Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children

Abstract

The success of allogeneic stem cell transplantation (allo-SCT) in children is mainly affected by relapse or graft rejection. We have recently shown in a study of 55 patients with acute leukemias (ALL 21, AML 20 and MDS 14), that patients who demonstrate increase amounts of autologous marrow repopulation (increasing mixed chimerism) have a significantly enhanced risk of relapse (P Ͻ 0.0001). Based on these findings, we asked whether post-transplant relapse can be prevented by withdrawal of immunosuppression and/or by donor lymphocyte infusion (DLI). We describe the results of a pilot study where adoptive immunotherapy was used to treat 12 patients (five ALL, three AML, four MDS) who showed increasing mixed chimerism (MC) post-transplant. A response to immunotherapy, defined as the re-establishment of complete chimerism (CC) and continuous complete remission (CCR), was achieved in four patients (two ALL, two AML) following withdrawal of CsA and in a further six patients (three ALL, three MDS) after additional DLI. One ALL patient, who initially responded to DLI, developed severe GVHD that required further immunosuppression. GVHD was controlled but this patient subsequently relapsed. Another patient with ALL became a CC but developed an isolated relapse in the bone marrow 260 days later. One patient with MDS developed severe GVHD after DLI and died. Two children (one AML and one MDS) did not show any response to interventional treatment and died due to relapse. Of the 12 patients treated, seven remain in CCR at a median follow-up of 747 days (range 351-1109 days). In summary, these results provide evidence that increasing MC can be used to guide adoptive immunotherapy strategies and that these treatment modalities can be used to prevent relapse in children with acute leukemias or MDS after allo-SCT.

Adoptive therapy with donor lymphocyte infusion after allogenic hematopoietic SCT in pediatric patients

“…In serial multicenter investigations, German authors proved, that in hematologic malignancies in children undergoing HSCT, promising results could be achieved with immunotherapy based on immunosupression cessation followed by DLI applied as pre-emptive therapy of impending relapse when compared with frank post transplant disease recurrence treatment. [28][29][30] Similar results were presented also by Rujkijyanont et al 31 In our cohort, in over 1/3 of patients, DLI complications of different severity were observed. The most frequent was GVHD, a further was BM aplasia.…”

“…Source of donor lymphocytes The source of donor lymphocytes was as follows: non-stimulated and unselected peripheral blood cells collected by apheresis (21), peripheral blood cells collected by apheresis after G-CSF mobilisation (29) and both methods (1 patient). The statistical analysis did not show any correlation between the source of lymphocytes and toxicity (P = 0.28), GVHD occurrence (P = 0.72) and outcome (P = 0.66) of DLI.…”

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

“…At this time definite recommendations for the intervals between the diagnostic follow-ups are difficult to define, but the intervals of follow-up diagnostics should always consider the kinetics of relapse. In AML frequent monitoring of MRD and of chimerism is recommended 60 to plan immunological intervention as early as possible, 6,7,59 whereas in disorders with slower kinetics such as the CMPD longer intervals might be justified.…”

“…57,58 The clinical value of regular monitoring of chimerism in myeloid malignancies after SCT is demonstrated by reports on the successful withdrawal of immunosuppression and adoptive immunotherapeutic intervention by DLI in case of decreasing chimerism as reported by Bader et al 59 in five pediatric patients with AML and MDS. The introduction of RIC has further increased the clinical importance of chimerism as patients show more frequently mixed chimerism (MC) when compared to standard conditioning regimens.…”

B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL

“…The first option is the reinforcement of the GVL effect by immunosuppression reduction or donor lymphocyte infusion (DLI); the second is the application of further cytoreductive therapy, including MoAb or specific tyrosine kinase inhibitors, in the case of BCR/ABL-positive ALL. [18][19][20][21][22][23][24][25][26] The benefit from such therapy has been described in a small proportion of ALL patients. To date, there is no general consent regarding the choice and timing of therapy in case of post transplant MRD positivity.…”