Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series

Abstract

The present study aimed to investigate single-agent liposomal all-trans retinoic acid (Lipo-ATRA) in untreated acute promyelocytic leukemia (APL). Induction therapy consisted of Lipo-ATRA 90 mg/m2 i.v. every other day. Patients in complete remission (CR) continued to receive Lipo-ATRA 90 mg/m2 i.v. three times a week for 9 months. Idarubicin was added only if a polymerase chain reaction test for promyelocytic leukemia-retinoic acid receptor alpha (sensitivity level, 10(-4)), performed every 3 months from CR, was positive. The results were compared with those of a historical control group treated with oral ATRA and idarubicin. Lipo-ATRA induced CR in 79% of patients; CR rates were 92% and 38% in patients with white blood cell (WBC) counts <10 x 10(9)/L and >10 x 10(9)/L, respectively. Ten of the 26 responders to Lipo-ATRA remain in first CR at a median of 6.4 years, despite never receiving idarubicin; all 10 had initial WBC counts <10 x 10(9)/L. The 5-year survival rate was 76% for patients treated with Lipo-ATRA. Comparisons with oral ATRA+idarubicin as given at M. D. Anderson are confounded because of their historical nature and the absence of ATRA from post-remission therapy in the former group. Nonetheless, a multivariate Cox model identified higher WBC counts and older age, but not treatment (historical vs. Lipo-ATRA), as being predictive of shorter relapse-free and overall survival. Lipo-ATRA can cure patients presenting with WBC counts <10 x 10(9)/L (low risk) without additional therapy, contrary to conventional ATRA, which, when given alone, probably cures no patients. The observation that patients can be cured of APL without the use of chemotherapy should encourage further study of 'targeted' therapy in APL and in other leukemias.

Therapy-induced PML/RARA Proteolysis and Acute Promyelocytic Leukemia Cure

“…This, and other evidence, has suggested that RA-induced LIC clearance was the consequence of PML/RARA catabolism, whereas induction of differentiation likely reflected reversal of PML/RARA-dependent transcriptional repression (73). Interestingly, the few patients that were actually cured with RA alone received a liposomal form, which allowed very high and prolonged plasma concentrations (76). Arsenic alone is only a modest inducer of differentiation.…”

Revisiting the differentiation paradigm in acute promyelocytic leukemia

“…Whereas complete differentiation of the leukemia clone is achieved even at low doses of RA, APL clearance (as assessed by survival or loss of clonogenic cells in transplantation assays) correlates almost linearly with the blood RA concentration (J.A., unpublished observations, 2010). This probably explains why, in patients, only liposomal RA, which yields much higher intracellular concentrations than the standard RA oral regimen, has led to some cures as a single agent 42 ( Table 1).…”

The induction of guerin's carcinoma cytochrome P450 hydroxylase activity by retinoids

“…В отношении злокачественно трансформированных клеток в ряде работ показана противоопухолевая активность различных форм витамина А [4,5], в то же время существуют экспериментальные данные, указывающие на опухолестимулирующее влияние ретиноидов [6][7][8]. Это, в первую очередь, результаты исследований опухолестимулирующей активности предшественников витамина А -b-каротина -у лиц с раком лёгких [7].…”

“…Витамин А и его природные и синтетические аналоги -ретиноиды -являются необходимыми факторами для нормального роста, развития и дифференциации [1,2], модулируя экспрессию более 500 генов и участвуя в регуляции пролиферации и апоптоза клеток [3]. В отношении злокачественно трансформированных клеток в ряде работ показана противоопухолевая активность различных форм витамина А [4,5]; в то же время существуют экспериментальные данные, указывающие на опухолестимулирующее влияние ретиноидов [6][7][8]. Опухолевый рост характеризируется высокой метаболической активностью трансформированных клеток и образованием значительных количеств токсических продуктов метаболизма, требующего высокого уровня активности компонентов клеточной системы детоксикации, ведущим элементом которой является микросомальная монооксигеназная система цитохромов Р450 (CYPs) [9].…”