Immunological Intervention Triggered by Decreasing CD34 ⁺ Lineage-Specific Donor Cell Chimerism to Prevent Relapse of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Abstract 3317

Poster Board III-205

Relapse of the underlying malignant disease remains the most frequent cause of treatment failure in patients with AML or MDS after allogeneic HSCT. Analysis of CD34+ lineage-specific donor cell chimerism (DCC) is a sensitive method for monitoring of minimal residual disease (MRD) in patients with AML or MDS with CD34 expression. Early detection of increasing MRD in this group of transplanted patients may provide an indication for clinical interventions as it has been shown for patients with chronic myeloid leukemia. Therefore, we retrospectively addressed the question whether immunological interventions in case of decreasing lineage-specific DCC may prevent overt hematological relapse. Between May 1999 and December 2008, 221 patients with AML (206) or MDS (15) received an allogeneic HSCT at our center. Inclusion criteria for this study were >100 days of follow up after HSCT and ≥3 informative chimerism analyses from bone marrow samples. Eighty-eight patients matched those criteria. At initial diagnosis, CD34 expressing leukemic cells were found in 72/88 patients. Unsorted and lineage-specific DCC (cell subset purification was performed by flow sorting) were measured on days +30, +60, +100, +180, +270 and +360 after transplantation and every 3 months in the second year. Impending relapse was defined as CD34+ donor cell chimerism <90%, bone marrow blasts <5% and no evidence of extramedullary relapse. Isolated decrease of CD34+ DCC was found in 26 patients (30%; 25/26 patients with CD34 positive AML at initial diagnosis). Twenty-one of the 26 patients received treatment for impending relapse consisting of rapid tapering of immunosuppressive medications (14) and/or infusion of donor lymphocytes (7). Twelve of these patients remained in hematological remission, 9 of the 21 patients relapsed of whom 5 achieved sustained complete remission after salvage treatment. Four of the 5 patients without intervention after detection of decreasing CD34+ DCC relapsed within 14-69 days. The remaining patient without relapse developed severe chronic graft-versus-host disease without intervention shortly after detection of impending relapse and converted to full DCC. Twelve of the 88 patients (14%) relapsed without evidence of isolated decreasing CD34+ DCC prior to hematological relapse. Mixed chimerism of the whole bone marrow in combination with mixed lineage-specific DCC was found in 4 patients and 9 patients showed stable DCC until hematological relapse was diagnosed. Six of these patients achieved sustained remission after salvage treatment. Median follow-up of surviving patients with impending relapse was 806 days after transplantation and 716 days after first detection of decreasing CD34+ DCC. Relapse free survival at 2 years of all 88 patients and of the 26 patients with impending relapse was 60% (95% C.I., 48-72%) and 56% (95% C.I., 36-76%), respectively. Overall survival rates were 76% (95% C.I., 66-86%) and 65% (95% C.I., 45-85%), respectively. These preliminary results with 46% of patients with impending relapse successfully treated only with immunological intervention suggest that analysis of CD34+ DCC may be an important tool in the management of AML and MDS patients after allogeneic HSCT. Furthermore, isolated decrease of CD34+ DCC with complete unsorted DCC indicated that CD34+ DCC is an important and highly sensitive marker for MRD in patients with AML or MDS expressing CD34 on their malignant cells.