Allogeneic Transplanst for ACUTE Myeloid Leukemia: Cut Off Levels of WT1 Expression in 207 Patients and Pre-Emptive Therapy of Relapse

Leukemia relapse remains a significant problem in patients with AML undergoing an allogeneic stem cell transplant(HSCT). Wilms Tumour 1 (WT1) expression has been shown to be a sensitive marker of minimal residual disease (MRD), both in patients after induction chemotherapy, as well as in patients undergoing an allogeneic HSCT.

Hypotheses. The present study had 2 hypotheses: (1) WT1 expression in marrow cells of AML patients post-HSCT, will predict leukemia relapse and (2) WT1 based pre-emptive immunotherapy (IT) such as abrupt cyclosporin discontinuation and/or donor lymphocyte infusion (DLI), will prevent leukemia relapse.

Patients. Bone marrow WT1 expression, was monitored in 207 patients with acute myeloid leukemia (AML) before and monthly after an allogeneic HSCT , until day +150, and then at every other outpatient access. Eligible for IT were patients without acute or chronic GvHD , with increased WT1 expression and a a marrow in hematologic remission. The trigger for IT was 180 WT1 copies in a first group of 122 patients (group A) : this was based on the fact that WT1 expression in normal bone marrow is up to 180 copies . In a subsequent group of 85 patients (group B) the cut off for IT, was 100 copies, due to the fact that a first analysis of group A had shown 100 copies to be an earlier predictor of relapse (BJH 2013; 160: 503) . DLI were given in escalating doses, starting at 1x10^5 CD3+ cells/kg in alternative donor grafts and at 1x10^6/kg in HLA identical grafts. DLI were escalated ½ log every month, in the absence of GvHD , to a maximum dose of 1x10^7/kg. Sixtyfour patients were eligible for IT, but only 35 received IT: reasons for non intervention were ongoing GHD, unavailable donor and delay in WT1 results.

Results- Hypothesis N.1.

Following transplantation, WT1 expression, was highly predictive of leukemia relapse : 12 relapses in 99 patients with WT1 < 100 copies /10^4 abl (12%) ; 19 relapses in 55 patients with WT1 between 101 and 180 copies (35%) and 37 relapses in 53 patients with WT1 >180 copies (70%) (p<0.0001). The median interval between WT1 positivity and relapse was 75 days in group A and 60 days in group B.

Results - Hypothesis N.2.  

35 patients received pre-emptive immune intervention, 17 in group A and 18 in group B. The latter had more patients beyond first remission at transplant (56% vs 23%) , more myeloablative regimens (100% vs 65%) and more family haploidentical donors (72% vs 6%); age was comparable. The risk of relapse was 13/17 (76%) for group A and 3/18 (17%) for group B (p<0.001), despite the larger proportion of patients beyond CR1 at transplant. GvHD following DLI occurred in 15% of patients. DLI-related mortality was 0%. The overall 3 year survival for patients in group A and B was 69% vs 47% (p=0.3). The relapse risk in patients of group A eligible but not receiving IT (n=21) was 74%; in group B (n=8) it was 50%.

In conclusion, WT1 expression post- transplant is a strong predictor of leukemia relapse in patients with AML, and can be used to trigger pre-emptive immunotherapy , in approximately 50% of eligible patients. IT triggered at a WT1 cut-off level of 100 copies in bone marrow cells, is more effective , as compared to 180 copies, in preventing leukemia relapse.