Abstract
Background: Adult patients with relapsed acute lymphoblastic leukemia (ALL) are candidates for allogeneic stem cell transplantation (SCT), if feasible. Despite the intensity of SCT treatment at least 40% of patients relapse. Survival is additionally negatively influenced by a high transplant related mortality. Therefore, markers that distinguish patients who will benefit from SCT from those who might profit from different therapeutic modalities or modification of SCT are highly warranted. Kinetics of minimal residual disease (MRD) can serve as molecular parameter of chemoresistance of the leukemia. The purpose of the current study was to investigate whether molecular resistance to front-line therapy can be overcome by allo-SCT following myeloablative conditioning.
Methods: MRD was analyzed before and after myeloablative SCT in adult patients with Philadelphia negative relapsed ALL. MRD kinetics were compared to previous molecular response to first-line treatment. For this purpose, cases with persistent detectable disease >1×E–04 at day+71/112 of first-line therapy were classified as primarily molecularly chemoresistant (PMR), cases with MRD values below 1×E–04 around day+71/112 of first-line treatment were categorized as primarily molecularly chemosensitive (PMS). Relapsed ALL patients were included if they had been treated according to the GMALL trials 06/99 or 07/03 with prospective MRD monitoring, and if they had bone marrow samples taken after relapse until day+100 after SCT. Real-time quantitative (RQ)-PCR analysis of patient specific immunoglobulin and T-cell receptor gene rearrangements were used as targets for quantification of MRD.
Results: 25 patients were eligible (15 T- and 10 B-lineage ALL). Median age was 22 (16–45) years. Median disease-free survival after front-line therapy was 17 (3 to 52) months. Eleven cases were classified as molecularly chemoresistant to front-line therapy, 14 ALL cases were categorized as primarily molecularly chemosensitive. In keeping with molecular response to initial treatment, PMR cases showed only a modest reduction of MRD in response to salvage chemotherapy with a median MRD value of 3×E–01 (range 2×E–03 to 1×E+00) before SCT. Median MRD levels within the first 100 days after myeloablative SCT decreased to 4×E–04 with a range between MRD negativity and 1.0×E+00. PMS cases showed a significantly better response to salvage chemotherapy: In contrast to PMR cases who were MRD positive prior to SCT in all analysed cases, four out of 7 PMS cases were MRD negative pre-SCT (range: MRD negativity to 4.2×E–03). Also within 100 days after SCT 13/16 analysed samples were MRD negative (compared to only 4/11 analysed PMR samples, p=0.02, see Figure). Taken together, these results show for relapsed ALL that molecular chemoresistance to front-line therapy correlates with a poor molecular response to second-line treatment in transplant recipients.
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