Use of All-Transretinoic Acid (ATRA) + Arsenic Trioxide (ATO) To Eliminate or Minimize Use of Chemotherapy (CT) in Untreated Acute Promyelocytic Leukemia (APL).

Abstract

Current therapy cures most patients (pts) with newly diagnosed APL. Therefore, by analogy to childhood acute lymphoblastic leukemia, focus reduction of therapy-associated toxicity appears appropriate. Such reduction implies less reliance on anthracyclines, which can, rarely but not inconsequentially, cause sepsis, myelodysplastic syndromes, and cardiotoxicity. An obstacle to eliminating anthracylines is the belief that ATRA-induced remissions are transient, unless anthracyclines are also given. We examined whether combining ATRA and ATO might allow elimination of CT. ATO (0.15 mg/kg/day) began 10 days after ATRA (45 mg/m2 twice daily). In CR, both drugs were to be continued until 6 months from CR date. CT (typically gemtuzumab ozogamycin, GO, 9 mg/m2 one dose) was only to be given (1) during induction (day 1) if the presenting WBC count was > 10,000/ml, (2) if 2 consecutive polymerase chain reaction (PCR) tests for PML-RARa (sensitivity level 10−4, tests repeated at 2–4 week intervals) were positive 3 months from CR date, or (3) for reversion of a negative PCR test to positive on 2 consecutive occasions as above (molecular relapse). 32 patients (median age 45, 13 with WBC > 10,000 = “high risk”, HR) went on study. The CR rate was 28/32 (88%, 11/13, 85% in HR). Median time to CR was 29 days. Three of the 32 pts died before receiving ATO; APL differentiation syndrome occurred in 5 pts. 25/26 evaluated pts were PCR positive at CR. However, 3 months later, 21/21 were PCR negative, with PCR negativity rates of 17/17, 12/13, 9/10, and 5/5 at, respectively, 6, 9,12, and 12–24 months from CR date. Both molecular relapses subsequently had clinical relapses. No other clinical relapses have occurred, with a median time from CR of 7 months (up to 24 months) in the 26 patients alive in 1st CR. GO was substituted for ATO in 5 patients because of toxicity (arrhythmias in 4, asymptomatic in 3). Among the 29 pts who began ATO, the incidence of arrhythmias was 2/2 in African Americans vs. 2/27 in Caucasians (p = 0.01). Recalling that high-risk pts received CT during induction and excluding pts in whom GO was substituted for ATO because of toxicity, rates of PCR negativity are as follows at 3,6,9,12,and 12–24 months from CR date (rates for high-risk patients in parentheses): 17/17(6/6), 14/14(7/7), 10/11(6/7), 8/9(4/5) and 4/4(3/3). Pending further follow-up, cure of untreated APL without (WBC < 10,000), or with only minimal use (WBC > 10,000) of, CT appears feasible.