Chemosensitivity of nonleukemic clonogenic precursors in AML patients in complete remission: association with CD34(+) mobilization and with disease-free survival.

A high number of CD34(+) cells in the peripheral blood during mobilization in patients with acute myeloid leukemia (AML) in complete remission (CR) is associated with a high relapse rate. The variability in chemoresistance of normal bone marrow precursors has been hypothesized as explanation for the variable CD34 mobilization in AML. In 37 patients with AML in CR, we determined the chemosensitivity of bone marrow clonogenic precursors to maphosphamide and etoposide, which was then correlated with the degree of CD34(+) mobilization. In an enlarged set of 49 patients, we also studied the importance of chemosensitivity of marrow precursors for disease-free survival and relapse incidence. Significant correlations were demonstrated between the peak number of CD34(+) cells and residual growth of colony-forming unit granulocyte-macrophage (CFU-GM) after maphosphamide (R = 0.550; p = 0.0003) and after etoposide (R = 0.793; p = 0.0003). It was possible to identify three groups of AML patients based on chemosensitivity. The mean CD34(+) peak was 33 × 10(6)/L in the hyperchemosensitive group, 141 × 10(6)/L in the normochemosensitive (p = 0.03), and 379 × 10(6)/L in the chemoresistant group (p = 0.002). Failed CD34(+) mobilization was observed in 72% of the hyperchemosensitive group, 23% of the normochemosensitive group, and 0% of the chemoresistant group (p = 0.001). Hyperchemosensitivity of CFU-GM, together with a low platelet count, were independent factors important in the failure of CD34(+) cell mobilization. A disease-free survival significantly inferior to that of all other patients was associated with chemoresistance of CFU-GM (log rank, p = 0.030) and with chemoresistance of burst-forming unit erythroid (BFU-E) (log rank, p = 0.033). Chemoresistance of CFU-GM (p = 0.048) and BFU-E (p = 0.017) was also associated with increase relapse incidence. Nonleukemic nature of these precursors was demonstrated studying minimal residual disease from single colony cells. In conclusion, we found that hyperchemosensitivity of normal nonleukemic CFU-GM is associated with a high risk of CD34(+) cell mobilization failure, while a chemoresistant pattern in CFU-GM and BFU-E is associated with poor disease-free survival and increased cumulative incidence of relapse.

Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation.

We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies.

Intermediate dose etoposide plus G-CSF 16 g/kg is more effective than cyclophosphamide 4 g/m(2) plus G-CSF 10 g/kg in PBSC mobilization of lymphoma patients.

We designed intermediate dose etoposide + G-CSF 16 microg/kg as a Peripheral Blood Stem Cell (PBSC) mobilization schedule suitable for outpatient administration. Forty-one Lymphoma patients received intermediate dose etoposide (200 mg/m(2) i.v. day +1, +2, +3) +G-CSF 16 microg/kg/day. Results of PBSC mobilization in these patients were compared with those of a group of 37 lymphoma patients mobilized using cyclophosphamide (CTX) at dosage of 4 g/m(2) + G-CSF 10 microg/kg/die. Mean peak of CD34+ cells achieved in P.B. and total CD34+ cells harvested were higher in patients mobilized with intermediate dose etoposide (p = 0.003 and p = 0.004, respectively). After transplantation recovery of polymorphonucleate neutrophils (PMN) > 0.5 x 10(9)/L did not differ significantly between groups: 11.7 days in intermediate dose etoposide group and 11.5 days in CTX group (p = 0.7). Intermediate dose etoposide + G-CSF 16 microg/kg resulted in a maximum length of neutropenia (PMN < 0.5 x 10(9)/L) of 2 days and neutropenic fever was registered during only 3/41 courses (7.3%). Intermediate dose etoposide + G-CSF 16 microg/kg is a highly effective mobilizing therapy, further, it has the advantage of low hematologic toxicity and can be easily administered as outpatient treatment.