Acute promyelocytic leukemia relapsed

Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiroka A, Karasuno T, Takeuchi M, Miyawaki S, Ueda R et al (1997) Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-tra 5-retinoic acid. Blood 90 967-973... 

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). 

Lo-Coco F, Cimino G, Breccia M, Noguera NI, et al. 2004. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 104 1995-1999. 

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). 

Roberts TF, Spragne K, Schenkein D, Miller KB, Relias V. Hyperleukocytosis during induction therapy with arsenic trioxide for relapsed acute promyelocytic leukemia associated with central nervous system infarction. Blood 2000 96(12) 4000-1. 

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). 

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. 

Doner D, Estey E, Santillana S, Bennett JM, Lopez-Bernstein G, Boehm K, Williams T. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood 2001 97(l) 73-80. 

Diverio D, Rossi V, Awisati G, De Santis S, PistiUi A, Pane F, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter AIDA trial. GIMEMA-AIEOP Multicenter AIDA Trial. Blood 1998 92 784-9. 

Niu C, Yan H, Yu T, et al. Studies of treatment of acute promyelocytic leukemia with arsenic trioxide remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999 94 3315-3324. 

Solignet S, Frankel S, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001 19 3852-3860. 

Arsenic trioxide is an antineoplastic agent that causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR alpha. It is indicated in the treatment of refractory or relapsed acute promyelocytic leukemia (APT). 

Grimwalde, D., Howe, K., Langabeer, S. et al. (1996) Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR evaluation of PML-RAR a and RAR a-PML assessment in patients who ultimately relapse. Leukemia, 10, 61-66. 

Huang, W, Sun, G-L, Li, X-S., Cao, Q., Lu, Y, Jang, G-S, Zhang, F-Q., Chai, J-R., Wang, Z-Y., Waxman, S., Chen, Z, and Chen, S-J (1993) Acute promyelocytic leukemia Clinical relevance of two major PML/RARot isoforms and detection of minimal residual disease by retro-transcriptase polymerase chain reaction to detect relapse Blood 82,1264-1269... 

A 35-year-old man with acute promyelocytic leukemia in relapse achieved a second remission with oral arsenic trioxide 10 mg/day for 30 days, followed by idarubicin 9 mg/day for 5 days. He was a chronic smoker (3 packs/... 

Combination stndies The effects of gemtuzumab in combination with other treatments have been studied in patients with relapsed CD33-positive acute myeloid leukemia [235<=, 236<=, 237, 238 ] and in patients with acute promyelocytic leukemia [239 ]. The Committee for Medicinal Products for Human Use (CHMP) noted that there were adverse reactions associated with gemtuzumab. These included severe and long-lasting bone marrow suppression causing reduced leukocyte and platelet counts, liver problems, and adverse reactions related to the infusion, such as chilk. 

Ding W, Li YP, Nobile LM, Grills G, Carrera I, Paietta E, Tallman MS, Wiemik PH, Gallagher RE (1998) Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARa fusion gene after relapse of acute promyelocytic leukemia from treatment with dW-trans retinoic acid and intensive chemotherapy [In Process Citation]. Blood 92 1172-1183... 

Takeshita A, Shibata Y, Shinjo K, Yanagi M, Tobita T, Ohnishi K, Miyawaki S, Shudo K, Ohno R (1996) Successful treatment of relapse of acute promyelocytic leukemia with a new synthetic retinoid, Am80. Ann Int Med 124 893-896... 

Fenaux P, Wattel E, Archimbaud E, Sanz M, Hecquet B, Guerci A, Link H, Fegueux N, Fey M, Castaigne S et al (1994) Prolonged follow up confirms that all-tran retinoic acid (ATRA) followed by chemotherapy reduces the risk of relapse in newly diagnosed acute promyelocytic leukemia (APL). Blood 84 666-667... 

Delva L, Comic M, Balitrand N, Guidez F, Miclea JM, Delmer A, Teillet F, Fenaux P, Castaigne S, Degos L, Chomienne C (1993) Resistance to AW-trans retinoic acid therapy in relapsing acute promyelocytic leukemia. Blood 2175-2181... 

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