The Outcome of Patients (pts) with Acute Promyelocytic Leukemia (APL) Who Fail Both All–Trans-retinoic Acid (ATRA) and Arsenic Trioxide (ATO).

ATRA-based therapy is effective for most pts with APL. For those who do not respond or relapse after ATRA, ATO induces remissions in most pts. Few pts may fail therapy with both agents, and the outcome of these pts is not known.

To investigate the outcome of pts who fail therapy with both ATRA and ATO, whether given concomitantly [ATRA+ATO induction] or sequentially [ATRA-based induction with ATO-based salvage].

Pts with APL who were treated with both ATRA and ATO at M.D. Anderson Cancer Center were reviewed. Response to both agents was scored according to standard criteria. Pts who failed both ATRA and ATO, whether given concomitantly or sequentially, were identified. Failure was defined as no response to therapy, relapse, or death from any cause (including during therapy or in complete remission –CR–). Overall survival (OS) was considered as the time from the date the pt started ATO (together with or after ATRA) to death.

A total of 113 pts have been treated with both ATRA and ATO therapy: 83 (73%) received ATRA and ATO as initial induction therapy and 30 (27%) received an ATRA-based induction regimen followed by ATO salvage therapy. Of them, 19 (17%) failed both agents. The median age at diagnosis was 48 yrs (range, 18 to 74). Of the 83 pts who received ATRA + ATO induction, 81 achieved CR and 4 subsequently relapsed. The other 2 pts died during induction. Two other pts who were initially treated elsewhere with chemotherapy alone (one also received stem cell transplant), received ATRA + ATO as salvage therapy upon relapse; one had sustained CR and the other had no response (NR). Thus a total of 7 patients (4 relapses after remissions of 9.2 mo, 13 mo, 9.1 mo, and 12.3 mo; 2 induction deaths; 1 NR) failed therapy with both ATRA + ATO. Among the 4 pts that relapsed, 3 received ATO + ATRA salvage therapy and achieved CR; 1 died in CR and 2 are alive in CR 70.2+ and 29.3+ months later. One pt declined further therapy. In addition, 30 pts received ATRA-based induction and, upon relapse, ATO-based salvage therapy (12 of them combined with ATRA). Twelve (40%) of these pts failed salvage with ATO: 1 had NR to therapy, 6 achieved CR and then relapsed (after median of 14.4 mo, range 3.2 to 48.9), and 5 died in CR (salvage with ATO alone in 3, ATRA+ATO in 2). Of the 7 pts with NR or relapse, 5 achieved CR with subsequent therapy (ATRA-based in 2, ATRA+ATO in 2, ATO-based in 1 on 2^nd salvage; ATO-based in 1, ATRA+ATO in 1, Tamibarotene in 1 on 3^rd salvage; gemtuzumab ozogamicin-based in 1 and ATRA-based in 1 as 4^th salvage). Of all 19 pts that failed both ATRA and ATO, 14 (74%) died: 7 during induction or in CR and 7 after failure. The median survival from failure to ATRA and ATO (excluding those who died during induction or in CR since death defines failure for these pts) is 42 mo, with 36% alive at 4 yrs.

The outcome of patients who fail both ATRA and ATO either concomitantly or sequentially is poor. Although some pts may respond to subsequent therapies, most ultimately succumb to their disease, and others die during therapy. New treatment options are needed for this group.

Ravandi:Cephalon: Advisory board, Honoraria. Cortes:CytRx: Research Funding; Wyeth: Research Funding.