Pulsed ATRA as single therapy restores long-term remission in PML-RAR alpha-positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study

All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) i s widely used to induce complete remission (CR) in newly diagnosed acute pr omyelocytic leukemia (APL). If used alone, ATRA results in a substantial pr oportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo ) stem cell transplantation (SCT), as early reports have shown that the con tinuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have s hown that induced resistance to ATRA is frequently suppressed by the Interm ittent use of the drug. In this study we applied an intermittent therapeuti c protocol with ATRA in five APL patients who were either molecularly refra ctory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. Th ey were treated with ATRA (45 mg/m(2)/day) for 21 days. The treatment was t hen prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as ass essed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantita tive RT-PCR confirmed these data, showing a progressive reduction (1 or 2 l ogs) to a 'negligible quantity' of PML-RAR alpha fusion transcript (ratio P ML-RAR alpha /ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quanti tative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission . To our knowledge, this is the first clinical observation that intermitten t ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This ap proach could therefore be effective, if confirmed in larger series, in rela psed/refractory patients unsuitable for high-dose therapy and SCT; it may b e proposed as induction therapy for selected older APL patients if consider ed not to be eligible for combined ATRA/CHT due to inadequate performance s tatus or concurrent disease.