Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively ...analyzed incidence and risk factors of infection in 62 patients undergoing NMSCT with low-dose TBI +/- fludarabine and postgrafting CsA and MMF. The proportion of patients with any infection was 77%, but the majority of infectious events occurred beyond day 30. Donor other than sibling, older age, early disease and male gender were significant risk factors. The incidence of bacteremia was 55% at 1 year and the number of bacteremic episodes was 0.9 per patient (0.08 before day 30). The risk of bacteremia increased with older age and the use of a donor other than an HLA-identical sibling, but not with neutropenia. The incidence of infections other than bacteremia correlated with the use of corticosteroids. The risk of CMV infection increased with high-risk CMV serology, and risk of CMV disease with high-risk CMV serology, older age, first transplantation and a diagnosis of lymphoma. In conclusion, after NMSCT, infections are not frequent in the first 30 days post transplant but careful long-term monitoring is necessary thereafter.
Chronic myelomonocytic leukemia (CMML) is a disease typically of the elderly. It is suspected when monocytosis reaches 1000/microl. It may be associated with "B" symptoms (fever, sweating, and weight ...loss) but also visceral, skin and autoimmune complications. Current treatment strategies aim at reducing the symptoms and have no curative goals. In this context hypomethylating agents have shown a good efficacy. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option but remains difficult to perform in elderly patients population, even if transplantation with a reduced intensity conditioning has reduced the risks. A new prognostic scoring helps to recognize the patients with poor prognosis and to better selected candidates for the HSCT.
Background: We report the results of a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT. Patients ...and Methods: 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (AranespR) 300 microg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (VenoferR) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb greater than or equal to 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Results: In intent to treat analyses, the proportion of complete correctors was 24% in group 1, 81% in group 2 (P<0.001 compared with group 1), and 92% in group 3 (P<0.001 compared to group 1, and P=0.099 compared to group 2). Median time to achieve Hb greater than or equal to 13 g/dL was not reached in group 1, 42 days in group 2 (P<0.001 compared to group 1), and 32 days in group 3 (P<0.001 compared to group 1 and P=0.127 compared to group 2). Mean + or - standard deviation total doses of darbepoetin-alfa administered were 1,445 + or - 489 microg in group 2 vs 1,272 + or - 443 microg in group 3 (P=0.06). Eight patients (2 in group 1, 4 in group 2, and 2 in group 3) required red blood cell transfusions on study, including 4 patients following early disease progression. In per protocol analyses, the proportion of complete correctors was 21% in group 1, 80% in group 2 (P<0.001 compared with group 1), and 96% in group 3 (P<0.001 compared to group 1, and P=0.029 compared to group 2). Median time to achieve Hb greater than or equal to 13 g/dL was 190 days in group 1, 44 days in group 2 (P<0.001 compared to group 1), and 31 days in group 3 (P<0.001 compared to group 1 and P=0.025 compared to group 2). There was no difference in ferritin levels, nor in rates of thrombo-embolic events, or other complications among the groups. Conclusions: This is the first prospective randomized trial demonstrating that darbepoetin alfa is safe and highly effective to ensure full erythroid reconstitution after autologous HCT when started on day 28 posttransplant. I.v. iron sucrose tended (not statistically significant in intent to treat analyses) to further fasten erythroid recovery with a lower dose of darbepoetin alfa required.
Mantle cell lymphoma is a rare form of non Hodgkin lymphomas. Diagnosis is made by demonstrating a typical immunophenotype as well as the presence of a translocation between chromosomes 11 and 14 ...with overexpression of cyclin D1. First line therapy for young patients consists in 3 cycles of "R-CHOP21" alternated with 3 "R-DHAP21" and followed by an autograft conditioned by total body irradiation, cyclophosphamide and aracytine. For patients over 65 years of age, the treatment of choice consists in 8 cycles of "R-CHOP21". Maintenance treatment is under evaluation. Allografting is the only chance of cure in relapsed patients with good performance status. Targeted therapies will improve the prognosis of this disease.
Background: Results of nonmyeloablative HCT in pts with HLA-mismatched donors have been disappointing due to high incidence of graft rejection and severe acute GVHD. Recent studies have suggested ...that infusion of mesenchymal stem cells (MSC) the day of HCT might promote engraftment and prevent acute GVHD after myeloablative allogeneic HCT. However, some studies suggested that MSC co-infusion might abrogate graft-versus-host alloreactivity and graft-versus-tumor effects. This prompted us to investigate whether MSC infusion a few hours before HCT could allow nonmyeloablative HCT from HLA-mismatched donors to be performed safely (i.e. with a 100-day incidence of nonrelapse mortality < 35%). Methods: 20 patients with hematological malignancies were given MSC (1-2 x 10E6 cells/kg) from third party donors a few hours before PBSC from HLA-mismatched unrelated donors, after conditioning with 2 Gy TBI and fludarabine 90 mg/m. Postgrafting immunosuppression included tacrolimus (day -3 to +180; tapered by day +365) and mycophenolate mofetil (tid days 0 to +42). HLA-compatibility was assessed at the HLA-A, -B, -C, -DRBI and DQBI loci: 13 pairs were mismatched for at least one HLA class I antigen (including 4 pairs who were also mismatched for 1 HLA-class II antigens (n=3) or 1 HLA-class I allele (n=1)), 1 pair was mismatched for 2 HLA class II alleles, while 6 pairs were mismatched for a single HLA class I (n=3) or HLA class II (n=3) alleles. Results: Median follow-up for surviving patients was 288 (range, 76-571) days. One patient with secondary AML had primary graft rejection, while the remaining 19 patients had sustained engraftment. Median donor T-cell chimerism levels on days 28, 100, 180 and 365 after HCT were 90%, 98%, 96%, and 98%, respectively. Grade II, III and IV acute GVHD were seen in 5, 2 and 1 patients, respectively, while 7 experienced NIH moderate/ severe chronic GVHD. Three of 7 patients with measurable disease at transplantation achieved complete remission on days 41, 104 and 353 after HCT. Two patients died of nonrelapse causes on days 74 and 114 after HCT, while 3 died of disease progression. Projected 1-yr overall and progressionfree survivals were 77% and 61%, respectively. Conclusions: HLA-mismatched nonmyeloablative HCT with MSC co-infusion appeared to be safe, with MSC co-infusion possibly mitigating graft-versus-host alloreactivity without abrogating graft-versus-tumor effects. Survival is encouraging.
Background. Low donor T-cell chimerism levels after allogeneic hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning have been associated with high risks of both graft rejection ...and relapse/progression (Baron et al., Blood 2004, vol 104, p2254 and Baron et al., J Clin Oncol 2005, vol 23, p1993). In a preclinical canine model, DLI preceded by 2 Gy TBI converted mixed to full donor chimerism after nonmyeloablative conditioning (Taranova et al., Blood 2003, vol 102, 256a). Here, we investigated the ability of donor lymphocyte infusion (DLI) preceeded (n=15; TBI/DLI group) or not (n=15; DLI (“historical”) group) by 2 Gy TBI (given a few hours before DLI) to increase donor T-cell chimerism levels in patients with low donor T-cell chimerism levels after HCT.
Methods. Conditioning regimen for HCT consisted of 2 Gy TBI with (n=15) or without (n=11) added fludarabine. 20 patients received PBSC from related, and 6 PBSC from HLA-matched unrelated donors. Peripheral blood stem cells (PBSC) were unmanipulated in 15 patients, and CD8-depleted in the 11 remaining patients. Indication for TBI/DLI included < 50% donor T-cell chimerism or decrement of donor T-cell chimerism by 20% (or 10% if below 60%). Depending of patient-donor relationship, DLIs were given at a dose of 1 to 10 × 107 T-cells/kg (median 2 × 107 T-cells/kg), 42 to 725 days (median 68.5 days) following HCT. Prophylactic postgrafting immunosuppression was pursued after DLI in all but one patients.
Results. Before DLI, donor T-cell chimerism levels ranged from 15 to 77% (median 44%) in the DLI group, versus from 24 to 66% (median 47%) in the TBI/DLI group (P=0.66). Two months after DLI, donor T-cell chimerism levels ranged from 15 to 93% (median 53%) in the DLI group (P=0.10 in comparison to before DLI), versus from 20 to 98% (median 56%) in the TBI/DLI group (P=0.04 in comparison to before DLI) (Figure 1). In addition, 0 of 15 patients in the DLI group versus 5 of 15 patients in the TBI/DLI group had > 25% increased T-cell chimerism levels 2 months after DLI (P=0.04). Highest T-cell chimerism levels after DLI ranged from 15 to 99% (median 71%) in the DLI group, versus from 43 to 100% (median 96%) in the TBI/DLI group (P=0.06). Further, 2 of 15 patients in the DLI group, versus 0 of 15 patients in the TBI/DLI group experienced graft rejection. In the DLI group, 3 patients developed grade II–IV acute GVHD (2 grade II and 1 grade IV), while 1 patient in the TBI/DLI group experienced grade II acute GVHD. TBI/DLI was followed by grade IV hematologic toxicities in most patients, but most of them remained treated in the outpatient clinic. One-year overall survival was 67% in the DLI group versus 73% in the TBI/DLI group (NS).
Conclusions. DLI increased donor T-cell chimerism levels in a number of patients when preceeded by low dose TBI. However, hematological toxicity of TBI/DLI was relatively high, with most patients requiring several RBC and Plt transfusions. Further studies are needed to assess its impact on HCT outcomes.
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On day 30 after autologous peripheral blood stem cell transplantation (PBSCT), 20 patients were randomized to receive either erythropoietin at a dose of 500 U/kg/week s.c. (Epo group) or no treatment ...(control group). After 3 weeks, hemoglobin (p<0.0001) and serum transferrin receptor (p<0.0001) concentrations were higher in the Epo group. Hb response (+2 g/dL) was achieved in 100% vs 28% (p<0.0001) and Hb correction (> or =13 g/dL) in 70% vs 10% (p=0.0238) of the patients, respectively. This is the first randomized study showing an efficacy of erythropoietin therapy on Hb levels after autologous PBSCT.
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