patients previously treated with chemotherapy alone (68) three of the 13 patients who received tretinoin had extramedullary involvement compared with none of the 11 patients previously treated with chemotherapy alone (RR = 2.1 Cl = 1.34, 3.29). The retinoic acid syndrome during prior induction treatment was significantly associated with extramedullary relapse (three of five patients with the retinoic acid syndrome versus none of eight without the syndrome (RR = 5.0 Cl = 1.4,17)). Thus, tretinoin may predispose patients with acute promyelocytic leukemia to extramedullary involvement at relapse and the retinoic acid syndrome is a risk factor. 

Leukemia cutis is very rare in acute myelocytic leukemia. Cutaneous relapse in acute promyelocytic leukemia has been reported during a period of complete hematological remission after treatment with tretinoin (100). 

Mann G, Reinhardt D, Ritter J, Hermann J, Schmitt K, Gadner H, Creutzig U. Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. Ann Hematol 2001 80(7) 417-22. 

Torromeo C, Latagliata R, Awisati G, Petti MC, Mandelli F. Intraventricular thrombosis during all-trans retinoic acid treatment in acute promyelocytic leukemia. Leukemia 2001 15(8) 1311-13. 

Raanani P, Segal E, Levi I, Bercowicz M, Berkenstat H, Avigdor A, Perel A, Ben-Bassat I. Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA—a manifestation of the basic disease or the treatment. Leuk Lymphoma 2000 37(5-6) 605-10. 

Sakamoto O, Yoshinari M, Rikiishi T, Fujiwara I, Imaizumi M, Tsuchiya S, linuma K. Hypercalcemia due to all-trans retinoic acid therapy for acute promyelocytic leukemia a case report of effective treatment with bis-phosphonate. Pediatr Int 2001 43(6) 688-90. 

Ko BS, Tang JL, Chen YC, Yao M, Wang CH, Shen MC, Tien HF. Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia—the occurrence of retinoic acid syndrome is a risk factor. Leukemia 1999 13(9) 1406-8. 

Sun GL. [Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) a report of five-year experience.] Zhonghua Zhong Liu Za Zhi 1993 15(2) 125-9. 

Tajima K, Sagae M, Yahagi A, Akiba J, Suzuki K, Hayashi T, Satoh S. [Scrotum exfoliative dermatitis with ulcers associated with treatment of acute promyelocytic leukemia with all-trans retinoic acid.) Rinsho Ketsueki 1998 39(l) 48-52. 

Mori A, Tamura S, Katsuno T, Nishimura Y, Itoh T, Saheki K, Takatsuka H, Wada H, Fujimori Y, Okamoto T, Takemoto Y, Kakishita E. Scrotal ulcer occurring in patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid Oncol Rep 1999 6(l) 55-8. 

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