Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Might Overcome the Adverse Effect of Minimal Residue Disease Pretransplant in Patients with Standard-Risk Acute Myeloid Leukemia

Backgrounds

In patients with acute myeloid leukemia (AML), detection of minimal residual disease (MRD) before allogeneic hematopoietic stem cell transplantation (HSCT) is correlated to the risk of relapse. Persistent intensive chemotherapy might further reduce the load of leukemia pretransplant, but it also brings the risk of treatment mortality. Unmanipulated haploidentical HSCT which was established by Peking University Institute of Hematology would induce a stronger graft-versus-leukemia (GVL) effect in compared with sibling transplantation. Moreover, our previous studies have demonstrated that the prophylactic use of modified donor lymphocyte infusion (DLI) would significantly increase the survival of patients with progressive acute leukemia. However, for those patients with standard-risk AML who has the detectable MRD before transplant, whether they would benefit from further chemotherapy to reduce MRD, or should receive active intervention strategy towards leukemia relapse is still unknown.

Methods

The MRD level was measured immediately before and after transplant in 86 standard-risk AML patients who received unmanipulated haploidentical HSCT at the Peking University Institute of Hematology from January, 2011 to May, 2012. All patients were selected from the clinical trial which was registered at http://www.chictr.org as No. ChiCTR-TRC-11001761 if the following criteria were met: having standard-risk AML, defined as first or second complete remission without t(9;22)(q34; q11), t(15;17), inv(16)(p13q22), t(16;16)(p13; q22) or t(8;21)(q22; q22) cytogenetic abnormalities. The duration of follow-up after HSCT was 980 days (range, 55-1277). MRD were examined by 8-color flow cytometry and real-time quantitative polymerase chain reaction (RQ-PCR). WT1+ was defined as a transcript >0.60% and FCM+ was defined as >0.01% of cells with leukemia-associated aberrant immune phenotypes (LAIPs). Patients had at least one of FCM+/WT1+ before transplant were termed as MRD+. The combinative criteria for positive MRD (MRDco+) were defined as 2 consecutive FCM+ or WT1+ results or both FCM+ and WT1+ in a single sample within 1 year after transplantation.

Results

Among these 86 AML patients, there were 42 and 44 cases in the 6mg/kg ATG and 10mg/kg ATG group, respectively. The proportion of patients with or without detectable MRD before transplantation was comparable in those two groups with different dose of ATG. During the follow-up, 9 patients underwent hematological relapse at a median time of 157 days (range, 30-726). Finally 18 patients died and 7 patients died of relapse. The number of FCM+/WT1+ patients pretransplant was 8 and 16, respectively. There were 18 patients met the criteria of MRD+ before HSCT. None of the FCM+, WT1+ and MRD+ pretransplant but the FCM+ (P=0.001), WT1+ (P=0.013) and MRDco+ (P<0.001) posttransplant was significantly correlated to relapse during univariate analysis. A multivariate Cox regression analysis that included age, sex, relationship and matched status of blood type between donor and recipient, GVHD and MRD status before and after transplantation was performed. It showed that only MRDco+ posttransplant was an independent risk factor of leukemia relapse (P=0.022, HR=4.653, 95%CI:1.249-17.334). Through Kaplan-Meier analysis, a significant difference in cumulative incidence of relapse between patients with or without posttransplant MRDco+ would be observed (P=0.012). However, it seemed that MRD status before transplant might not affect leukemia relapse after haploidentical HSCT.

Conclusion Although detectable MRD before HSCT is a strong prognostic factor, its adverse impact could be diminished and overcome in patients with standard-risk AML receiving our unmanipulated haploidentical HSCT. These kinds of patients might not need to receive further intensive chemotherapy or active intervention around HSCT.