Transplant characteristics: minimal residual disease and impaired megakaryocytic colony growth as sensitive parameters for predicting relapse in acute myeloid leukemia

Dose escalation during consolidation therapy of de novo AML, including myel oablative chemotherapy supported with autologous peripheral blood stem cell transplantation (aPBSCT), continuously improved outcome. Therefore, qualit y control of transplants is getting increasing interest. We studied leukaph eresis products (LPs), consecutively collected during postremission treatme nt of 20 patients with de novo AML for minimal residual disease (MRD) by B- parametric flow cytometry and for myelodysplasia (MDS)-associated alteratio ns by paired lineage-selected colony assays for colony-forming units-megaka ryocytes (CFU-mega) and burst-granulocytes-monocytes colony-forming units ( CFU) to evaluate the predictive value of these transplant-associated parame ters on outcome. We defined the leukemia-associated immunophenotype at diag nosis and studied the impact of MRD detection in LPs collected after double induction with TAD (thioguanine, daunorubicin, cytarabine) and HAM (mitoxa ntrone, high-dose cytarabine, n=18 patients) and TAD consolidation treatmen t (n=20 patients) on outcome after aPBSCT. The level of MRD in the transpla nts correlated with the relapse-free survival (RFS) using a cut-off level o f 1x10(-3) residual leukemic cells. The median RFS was 6 months for the gro up with greater than or equal to 1 x 10(-3) residual leukemic cells and has not been reached in the group with low MRD levels (<1 x10(-3)). By using t he same cut-off level a weak correlation could also be demonstrated between MRD in the pregraft bone marrow and RFS (P = 0.04). Quantitatively abnorma l megakaryocytic colony growth in the back-up LPs collected after double in duction and in the transplant LPs was characterized by the ratio CFU-mega/C FU. In the group of relapsing patients the ratio CFU-mega/CFU was significa ntly lower than in the group of patients with CCR (P = 0.004), both in the back-ups and in the transplants. All patients with CFU-mega/CFU ratios <0.1 2 relapsed, five of seven patients developed MDS before progressing to full leukemic relapse. Using the optimized cut-off level for the ratio CFU-mega /CFU (< vs greater than or equal to 0.12), seven of 10 relapsing patients ( 70%) could be identified to be at risk of relapse, whereas MRD in the trans plants identified only 50% of the relapses and MRD in the pregraft bone mar row 25%. In conclusion, the study could identify two pretransplant risk fac tors predicting relapse in patients with AML receiving aPBSCT in first CR: MRD in transplants as well as MDS-like alterations within the transplants. These results may have multifold implications on the design of risk-adapted chemotherapy as well as on purging techniques and may contribute to a bett er understanding of leukemogenesis.