From December 1979 to August 1982 158 patients were registered for an adjuvant chemotherapy (CT) study COSS -80. To compare the effect of cisplatin (CPL) to that of the drug combination bleomycin, cyclophosphamide, and dactinomycin (BCD), patients were randomized to receive either drug(s) within a course of sequential multidrug CT including doxorubicin and high-dose methotrexate (HDMTX). Definite surgery was done 10-18 weeks after the start of CT. Patients were randomized a second time to receive or not to receive fibroblast interferon in addition to CT beginning at week 16. At a median observation time of 19.5 months (range, 4-34 months), 116 (73%) of 158 patients were continuously disease-free (CDF). After exclusion of 42 patients because of some deviation in history and/or management, 86 (74%) of 116 patients actually were CDF with a 30-month calculated CDF-rate of 68%. There was no difference in CDF rates in the patients receiving BCD versus CPL or receiving interferon versus no interferon. Whereas, in comparison to the previous study COSS -77, the over-all increase in CDF rate does not reach statistical significance, it does, however, for the younger (less than or equal to 12 years) and for male patients, which is assumed to be the effect of increasing the methotrexate dose from 6 to 12 g/m2 in the COSS -80 study.

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.

Initial therapy should be more individualized, taking the above risk groups (age in non-anaplastic WTs, poor response, anaplasia, etc.) into account, as morbidity even after relapse therapy with ifosfamide, carboplatin and etoposide was not high. Milder therapy in low stages of differentiated and of well responding WTs should be tested.

Summary:Children with leukemias and increasing mixed chimerism (increasing MC) after allogeneic stem cell transplantation have the highest risk to relapse. Early immunological intervention was found to be effective in these cases. To substantiate this on a defined group of pediatric acute myelogenous leukemia (AML) patients, we performed serial analysis of post transplant chimerism and preemptive immunotherapy in patients with increasing MC. In total, 81 children were monitored, 62 patients revealed complete chimerism (CC), low-level MC or decreasing MC. Increasing MC was detected in 19 cases. Despite early immunological intervention relapse was still significantly more frequent in patients with increasing MC (9/19) than in patients with CC, low-level or decreasing MC (8/62, Po0.005). The probability of 3-year eventfree survival (EFS) was 52% for all patients (n ¼ 81), 59% for patients with CC, low-level MC, 60% for patients with decreasing MC (n ¼ 62), and 28% for patients with increasing MC (n ¼ 19, Po0.005). Patients with increasing MC who received early immunological intervention showed a significantly enhanced probability for event-free survival (pEFS 36%, n ¼ 15) compared to patients with increasing MC without intervention (pEFS 0%, n ¼ 4, Po0.05). These results prove that pediatric AML patients with increasing MC are at highest risk for relapse and that early immunological intervention can prevent relapse in these patients. Keywords: allogeneic stem cell transplantation; AML; childhood; chimerism; adjuvant immunotherapy Allogeneic stem cell transplantation (allo-SCT) has evolved to a convincing treatment modality for children with a high-risk acute myelogenous leukemia (AML), but the success is still mainly threatened by relapses. 1 In case of relapse, an additional allo-SCT may provide a small curative chance, but success is limited by the high lethality. 2-5 Therefore, a wide range of procedures has been tried in patients with relapses, all following the same principle to control malignant cells by engendering a graftversus-leukemia (GVL) effect. 2-4,6-13 These treatment regimens were based on (1) cessation of cyclosporine A (CSA) or other immunosuppressive drugs, 14,15 (2) administration of lymphocyte activating cytokines 6,11,16 and (3) additional infusion of donor lymphocyte (DLI) eventually supported by cytokines. 17,18 These attempts are convincing in patients with chronic myelogenous leukemias (CML) 13,19-22 but still questionable in patients with relapsed acute leukemias. 9,11,18,23 A major risk of this approach is the induction of severe graft-versus-host disease (GVHD), caused by the high cell numbers given, which are necessary in the treatment of an open relapse.Vice versa, pre-emptive treatment of an impending relapse might allow DLI with low cell numbers, which in turn might prevent the occurrence of GVHD. 18,[24][25][26] In previous studies we found evidence that patients with different types of high-risk leukemias and myelodysplastic syndromes (MDS) who developed a dynamic increase of auto...

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