The Use of alpha Interferon To Augment the Graft-Versus-Leukaemia Effect of 2nd Stem Cell Transplants and Donor Lymphocyte Infusions in High Risk Paediatric Leukaemias.

Childhood leukaemia which is refractory to chemotherapy or which relapses early following stem cell transplantation (SCT) has a very poor prognosis, with few patients becoming long-term survivors. Establishing limited graft-versus-host disease (GVHD) in an attempt to exert a graft-versus-leukaemia (GVL) response in these patients remains the only curative option. Second SCT procedures and/or donor lymphocyte infusions (DLI) have achieved some success but the pace of acute leukaemia is often too fast and the occurrence of GVHD/GVL too unpredictable to achieve this goal. We postulated that the addition of alpha interferon (alphaIFN) might induce/augment and control GVHD/GVL in this group of patients and so improve outcome. Thirteen patients underwent initial SCT, for cALL CR2 (n=1), Philadelphia positive ALL CR1 (5), MDS/AML (2), refractory AML (2), and CML (3), with unrelated (9) or sibling donors (4). Eight patients subsequently had a frank haematological relapse and 4 patients a molecular relapse of their leukaemia at a median of 10 months (2–18 months) from 1st SCT. Six patients underwent a 2nd SCT from the same donor, all with reduced intensity conditioned regimes; all received alphaIFN when GVHD did not occur after early withdrawal of immunosuppression. One (ALL CR2) received DLI 2 months after 2nd SCT for mixed chimerism. A further six patients received DLI plus alphaIFN, 3/6 together with low dose DLI (<106/kg); 3/6 had previously received108/kg DLI alone without response. One patient with refractory AML received alphaIFN in conjunction with the initial transplant. The dose of alphaIFN was escalated from 3–5 megaunits/m2 subcutaneously 3–5 days per week as tolerated and continued in the absence of GVHD for up to one year. 3 patients (CML) received concomitant therapy with Glivec, which has now been stopped. Following therapy, 9/13 (69%) patients developed aGVHD: Grade I (1), grade II (4), grade III (4); and 7/11 evaluable patients cGVHD: limited (4), extensive (3). 8 of 13 (62%) remain well and in remission, a median of 23 months (range 12 to 100) from alphaIFN therapy. Five have died: 2 from relapse, one from lung GVHD, one from idiopathic pneumonitis and one from aspergillus infection. Two of 8 surviving patients have ongoing cGVHD requiring immunosuppressive therapy. This data shows promising results for the use of alphaIFN to augment GVL responses in patients with high-risk leukaemia not cured with standard transplant procedures with 62% disease free survival and minimal residual symptoms. Further analysis is warranted.