Additional immunotherapy on the basis of increasing mixed hematopoietic chimerism after allogeneic BMT in children with acute leukemia: is there an option to prevent relapse?

Abstract

Summary:Case reports Patient No. 1 The success of allogeneic BMT (allo-BMT) in children with acute leukemias is mainly affected by relapse.The first patient, a 2-year-old boy with MDS (CMML and There is evidence that these patients have only a little monosomy 7), was referred for BMT. After conditioning or no benefit from additional immunotherapy if the with busulfan (BU) 20 mg/kg, etoposide (VP16) 40 mg/kg treatment is started in frank hematological relapse.and cyclophosphamide (CY) 120 mg/kg, the patient was Recently we were able to demonstrate that pediatric grafted with the marrow of an HLA-identical family donor patients with acute leukemias and increasing mixed (cousin). The MLC reaction was negative. GVHD prophychimerism (MC) post-transplant have a significantly laxis consisting of cyclosporin A (CsA) 3 mg/kg/day was enhanced risk of developing relapse. We asked whether started on day −3. Unmanipulated bone marrow comprising there is a possibility of preventing relapse, eg by with-3.7 × 10 8 /kg nucleated cells was transfused on day 0. After drawal of post-tranplant immunosuppression or by engraftment chimeric analysis on day +24 revealed increasadministration of donor lymphocytes in an early phase ing autologous patterns until no donor hematopoiesis was of the development of relapse. We present the case detectable on day +70 (Figure 1) when typical dysplastic reports of two children (MDS and AML) with rapidly cells and leukemic blasts with recurrence of monosomy 7 increasing MC in whom withdrawal of post-transplant were detected in the peripheral blood. Thereafter the disimmunosuppression or donor lymphocyte infusion ease was controlled by treatment with thioguanine until 10 (DLI) did prevent relapse. months after BMT. At that time leukocytes increased and Keywords: acute leukemia; hematopoietic chimerism; additional therapy with cytarabine (Ara-C) 20 mg/day for adoptive immunotherapy 5 days and hydroxyurea 250 mg/day was initiated. One year after the first transplantation, the patient was reconditioned with fractionated total body irradiation (TBI) (6 × 2 Gy), thiotepa 10 mg/kg, CY 120 mg/kg and antilymphocyte Although allogeneic BMT (allo-BMT) has been performed globulin (ALG) 30 mg/kg/day for 3 days. The boy was rewith increasing success in the situation of particular unfavinfused with 2.5 × 10 8 /kg nucleated bone marrow cells from orable acute leukemias in children over the last decades, the same donor on day 0. CsA was started at 3 mg/kg/day the outcome is mainly affected by relapse in this cohort of patients. 1 Treatment by which long-term remissions could be re-achieved is mainly restricted to additional marrow transplantation with a significantly increased rate of complications. 2,3 Recently we were able to demonstrate that patients with increasing amounts of autologous marrow repopulation (mixed chimerism MC) after allo-BMT have an increased risk (P = 0.0078) of developing relapse or graft rejection. 4 We subsequently asked whether treatment modalities, eg withdrawal of post-transplant immunos...

Leukemia lineage-specific chimerism analysis is a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation

“…From the data presented in this study, additional immunotherapy -ie tapering of immunosuppression followed by DLI, if needed, may be given when MC is detected in the leukemiaaffected cell lineage in PB Ͼ1 month after SCT. Bader et al 6,57 have also reported promising results using this approach. However, more data from different laboratories are needed to evaluate the impact of MC in BM and also in PB before any definite treatment recommendations can be made.…”

Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers

“…6,8,9,[33][34][35] Although persistent recipient cells are not necessarily associated with an increased relapse rate, 36 several reports have shown, that the incidence of recurrent disease is significantly increased in the group of patients with unstable mixed chimerism showing increasing host signals compared to patients presenting with stable complete chimerism or patients with mixed chimerism turning into complete chimeras. 24 In this situation it is of critical importance to have a quantitative method for the evaluation of chimerism to provide useful information which could serve as a basis for clinical decision making.…”

“…4 Thus, careful monitoring of the dynamics of chimerism has become especially important to schedule therapeutic intervention. [5][6][7][8][9] In sex-mismatched transplantation, FISH analysis of X and Y chromosomes can easily be performed to quantify donor and recipient hematopoiesis. [10][11][12][13][14] Established procedures are commercially available, thus making standardization of the methods possible and ensuring comparable results.…”

How and when should we monitor chimerism after allogeneic stem cell transplantation?

“…These patients are then referred to have an 'increasing' or an 'decreasing mixed chimerism'. 14,16,17 Peripheral blood or bone marrow is most often used for chimerism analysis with or without further manipulation of different cell subpopulations. It is important to realize that patients could show complete chimerism in one compartment, for example, NK cells, whereas others could be totally or in part recipient derived.…”