The Role of GM-CSF in Haplo-Identical Transplant Patients Who Do Not Benefit from NK Alloreactivity.

Haplo-identical transplant is now established as a procedure of choice for patients who lack a compatible donor. It might even be the best choice for AML, provided there is a GvH NK allo-reactivity. However, patients are still referred too late, heavily pre-treated, at very advanced stages. We initiated a three-step phase I study trying improve transplant related mortality, relapse rate and immunity:

1. : G-CSF + DLI,

2. : GM-CSF + DLI,

3. : patient and disease adapted strategy.

Thirty-six consecutive leukemia patients, aged 18–55, were investigated (20 very poor risk, 12 poor risk and 4 better risk). GvH type NK alloreactivity was chosen when possible (21/36) and balanced across the 3 groups. In the first 9 patients, G-CSF was used pot-transplant and prophylactic DLI were given at month 1, 2 and 3. The use of G-CSF and 1 to 3 DLI (10exp4 CD3/kg) was found safe. It resulted in faster CD4 recovery and a low rate of infections. However, it was insufficient to induce a protective GVL effect. In the next 12 patients, GM-CSF was used plus 1 DLI (104 CD3/kg) at day 30 unless aGVHD (3 pts). The comparison between the 2 first groups can be summarized as follows: G-CSF + DLI: TRM at day 100: 0, RR: 6/9, severe aGVHD:0. GM-CSF + 1 DLI group: RR: 1/12, TRM at day 100: 3, aGVHD grade 2 or more: 9/12; price to pay: GVHD resulting in 5 deaths in total. Median time to relapse in the 21 first patients was 6 months range (4 – 9). Step 3 (17 patients) consists of a patient adapted strategy: no more aspecific DLI (selected anti-CMV and aspergillus DLI planned in all patients); in myeloid disorders with NK allo-reactivity: no GF. In the other cases, GM-CSF (at a reduced total dose of 500 mcg) is given from day 5 to day 9. The follow-up of patients alive in CCR (12), although promising (3 relapses), is currently short (median 8 months), compared to the median of relapse in the 2 first groups (6 months). Overall, TRM at day 100 is 2/29, reflecting the good tolerance of the conditioning in a heavily pre-treated population (median age: 43). Overall relapse rate for all patients treated with GM-CSF, without the benefit of NK-alloreactivity, is 6/16 (median FU: 15 months). We conclude that the third strategy might improve the outcome and the relapse rate without exposing patients to unnecessary severe GVHD. These data will be updated with 6 months more follow-up and 3 more patients.