Comparison of HLA antibody identification methods for the selection of platelet products for HLA-mediated platelet refractory patients.

In an ineffective transfusion context, solid-phase immunoassays using the Luminex platform for the detection and characterization of HLA antibodies are currently used to select HLA-compatible platelet products. A new HLA antibody identification method, the HISTO SPOT® HLA AB test (BAG Health care GmbH, Lich, Germany), based on the detection of antibodies directed against a recombinant single antigen (SA) by colored spots detected by HISTO MATCH HLA AB module software, runs fully automated on the MR.SPOT®. The aim of this study was to compare the ability of the HISTO SPOT HLA AB and C1qScreen™ (C1q SAB) assays with that of the Labscreen single antigen class I (OL SAB) assay to detect anti-HLA class I antibodies in 56 serum samples from 54 platelet refractory acute myeloid leukemia patients who received HLA mismatch platelet concentrates at a single oncohematology center. In total, 1414 class I specificities, 433 HLA-A and 981 HLA-B, were detected by the OL SAB test. The mean fluorescence intensity (MFI) was >5000 for 874 antigens and <5000 for 655 antigens. The HISTO SPOT® HLA AB and C1q SAB tests identified 85% and 79% of OL SA-detected antigens with an MFI >5000, respectively, but did not identify 34% and 44% of OL SAB-detected antigens, highlighting the lower sensitivity of these techniques. Interestingly, the donor-specific antibodies (DSAs) identified by the HISTO SPOT® HLA AB and C1q SAB assays reacted against HLA mismatch platelet concentrates with the same specificity (86%) and positive predictive (77%) value as in the OL SAB test when the MFI threshold was >2000 for DSA detection. Although the HISTO SPOT® HLA AB test is less sensitive than the OL SAB test, this test could be used for the selection of HLA-compatible platelet products.

Therapeutic efficacy of platelet transfusion treated with amotosalen/UVA pathogen inactivation technology (INTERCEPTTM Blood System) in acute myeloid leukemia patients undergoing chemotherapy with curative intent: a single center experience.

BACKGROUND: The INTERCEPTTM Blood System (Intercept Blood System, Cerus Europe BV, Amersfoort, the Netherlands) has been used to reduce or inactivate pathogen load in platelet concentrates in France for three years. MATERIALS AND METHODS: After comparing the transfusion efficiency between pathogen-reduced platelets (PR_PLT) and untreated platelet products (U_PLT), our single-center observational study assessed the effectiveness of PR_PLT for the prevention of bleeding and for therapeutic treatment of WHO grade 2 bleeding in 176 patients undergoing chemotherapy with curative intent for acute myeloid leukemia (AML). The main endpoints were the 24-hour (h) corrected count increment (24h_CCI) after each transfusion, and time to next transfusion. RESULTS: Whereas the transfused doses tended to be higher in the PR_PLT group compared to U_PLT, there was a significant difference in intertransfusion interval (ITI) and 24h_CCI. In prophylactic transfusions, PR_PLT transfusions of >0.65×1011/10 kg, regardless of the age of the product (day 2 to day 5), resulted in a 24h_CCI similar to that of the untreated platelet product; this meant the patient could be transfused at least every 48h. In contrast, most PR_PLT transfusions of <0.55×1011/10 kg did not achieve a transfusion interval of 48h. In the context of WHO grade 2 bleeding, PR_PLT transfusions >0.65×1011/10 kg and storage of less than 4 days seems more effective in stopping bleeding. DISCUSSION: These results, which must be confirmed by prospective studies, indicate the need for vigilance regarding the quantity and quality of PR_PLT products used to treat patients at risk of bleeding crisis. Future prospective studies are needed to confirm these findings.

Comparison of the Hemostatic Efficacy of Pathogen-Reduced Platelets vs Untreated Platelets in Patients With Thrombocytopenia and Malignant Hematologic Diseases: A Randomized Clinical Trial.

IMPORTANCE: Pathogen reduction of platelet concentrates may reduce transfusion-transmitted infections but is associated with qualitative impairment, which could have clinical significance with regard to platelet hemostatic capacity. OBJECTIVE: To compare the effectiveness of platelets in additive solution treated with amotosalen-UV-A vs untreated platelets in plasma or in additive solution in patients with thrombocytopenia and hematologic malignancies. DESIGN, SETTING, AND PARTICIPANTS: The Evaluation of the Efficacy of Platelets Treated With Pathogen Reduction Process (EFFIPAP) study was a randomized, noninferiority, 3-arm clinical trial performed from May 16, 2013, through January 21, 2016, at 13 French tertiary university hospitals. Clinical signs of bleeding were assessed daily until the end of aplasia, transfer to another department, need for a specific platelet product, or 30 days after enrollment. Consecutive adult patients with bone marrow aplasia, expected hospital stay of more than 10 days, and expected need of platelet transfusions were included. INTERVENTIONS: At least 1 transfusion of platelets in additive solution with amotosalen-UV-A treatment, in plasma, or in additive solution. MAIN OUTCOMES AND MEASURES: The proportion of patients with grade 2 or higher bleeding as defined by World Health Organization criteria. RESULTS: Among 790 evaluable patients (mean [SD] age, 55 [13.4] years; 458 men [58.0%]), the primary end point was observed in 126 receiving pathogen-reduced platelets in additive solution (47.9%; 95% CI, 41.9%-54.0%), 114 receiving platelets in plasma (43.5%; 95% CI, 37.5%-49.5%), and 120 receiving platelets in additive solution (45.3%; 95% CI, 39.3%-51.3%). With a per-protocol population with a prespecified margin of 12.5%, noninferiority was not achieved when pathogen-reduced platelets in additive solution were compared with platelets in plasma (4.4%; 95% CI, -4.1% to 12.9%) but was achieved when the pathogen-reduced platelets were compared with platelets in additive solution (2.6%; 95% CI, -5.9% to 11.1%). The proportion of patients with grade 3 or 4 bleeding was not different among treatment arms. CONCLUSIONS AND RELEVANCE: Although the hemostatic efficacy of pathogen-reduced platelets in thrombopenic patients with hematologic malignancies was noninferior to platelets in additive solution, such noninferiority was not achieved when comparing pathogen-reduced platelets with platelets in plasma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01789762.

Impact of pretransplant donor and recipient cytomegalovirus serostatus on outcome for multiple myeloma patients undergoing reduced intensity conditioning allogeneic stem cell transplantation.

Scope of the study was to investigate the impact of pre-transplant CMV serostatus of the donor and/or recipient on the outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). To our knowledge no data are available in the literature about this issue. We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer center at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R] -) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk - either (D-/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%). Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26-318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs. intermediate: 29% vs. high: 50%; p=0.001) and the presence of grade II-IV acute GvHD (Hazard Ratio: HR=2.1 [1.1-3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II-IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two-year overall and progression free survival were 56% and 34%, respectively. Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this group of patients, warranting further prospective studies.

Long-term outcome after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with multiple myeloma.

This study examines the long-term outcomes of a cohort of patients with myeloma who were treated with reduced-intensity conditioning (RIC) regimens after a minimum follow-up of 5 years at our centre. A total of 53 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem-cell transplantation (Allo-SCT) between January 2000 and January 2007 were identified. The median follow-up of living patients was 84 months (51-141). The median age of the MM patients was 50 (28-70) years. Fifty-one patients (96%) received a transplant from a sibling donor. The median time between diagnosis and Allo-SCT was 34 months (6-161), and the median time between auto-SCT and Allo-SCT was 10 months (1-89). Fifty-one patients (96%) received at least one auto-SCT; 24 patients (45%) received a tandem auto-Allo-SCT. At last follow-up, 21 patients (40%) are alive > 5 years post RIC Allo-SCT. At last follow-up, 14 (26%) are in first complete remission (CR), and four patients (8%) in second CR after donor lymphocyte infusion or re-induction with one of the new anti-myeloma drugs (bortezomib or lenalidomide) after Allo-SCT. Eight patients (38%) among these long survivors received one of these new drugs as induction or relapse treatment before Allo-SCT. Disease status and occurrence of cGvHD were significantly associated with progression-free survival (PFS); hazard ratio (HR) = 0.62 (0.30-1.29, P = 0.20). Acute GvHD was correlated with higher transplant-related mortality; HR = 4.19 (1.05-16.77, P = 0.04). No variables were associated with overall survival (OS). In conclusion, we observe that long-term disease control can be expected in a subset of MM patients undergoing RIC Allo-SCT. After 10 years, the OS and PFS were 32% and 24%, respectively. The PFS curve after Allo-SCT stabilizes in time with a plateau after 6 years post Allo-SCT.

Donor CD3(+) lymphocyte infusion after reduced intensity conditioning allogeneic stem cell transplantation: single-center experience.

Donor lymphocyte infusions (DLI) can induce remission in patients with hematologic malignancies who relapse after allogeneic stem cell transplantation. However, graft-vs-host disease (GVHD) remains a major complication of this strategy. We have used escalating doses of DLI for many years, and wanted to assess the risk factors for GVHD and transplant-related mortality as well as disease outcomes according to the reason for DLI. We analyzed 65 patients who received a total of 111 DLI for different reasons and at different intervals after transplantation. Median number of DLI was 2 (range, 1-4), median interval between transplantation and DLI was 9 months (range, 1-41 months) and median number of infused CD3(+) cells/kg recipient body weight was 2.5 × 10(7) (range, 1 × 10(6)-11.8 × 10(7)). Reasons for DLI were relapse or progression in 37 patients (57%), residual disease in 15 patients (23%), and persistence of mixed chimerism in 13 patients (20%). Seven patients (11%) developed acute GVHD grade II to IV and 5 patients (8%) developed extensive chronic GVHD. In univariate analysis, we could identify a transplantation-DLI interval ≤6 months, the dose of DLI (≥1 × 10(7)), and DLI number as predictive factors of GVHD. In multivariate analysis, these results were confirmed only for the transplantation-DLI interval (hazard ratio = 19.48; 2.23-170.34; p = 0.007). Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD and transplant-related mortality, supporting further investigation as an upfront modality to enhance the graft-vs-tumor response in high-risk patients.

Acute GVHD is a strong predictor of full donor CD3+ T cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation.

The monitoring of chimerism is a standard procedure to assess engraftment and achievement of full donor lymphoid cells after reduced intensity conditioning (RIC) stem cell transplantation (Allo-SCT). However, there is no consensus on when and how often to monitor post-transplant chimerism. We retrospectively analyzed our experience regarding the impact of acute graft versus host disease (GVHD) for the prediction of allograft chimerism. One-hundred-and-fifteen patients transplanted between 2001 and 2010 were identified. This group included 57 females and 58 males with a median age of 50 years (range: 26-68). Patients evaluated in this study were adult patients with hematologic malignancies, who received transplants from an HLA-matched sibling donor or matched unrelated donor (MUD) at allele level so-called 10/10, and received the RIC regimen including fludarabine/busulfan and anti-thymoglobulin (ATG). Mixed T-cell chimerism was defined as between 5 and 94% recipient cells, and full chimerism was defined as the presence of more than 95% donor T-cell chimerism (TCC). Full donor TCC was achieved in 93 patients (81%) at a median of 77 days (range: 30-120) post-transplant. The cumulative incidence of Grade 2-4 GVHD in our population was 25% (95% CI 17-34). The analysis of the population of patients with acute GVHD grade ≥2 showed that at day 120 after Allo-SCT they all had a total full donor TCC. On the other hand, 78 (68%) patients without acute GVHD grade ≥2 presented with mixed chimerism (p = 0.002) on day 120 post-transplant. Interestingly, patients who received ATG 5 mg/kg obtained a higher probability of complete chimerism compared with those receiving 2.5 mg/kg (p = 0.03). In conclusion, our study demonstrates that acute GVHD was predictive of full donor TCC after RIC Allo-SCT. Therefore, our data may challenge the concept of the frequent or close monitoring of donor chimerism in some patients with ongoing acute GVHD. However, chimerism testing could represent an attractive modality for minimal residual disease detection or for impeding relapse warranting further prospective studies.

Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma.

Myeloma relapse is the main cause of death after allogeneic stem cell transplantation. The aim of our observational study was to evaluate the anti-myeloma effect of lenalidomide followed by donor-lymphocyte infusion (DLI) as post-transplantation adoptive immunotherapy. Twelve patients with refractory myeloma were analyzed. The median age at transplantation was 56 years (range, 46-64 years). All patients received reduced-intensity conditioning. Patients were included if progressive or residual disease was observed at day +100 and if no signs of graft-vs-host disease were evident. DLIs were administered after two cycles of lenalidomide. Median dose of lenalidomide was 15 mg (range, 10-25 mg). Patients received a median of six cycles (range, 1-10 cycles). Nine patients (60%) received an escalating dose of DLI. The 1 and 2-year probability of progression-free survival was 75% and 50%, and overall survival was 83% and 69%, respectively. Median overall survival was not reached and median progression-free survival was 23 months. Lenalidomide is well tolerated after allogeneic stem cell transplantation; the combination with DLI did not cause a higher risk of graft-vs-host disease; an immunological synergistic effect was probably present with this strategy. This combination should be evaluated further in a larger cohort of patients.

Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma.

The purpose of this study was to assess the results of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning (RIC) from matched related donors (MRD) and unrelated donors (URD) in 40 patients with high-risk multiple myeloma (MM) in a single centre. Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had URD and MRD, respectively. Thirty-nine patients (98%) received one or more autologous transplantation. The median follow-up was 22 months (1-49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-IV acute GVHD was higher (47%) for the URD vs. (17%) for the MRD (P = 0.092). The cumulative incidence of chronic GVHD was no different between the two groups (24% vs. 30%, respectively). At 2 yr, the TRM probabilities were lower in the unrelated group 12% vs. 22% in the related group (P = 0.4). Also at 2 yrs, for patients receiving unrelated transplantation overall and progression-free survivals, 59% and 42%, respectively compared to patients with related donor transplantation, 66% and 44% (P = 0.241). In conclusion, these results suggest that URD in MM is feasible. The small number of patients with URD emphasizes the need to delineate indications and perform prospective protocols.

Age at transplantation and outcome after autologous stem cell transplantation in elderly patients with multiple myeloma.

BACKGROUND AND OBJECTIVE: The optimal treatment of patients with multiple myeloma (MM) is not well defined, in part because these patients are underrepresented in clinical studies. Autologous stem cell transplantation (auto-SCT) after high-dose melphalan chemotherapy can result in a prolonged response duration and survival in patients under 65 years of age. DESIGN AND SETTING: Single-center, retrospective study of patients treated at Paoli-Calmettes Institute Cancer Centre, between January 1994 and January 2007 (96 months) PATIENTS AND METHODS: We compared the outcome of elderly (age >65 years) patients with younger patients aged between 60 and 65 years with MM. RESULTS: We compared 82 elderly patients with 104 younger patients. Except for age, both groups had comparable demographic features, disease characteristics, and prognostic factors. Induction VAD chemotherapy was comparable between the elderly (87%) and younger (94%) group. Prior to auto-SCT, the calculated hematopoietic cell transplantation-specific co-morbidity index was also comparable. With a median follow-up of 41 months (range, 5-227 months) after auto-SCT, 120 patients were still alive. Disease progression (n=40; 61%) was the main cause of death, and it was comparable in the two groups. Auto-SCT-related mortality was 3.8% (n=4/104) in younger and 3.7% (n=3/82) in older patients. Comparing younger/older subjects, progression-free survival was significantly higher in the younger group (P<.0001). However, disease response rates after the first auto-SCT was comparable and overall survival (OS) was also comparable (57% vs. 54% at 5 years, P=NS; 32% vs. 24% at 10 years, P=NS). In a Cox multivariate analysis model, none of the relevant characteristics was shown to be a critical prognostic feature for OS. CONCLUSIONS: Age was insignificant for both OS and transplant-related mortality. We conclude that there is no biological justification for an age-discriminate policy for MM therapy. Physiologic aging is likely more important than chronologic aging.

Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies.

OBJECTIVE: The development of reduced-intensity conditioning regimens rather than myeloablative regimens for allogeneic stem cell transplantation has led to decreased treatment-related mortality and increased use of this treatment modality, especially in older patients with hematological malignancies. No randomized controlled trials have been performed resulting in determining effectiveness on phase II studies, which rarely report on long-term survival. MATERIALS AND METHODS: In an attempt to address this limitation, we analyzed a single-center cohort of 100 consecutive patients with hematological malignancies undergoing allogeneic stem cell transplantation from a human leukocyte antigen-matched related donor with median follow-up of 60 months. The reduced-intensity conditioning regimen consisted of oral Busulfan, rabbit anti-thymocyte globulin, and Fludarabin. RESULTS: Median age was 50 years (range, 18-64 years). The incidences of acute and chronic graft-vs.-host disease were 43% and 81%, respectively. The probability of nonrelapse mortality at 1 and 5 years was 15% and 25%, respectively. Nonrelapse mortality was adversely associated with acute graft-vs.-host disease (hazard ratio = 6; p = 0.0002). Of the 52 patients with measurable disease, 37 (71%) achieved a response. Relapse/progression occurred at a median of 11 months (range 1-52 months) in 21 patients, for a cumulative incidence of 22%. The probability of overall survival and progression-free survival at 5 years were 60% and 54%, respectively. Overall survival and progression-free survival were favorably influenced by having had previous autologous stem cell transplantation and a low CD34(+) cell dose. Overall survival, progression-free survival, and nonrelapse mortality improved over time in this cohort of patients. CONCLUSIONS: These results are encouraging for populations different in term of age, diagnosis, and disease status.

Platelet recovery and transfusion needs after reduced intensity conditioning allogeneic peripheral blood stem cell transplantation.

OBJECTIVE: The aim of this retrospective study was to assess platelet transfusion needs and the kinetics and predictive factors for platelet recovery after reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: The profile of platelet recovery and transfusion needs in the first 100 days after RIC allo-SCT from a human leukocyte antigen-identical sibling donor was analyzed in a single-center series of 166 consecutive patients. RESULTS: Platelet recovery (>20g/L) was observed at a median of 9 days (range, 0-99 days) after allo-SCT. One-hundred forty-five patients could be assessed for platelet recovery at day +100, of which 99 (68%) had a platelet count >99g/L. In the multivariate analysis, a lower platelet counts before the start of conditioning, and occurrence of grade III to IV acute graft-vs-host disease significantly influenced day-100 platelet recovery >100 x 10(9)/L (odds ratio [OR] = 2.51; 95% confidence interval [CI], 1.13-5.61; p = 0.025; and OR = 7.6; 95% CI, 3.0-19.29; p = 0.00002, respectively). Eighty-three patients (50%) did not require any platelet transfusion during follow-up. Multivariate analysis found the following parameters to be significantly associated with platelet transfusion needs: conditioning regimen type (use of antithymoglobulin: OR = 3.96; 95% CI, 1.77-8.89; p = 0.008), platelet count prior to RIC administration (>144g/L; OR = 0.18; 95% CI, 0.08-0.39; p = 0.00001) and occurrence of grade III to IV acute GVHD (OR = 11.62; 95% CI, 4.01-33.66; p = 0.000006). CONCLUSIONS: Overall, these observations show a lower rate of platelet transfusion and faster platelet recovery kinetics after RIC HSCT, but also highlight the negative effect of severe acute GVHD as a risk factor for increased need for platelet transfusions.

Occurrence and severity of adverse events after autologous hematopoietic progenitor cell infusion are related to the amount of granulocytes in the apheresis product.

BACKGROUND: Adverse events (AEs) after hematopoietic progenitor cell (HPC) infusion are rare but might be life-threatening. These reactions have traditionally been associated with the amount of infused cryoprotectant, but persistence of such events after dimethyl sulfoxide (DMSO) depletion has questioned this assumption. STUDY DESIGN AND METHODS: The incidence of AEs on a cohort of 460 patients (490 HPC infusions) undergoing autologous DMSO-reduced HPC transplantation was prospectively evaluated. HPCs were collected from adult patients with various hematologic or solid malignancies. After quality control (QC) on fresh apheresis products and subsequent cryopreservation, HPC grafts were thawed and washed at the cell therapy facility. QC was performed on each graft after washing, and clinical data were collected for each infusion. RESULTS: AEs were reported in 66 cases (13.5%) and were graded according to the NCI-CTC scale from 1 to 4. Although none of the factors associated with patient characteristics or infusion procedure were different between the two groups (no AE vs. occurrence of AE), it was found that the absolute number of granulocytes measured before freezing was considerably higher in the AE group. Furthermore, within this group, there was a strong correlation between the amount of granulocytes and the grading of the reaction. CONCLUSION: This survey demonstrates that AEs occurring in the setting of DMSO-reduced HPC grafts are directly related to the amount of granulocytes and thus emphasizes the need for high-quality apheresis products so as to improve the safety of HPC infusion.

Clinical experience with the delivery of thawed and washed autologous blood cells, with an automated closed fluid management device: CytoMate.

BACKGROUND: Washing out of thawed autologous grafts, before reinfusion in poor-prognosis cancer patients who undergo high-dose chemotherapy, is desirable. The procedure allows for the reduction of infused dimethyl sulfoxide (DMSO) quantities and the performance of biologic controls on the infused cell product. STUDY DESIGN AND METHODS: Three-hundred four patients were treated with intensified chemotherapy and autologous transplantation at a single institution. Fifty-four of them received washed cell products, because three or more bags were to be reinfused. The recently available, closed, automated, and current good manufacturing practice-compliant device (CytoMate, Baxter Oncology) was used for this purpose. RESULTS: The performances of the device were similar to previously reported results, with greater than 75 percent CD34+ cell recovery. Neutrophil and platelet (PLT) recoveries were similar in the group of patients receiving washed cells and in the group of patients for whom cell products were extemporaneously thawed at the bedside. Adverse events that are typically reported after DMSO infusion were significantly less frequent and less severe in patients who received washed cells. Finally, the nurse staff on the transplant ward reported a decreased workload and more satisfactory procedure when infusing washed cell products. CONCLUSION: The CytoMate device allows for a significant reduction in DMSO infusion, with a diminished frequency and severity of immediate side effects and does not compromise neutrophil or PLT engraftment.

CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.

OBJECTIVE: Acute graft-vs-host disease (aGVHD) remains an important cause of morbidity after reduced-intensity conditioning (RIC) allogeneic transplantation (allo-SCT). It has been shown that antithymocyte globulin (ATG) dose infused during RIC is a major determinant for the likelihood of developing aGVHD. The ATG modulation on aGVHD is likely related to in vivo T-cell depletion. PATIENTS AND METHODS: We therefore investigated the relationship between the cellular composition of the allograft and clinical outcome in 57 patients who received allogeneic peripheral blood stem cells from HLA-identical siblings following an ATG-based RIC. RESULTS: In a multivariate analysis, the CD8+ T cell dose infused was the only parameter associated with the risk of aGVHD (p=0.031; RR=1.96; 95% CI, 1.1-3.6). When looking at the extremes, patients experiencing grade III-IV aGVHD received a median of 143 x 10(6)/kg CD8+ T cells, while patients without aGVHD received a median of 96 x 10(6)/kg CD8+ T cells (p=0.021). None of the different cell subtypes contained in the allograft was associated with a significant probability of developing chronic GVHD. Patients with grade II aGVHD who received an intermediate dose of CD8+ T cells (median, 111 x 10(6)/kg) had a significantly better overall survival in comparison to patients with grade 0-I or grade III-IV aGVHD (p=0.009). CONCLUSION: In comparison to myeloablative allo-SCT, these results demonstrate that a cautious monitoring of the number of cells infused, at least in the context of ATG-based RIC, may represent an important predictive indicator of early transplant-related events and outcome after RIC allo-SCT.

Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen.

OBJECTIVE: Reduced-intensity conditioning regimens (RIC) and peripheral blood stem cells (PBSC) are increasingly used for allogeneic stem cell transplantation (allo-BMT). RIC has been shown to allow engraftment with minimal early transplant-related mortality (TRM). However, in the context of RIC, the use of bone marrow (BM) as stem cell source is still little evaluated. PATIENTS AND METHODS: In this report, we analyzed the outcome of 32 high-risk patients with hematological malignancies who received an HLA-identical sibling allo-BMT after RIC including fludarabine, busulfan, and anti-thymocyte globulin (ATG). RESULTS: Sustained neutrophil and platelet recovery occurred at a median of 13 days (range, 10-19) and 17 days (range, 0-45) respectively. Early and durable full donor chimerism could be established as soon as the first month after allo-BMT. Also, a sustained and early CD8(+) T-cell recovery was observed, but the CD4(+) T-cell compartment remained profoundly low. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 26% (95% CI, 11-41%) and 31% (95% CI, 15-47%) respectively. The overall cumulative incidence of TRM was 28% (95% CI, 12-44%) occurring mainly in patients aged over 50. In this setting, GVHD showed a protective effect on disease progression or relapse with better progression-free survival for patients with GVHD as compared to patients without GVHD (p=0.03). CONCLUSIONS: Collectively, these results confirm that the use of BM grafts for RIC is feasible with durable donor engraftment and no detrimental GVHD.