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.
Defibrotide has been proposed as preventive treatment of Veno Occlusive Disease (VOD), data on its use are, however, limited and its effectiveness not yet demonstrated. We have administered Defibrotide as prevention of VOD in pts treated with HSC transplantation because of haematological malignancies, all patients were at high VOD risk because of hyper-ferritinemia (>800 ng/ml) or because not in CR of their underlying disease at time of transplant or being overweight (Actual BW>20% of Ideal BW) or because Hepatitis virus B or C sero-positive. 120 pts were treated with Defibrotide, 77 pts received allogeneic HSC tx and 43 autologous HSC tx, 105 received a myeloablative conditioning (55 pts it was based on busulfan) and 15 pts received a RIC. 48% of patients were affected with Acute leukemia, 23% with Lymphomas, 17% with Multiple Myeloma, 12% by other malignancies. Defibrotide was administered i.v. at dosage of 600 mg/d. from the day of conditioning was started to day +25 together with heparin at low dose (100 IU/Kg c.i.). RESULTS: after prophylaxis with Defibrotide a bilirubin value above 2.5 mg/dl during the first 30 days was observed in 16/120 pts (13%), 7/120 pts (5%) reached Seattle’s VOD criteria but had spontaneous resolution of liver toxicity, only 1 patient (0.8%) had a severe VOD and MOF. Overall survival at 3 years was 60% and it was 54% in allo-transplanted patients. We compared results with those obtained in a group of 78 pts treated by allogeneic or autologous transplants and who received low dose heparin only and not Defibrotide because they were considered at low risk of VOD. Percentage of pts who developed a bilirubin level > 2.5 mg/dl (p=0.12) and percentage of patients that reached criteria for VOD were not different (p= 0.08) in these two groups, numbers of red blood cell transfusions were comparable (p=0.07). When all the 198 studied patients were analyzed using logistic regression for factors important in the development of a bilirubinemia above 2.5 mg/dl we found to be important: use of MTX as prophylaxis of GVHD (P=0.004; Odds ratio 5,153), allogeneic transplant (P=0.007; Odds ratio 7,127) and baseline value of bilirubin (P=0.02; Odds Ratio 4,690). Conclusions: Use of Defibrotide in prophylaxis of VOD after HSC transplantation is safe and when employed in patients at high risk of VOD, it leads to an incidence of severe VOD below 1% with a frequency of liver toxicity equivalent to that found in patients having low risk features. To conclude on efficacy of Defibrotide in comparison to low dose heparin alone, a large randomised comparison is warranted.
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.
We have prospectively collected data on Adverse Events (AE) that occurred in 179 Hemopoietic Progenitor Cell (HPC) infusions performed in patients affected with haematological neoplasm, after high dose chemotherapy. Stem cell source was Hemopoietic Progenitor Cells Aphaeresis (HPC-A) in 157 cases and Hemopoietic Progenitor Cells Bone Marrow (HPC-BM) in 22 cases. In all cases, an endotoxin-free DMSO was used. One or more AE were registered in 51/179 infusions (28.6%). Frequency of AE was higher after HPC-A than after HPC-BM (31.3% versus 4.5%, (chi square test: p=0.008). In univariate logistic regression other factors found important for AE were: Age (p=0.028), Number of Total Nucleated Cells infused/kg (P=0.002), Volume/kg infused (p=0.057), Volume of Packed Red Blood Cells (p=0.019), a content of Non-Mononuclear Cells >0.500 × 108/Kg (<p=0.0001) and Actual Time of infusion (p=0.058). When all aforementioned factors were evaluated in multivariate logistic regression only Age of patient (P=0.024) and a content of Non-Mononuclear Cells > 0.5×108/kg (P=0.0003) remained significant. No cardiovascular events were recorded during infusions. A significant correlation existed between reduction of cardiac frequency both with Volume/Kg infused (r 0.221; p=0.02) and with Actual Time of infusion (r 0.269; p=0.005). In conclusion, while Cardiovascular Changes are influenced by Volume/Kg infused and by Actual Time of infusion, Non-Cardiovascular AE are dependent on patient Age and on contamination by Non-Mononuclear Cells in apheretic harvests.
Background: Low CD34+ cell mobilization in P.B. has been found in a quota of AML patients (10–30%). Contrary to what has been observed in CD34+ mobilization in other haematological afflictions, in AML no features pertaining to the disease or to the patient have been found to be predictive of CD34+ cell mobilization failure. A possible explanation for this particular aspect of CD34+ mobilization in AML patients could be an intrinsic abnormality of non leukemic hematopoietic cells determining an increased chemo-sensitivity to anti-neoplastic drugs. To test this hypothesis we assessed, in AML patients, frequency of various types of clonable precursors (CFUs) present in BM at the time of CR and their in vitro chemosensitivity. We also correlated this data with the efficiency of CD34+ cell mobilization in P.B. Methods: 31 consecutive patients, affected with AML and a group of 15 normal BM donors were prospectively studied. Baseline CFU-GEMM, BFU-E, CFU-GM, CFU-E as well as the sensitivity of these precursors to two chemotherapeutic agents (ASTA-Z and VP-16) were assayed on BM cells obtained in first CR after consolidation chemotherapy. Chemo-sensitivity (100 - normalized residual CFU) was studied after short term in vitro incubation of bone marrow precursors at various drug concentrations. All pts underwent a CD34+ mobilization attempt and, as measure of mobilization strength, peaks of CD34+ cells reached in P.B. were determined. Results: In AML patients, after induction and consolidation schedules, a reduced number of all types of CFUs were found in BM compared to normal controls. The frequency of any types of CFUs and the chemo-sensitivity of CFU-GEMM, BFU-E and CFU-E were not correlated to CD34+ peak reached in P.B. However, in AML patients, an inverse correlation was found between chemo-sensitivity of CFU-GM and maximum CD34+ cells peak reached in P.B. during mobilization (r= − 0.807 and p=0.0001, when ASTA-Z was used at 100 mcg/ml). In univariate and multivariate logistic regression, chemo-sensitivity to ASTA-Z of CFU-GM was the only factor significantly associated with mobilization failure (P=0.02), independently of age and cytogenetical risk. Chemosensitivity of CFU-GEMM, BFU-E and CFU-E after in vitro incubation with chemotherapeutic drugs was not different in AML patients compared to CFU obtained from normal control. The contrary was found for CFU-GM and, overall, CFU-GM from AML patients had a significantly higher chemosensitivity to ASTA-Z compared to CFU-GM of normal controls (p= 0.01 at 50 mcg/ml). Conclusions: We found that an abnormal high chemo-sensitivity of CFU-GM to some chemotherapy drugs in AML patients is associated with a high risk of CD34+ cell mobilization failure. This abnormality of non leukaemic bone marrow cells, present in CR, is restricted only to CFU-GM and is not evident in other CFUs. Figure Figure
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