Molecular Relapse Monitoring and Treatment in Acute Promyelocytic Leukemia (APL) Patients.

Molecular monitoring of PML/RARA chimeric gene expression is stated to be necessary for diagnosis of acute promyelocytic leukemia (APL), as well as for monitoring of minimal residual disease (MRD). In our study we aimed to modify leukemia treatment according to MRD results. PML/RARA expression was measured by RT-PCR. Synthesis of primers and RT-PCR were performed using recommendations of BIOMED-1 Concerted Action (1999). Sensitivity of method was estimated as 10⁻⁴ – 10⁻⁶. Fresh bone marrow (BM) aspirates were investigated before treatment, during induction and consolidation, every 2–3 months during maintenance therapy, and after completion of treatment. A total of 73 morphologically suspected APL patients were included in the study; expression of PML/RARA was found in 69 patients (94.5%), bcr1/2 type in 31 patients (45%), and bcr3 type in 38 patients(55%). MRD screening during maintenance therapy was performed in 47 PML/RARA-positive APL patients. Median follow-up was 4 years (2 mo – 8 years). If chimerical transcript was revealed in a BM sample once, this was considered probable molecular relapse, and when PML/RARA was find twice in 2–3 weeks, we considered this proven molecular relapse. Molecular relapses were revealed in 19 of 47 (40.4 %) APL patients. In 6 of 19 patients (31.5 %) relapses were proven, and in 13 (68.5%) relapses were probable. When the molecular relapses were detected, maintenance chemotherapy was changed in 3 of 13 (23%) patients with probable relapses and in 5 of 6 (83%) patients with proven relapses. None of them developed hematological relapse. Therapy was not changed in 11 patients, and 3 of 10 (30%) patients with probable molecular relapse and 1 pt with proven relapse demonstrated recurrence of the disease. Thus, 4 of 11 (36%) patients with unchanged therapy developed hematological relapse. These results are significantly different from patients with modified maintenance treatment (P=0.01). Interesting data were obtained while investigating BM samples obtained from 5 patients in whom BM sampling were performed at 2 different sites (sternal and iliac). Simultaneously performed RT-PCR of those samples showed different results in 3 of 5 (60%) patients.

Though we have a small cohort of patients, we may conclude that it is advisable to change chemotherapy when proved or probable molecular relapse is revealed., When the single positive result of chimerical transcript expression is obtained, it is important to repeat RT-PCR analysis in 2–4 weeks in order to prove the molecular relapse, and then to adjust the maintenance program. However, even when it is impossible to perform the second analysis, changing the therapy may be advisable.