Monitoring of Minimal Residual Disease in Children with Acute Promyelocytic Leukemia by RT-PCR Detecting PML/RAR.ALPHA. Chimeric Gene: A Retrospective Study of Clinical Feasibility.

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Abstract
We studied retrospectively the clinical feasibility of minimal residual disease (MRD) monitoring by reverse transcription-polymerase chain reaction (RT-PCR) detecting the PML/retinoic acid receptor α (RARα) chimeric gene in children with acute promyelocytic leukemia (APL). MRD monitoring of APL was performed with standard and nested RT-PCR for PML/RARα gene, the sensitivity of which was 1 leukemic cell in 103-104 and 1 in 104-105 cells, respectively. Patients were nine children with APL (average age: 8.3 year; average period of follow-up: 69.2 months) who, after achieving remission with all-trans retinoic acid (ATRA), received treatment either with multidrug chemotherapy or with a combination of chemotherapy and ATRA. Out of six patients treated with multidrug-combined chemotherapy, two patients exhibited PCR positivity after six months of post-remission therapy, which shifted from the detectable range of the nested PCR to that of the standard PCR. These two patients subsequently relapsed and, together with two of the other patients receiving multidrug-combined chemotherapy, underwent allogeneic bone marrow transplantation. No MRD was detected in these patients after transplantation. In the remaining three patients who underwent cyclic treatment with alternative chemotherapy and ATRA, two showed positive RT-PCR at the nested or standard level, respectively, after six months of combined therapy, and one of them relapsed. Overall, three of four patients with MRD detected in post-remission period ultimately relapsed, while all of five patients without detectable MRD had a good prognosis. These findings suggest that impending relapse may be predicted by the detection of preceding PCR positivity with an increasing quantity of the PML/RARα mRNA that appears beyond six months of post-remission chemotherapy, with or without combined ATRA therapy.

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