The stem cell mobilizing capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of the EORTC-GIMEMA AML-10 trial

Abstract

Variable numbers of CD34 + cells can be harvested from the blood of AML patients in CR after G-CSF supported mobilization following consolidation chemotherapy. We hypothesized that a decreased ability to mobilize stem cells reflects a chemotherapy-induced reduction in the number of normal and leukemic stem cells. We therefore analyzed whether the mobilizing capacity of these patients was of prognostic significance. 342 AML-patients in first CR received daily G-CSF from day 20 of the consolidation course and underwent 1-6 aphereses to obtain a minimum dose of 2 x 10 6 CD34 + cells/kg. Afterwards they were randomized for autologous bone marrow (BM) or blood SCT. As a surrogate marker for the mobilizing capacity, the highest yield of CD34 + cells of a single apheresis was adopted. Patients could be categorized into four groups: no harvest (n = 76), low yield (Ͻ1 x 10 6 CD34 + /kg; n = 50), intermediate yield (1-6.9 x 10 6 CD34 + cells/kg; n = 128) and high yield (Ն7 x 10 6 CD34 + cells/kg; n = 88). The median follow-up was 3.4 years; 163 relapses and 16 deaths in CR were reported. Autologous blood or BM SCT was performed in 36%, 64%, 81% and 88%, respectively, of the patients assigned to the no harvest, low, intermediate and high CD34 + yield group. The 3-year disease-free survival rate was 46.7%, 65.0%, 50.4% and 26.9% (P = 0.0002) and the relapse incidence was 47.5%, 30.1%, 43.1% and 71.9% (P Ͻ 0.0001). Multivariate Cox's proportional hazards model showed that the CD34 + yield was the most important independent prognostic variable (P = 0.005) after cytogenetics. Patients with the highest mobilizing capacity have a poor prognosis due to an increased relapse incidence.

High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT

“…The total number of CD34+ cells collected during all subsequent mobilization rounds could not be used for this purpose as this was influenced by the predetermined target of 2 × 10 6 CD34+ cells/kg (Table 3). Previously, 17 we analyzed the DFS according to the number of collected CD34+ cells, irrespective of the treatment administered to the patient. In the present study, we compared the outcome (DFS and DFI) in both treatment arms: APBSCT vs ABMT on an intention-to-treat basis after adjustment for the number of CD34+ cells, cytogenetics and number of courses to reach CR, age and treatment to remission-induction treatment (Table 4; for more details, see Supplementary Table 1).…”

“…19,20 In an earlier analysis, we showed that the duration of hypoplasia after the consolidation course was short in the group of patients with a high CD34+ cell harvest, probably reflecting an in vitro purging of the normal and leukemic stem cells. 17 A shorter duration of pancytopenia after the consolidation course, and especially the duration of neutropenia, was associated with a worse prognosis. Genetic polymorphisms in the ABCG2 transmembrane transporter protein may contribute to differential survival outcomes in AML patients by a decreased drug efflux and higher cytotoxicity in both normal progenitors and AML cells and a longer hypoplasia after the consolidation course.…”

“…Other retrospective studies 13,14 showed higher relapse rates after APBSCT after reinfusion of higher numbers of leukemic CD34+ cells. 14 In a previous analysis, 17 we showed that high numbers of mobilized CD34+ cells were an important, independent poor prognostic factor. Our present study confirms the shorter DFS in the group with high numbers of mobilized CD34+ cells when compared with low numbers of mobilized CD34+ cells or a failed mobilization.…”

Tandem versus single autologous peripheral blood stem cell transplantation as post-remission therapy in adult acute myeloid leukemia patients under 60 in first complete remission: results of the multicenter prospective phase III GOELAMS LAM-2001 trial

“…There is no clear evidence to explain this phenomenon, as the incidence of high-risk patients was equally distributed between both arms. Keating et al 4 have reported that the capacity to harvest high numbers of CD34 þ cells can be considered as an independent poor prognosis factor, reflecting a low sensitivity for chemotherapy with less efficient in vivo purging of leukemic stem cells. In this study, most of the patients (75%) in each arm received a graft collected after early intensification, and the capacity of mobilization was indeed significantly higher in arm B.…”

Prognostic value of CD34+ peak in peripheral blood during mobilization in intermediate-risk AML patients treated in first CR by autologous or allogeneic transplantation

“…1,2 These data, however, still await confirmation. Further, it is not known if the prognostic value of CD34 þ cell mobilization can be overcome by allogeneic transplantation.…”