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L’allogreffe de cellules souches hématopoïétiques (CSH) se complique de pneumopathies qui peuvent lourdement grever la mortalité liée à la procédure.

The authors have previously shown that mononuclear cells derived from patients with resistant chronic graft-versus-host-disease (GVHD) express high calcineurin (CN) activity, suggesting that in vitro assessment of CN activity may be a useful index to estimate the degree of immunosuppression afforded by cyclosporine A (CsA). The goal of this study was to assess CN activity during the first 2 months after allogeneic stem-cell transplantation (SCT) and to correlate its evolution with the occurrence of acute GVHD.

The toxicity of autologous bone marrow transplantation (ABMT) is correlated to neutropenia. Although recombinant human granulocyte- macrophage colony-stimulating factor (rhu GM-CSF) seems to hold promise in accelerating neutrophil recovery, few analyses from randomized studies are presently available. Ninety-one patients with non-Hodgkin's lymphoma receiving high-dose ablative chemotherapy followed by ABMT with unpurged or purged marrow were included in a randomized, double- blind, placebo-controlled trial. Forty-four patients received 250 micrograms rhu GM-CSF (Escherichia coli)/m2 and 47 patients received placebo. Treatment was administered daily as continuous infusion from day of ABMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/L for 7 days or until day 30, whichever was first. With rhu GM- CSF, 50% of the patients reached an ANC count greater than 0.5 x 10(9)/L at day 14 as opposed to day 21 with placebo (P less than .0001). Patients transplanted with marrow purged by mafosfamide also recovered earlier when treated with rhu GM-CSF (16 v 20.5 days, P = .013). The hospitalization duration was shorter in the rhu GM-CSF group (median, 23 v 28 days, P less than .05). No difference was observed in fever, number of infections, and antibiotic administration between the two groups. The major adverse event ascribed to rhu GM-CSF was a capillary leak syndrome in three patients graded as severe in two patients, moderate in one, and reversible in all three patients. In addition, one patient in the rhu GM-CSF group died suddenly with no explanation. In long term follow-up, the relapse rate was identical in both groups and there was no significant difference in the number of deaths at 1 year (12 with rhu GM-CSF v 9 with placebo), although deaths seemed to occur slightly earlier in the rhu GM-CSF group. We conclude that after ABMT with purged or unpurged marrow, rhu GM-CSF (E coli) significantly reduces neutropenia duration and hospitalization stay. A positive causative relation between the study drug and/or its mode of application with an increased toxicity as compared with GM-CSF from other sources and/or other modes of application cannot be deduced from the experiences in this study. Additional randomized trials would be necessary for an appropriate answer.

We have used DNA sequence polymorphism analysis to document engraftment after T cell-depleted bone marrow transplantation (BMT), with a selected panel of four DNA probes. In contrast to nondepleted BMT recipients, the patients who received T cell-depleted marrow exhibited a mixed blood chimerism. This mosaicism was observed before graft failure or relapse in six patients. However, in five other patients, this mixed chimerism was not followed by these complications with a follow-up of 9 to 31 months after transplantation. Our results support the hypothesis that transplanted bone marrow T cells may help to maintain engraftment by eliminating host cells that can cause graft failure.

Seventeen patients with Hodgkin's disease (HD) were treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT). Eleven patients were resistant to initial therapy. Three patients had relapsed and were still responders to second or third line therapy. Three patients had relapsed but were progressing under second or third line therapy. Pre-ABMT chemotherapy included high dose cyclophosphamide in all patients (50 mg Kg-1 day-1 bolus for 4 days), most often associated with BCNU or CCNU, aracytine and 6 thioguanine. Four patients received additional TBI (10 Gy). In 9 patients complete remission (CR) was achieved, 4 failed to respond and 4 cases were not evaluable due to early death. Among CR patients, 2 died from late toxicity, 4 relapsed between the 2nd and 5th months, but 3 patients remain in CR, off therapy at 25+, 43+, and 66+ months, including 1/11 initially resistant and 2/6 who had relapsed. There were 9 treatment related deaths: 6 due to infection, 1 cardiac failure and 2 multiorgan failure. The high complete response rate in these heavily pretreated patients suggests that there may be an indication for high dose therapy earlier in resistant HD. Moreover under such conditions, treatment related morbidity would be expected to be lower.

From October 1987 to December 1990, 101 patients with acute myeloid leukemia (AML) were randomized to be transplanted in first complete remission (CR1). Preparative regimen including Cytoxan (120 mg/kg) with total body irradiation (CYTBI) (N = 50) or busulfan (16 mg/kg) (BUSCY) (N = 51) was followed by allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling. Mean time between diagnosis and BMT was 119 days. The outcome for CYTBI at 2 years is better for probability of disease-free survival (DFS) (72% v47%) (P <. 01), survival (75% v51%) (P <. 02), relapse (14% v34%) (P< .04), and transplant mortality (8% v27%) (P <. 06). In multivariable analysis, higher relapse and decreased survival and DFS were associated with BUSCY regimen, while chronic graft-versus-host disease also influenced independently the probability of relapse. This demonstrates the present limitation of busulfan use in this setting, possibly due to probable individual variations in biodisponibility. Furthermore, besides the antileukemic effect of preparative regimens, this trial points out the progress accomplished in BMT management (transplant mortality = 8% in CYTBI) over the last 20 years as well as the effectiveness of transplant in early first CR after CYTBI (DFS = 72% at 2 years).

We report on 71 consecutive patients with de novo myelodysplastic syndromes referred to physicians belonging to the Societe francaise de greffe de moelle from 1982 through 1991 and transplanted with marrow from HLA-identical siblings. There were 16 cases of refractory anemia, 27 of refractory anemia with excess of blast cells, and 28 of refractory anemia with excess of blast cells in transformation. Seventeen patients had received cytoreductive chemotherapy before the graft. The disease progressed in 17 patients between diagnosis and grafting. Twenty-three patients are alive with a median follow-up of 6 years, whereas 24 died from relapse and 24 from transplant-related complications. Kaplan-Meier estimates of event-free survival, relapse and transplant-related mortality at 7 years were 32%, 48%, and 39%, respectively. The log-rank test and Cox's model revealed better outcome among young patients, patients in an early stage of the French-American- British (FAB) classification or with a low percentage of marrow blasts before transplantation, patients who did not undergo cytoreductive chemotherapy before transplantation, and patients conditioned with total body irradiation and cyclophosphamide. The high rate of relapse in advanced FAB stages has led us to graft patients earlier in the course of the disease, and we are currently conducting a multicenter, randomized study to determine the value of intensive chemotherapy before grafting in patients with an excess of marrow blasts.

We report a case of mild, clinically asymptomatic, immune thrombocytopenia after allogenic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML) caused by the presence of a recipient- origin Br(a) antibody that recognized the donor platelets. Although the antibody titer decreased, it remained detectable more than 3 years after BMT. Chimerism studies were performed combining cytogenetics, blood cell phenotype studies, and genomic amplification of hypervariable sequences. Cytogenetic studies and molecular analysis of peripheral blood cells, purified B- and T-lymphocyte subpopulations, and bone marrow colonies showed the hematopoiesis to be of donor origin, but absorption-elution experiments with peripheral RBCs showed a small amount of recipient RBCs. The CML chimeric transcript was also detected by means of polymerase chain reaction on samples collected until day +867 post-BMT. This case shows that recipient-origin platelet alloantibodies can cause thrombocytopenia after BMT and that the persistence of small numbers of recipient cells (even leukemic) is not necessarily associated with hematologic relapse.

We have used DNA sequence polymorphism analysis to document engraftment after T cell-depleted bone marrow transplantation (BMT), with a selected panel of four DNA probes. In contrast to nondepleted BMT recipients, the patients who received T cell-depleted marrow exhibited a mixed blood chimerism. This mosaicism was observed before graft failure or relapse in six patients. However, in five other patients, this mixed chimerism was not followed by these complications with a follow-up of 9 to 31 months after transplantation. Our results support the hypothesis that transplanted bone marrow T cells may help to maintain engraftment by eliminating host cells that can cause graft failure.

We recently reported the results of a randomized study comparing allo BMT (N = 53) and BCT (N = 48) (JCO, Vol. 18, N.3, Feb 2000) for early stage leukemia: this study establishes that BCT is associated with better hematological recovery, lower costs, no more AGVHD and identical outcome. In the present analysis, with a longer follow-up (27 mths (13-41)), we focus on cGVHD. cGVHD is more frequent after BCT (28/48 (58%) vs. 16/53 (30%) (p < 0.02)) and more severe (extensive cGVHD = 61% after BCT vs. 25% (p < 0.05)). In addition there is a trend for late cGVHD in BCT (43% started after 6 months vs. 19% in BMT). No causal factor has been found so far. cGVHD has a major effect on relapse control : only 1 pt relapsed of the 39 with cGVHD vs. 7 of 55 without (2 year relapse KM estimate by : 4% (1-18) vs. 18% (9-34) : p < 0.03). This effect persisted when the analysis was restricted to BCT population (patients with c GVHD : 0 relapse out of 24 patients; without cGVHD : 3 of 20 (2 year KM relapse estimate = 22% (7-51)) : p < 0.04). However this did not equate so far into a clear survival advantage. We confirm that BCT is associated with a higher incidence of chronic GVHD an a better relapse control Longer follow-up will be presented with the extensive review focused on cGVHD which is currently under process.

Introduction: HSCT has been developed in few Wm cases and is nowadays challenged by other innovative approaches. However, high dose therapy followed by autologous HSCT (HD-auto) produces high response rate and some long term responses while allogeneic HSCT performed after either myeloablative (MA-allo) or reduced intensity conditioning (RIC-allo) regimens may be cure of Wm (Dreger 1998, Tournilhac 2003, Maloney 2006). Methods: We updated and extended our retrospective experience on 32 HD-auto, 11 MA-allo and 11-RIC-allo performed from 1990 to 2006 in 51 patients from 18 institutions. A MA-allo and a RIC-allo were performed in 1 and 2 cases respectively following relapse after a 1st HD-auto. Results: Data are presented in the table. HD-auto MA-allo RIC-allo Nb 32 11 11 Median age at transplant 56 46 56 Interval: diagnosis-transplant 38 50 74 Chemoresistance at transplant 25% 36% 55% Conditioning regimen BEAM (13), TBI/melphalan (9), TBI/endoxan (7), other (3) TBI/endoxan (9), other (2) TBI/fluda (10), other (1) Donor Sibling (9), unrelated (2) Sibling (8), unrelated (2), cord blood (1) Median follow up (m) 45 (3–121) 68 (3–132) 22(2–60) Relapse 18 (56%) 4 (36%) 0 Transplant related mortality 12,5% (one 2th cancer) 36% 27% (one 2th cancer) overall survival (1;3;5y) 87%, 77%, 58% 64%, 54%, 54% 82%, 68%, 68% Event free survival (5y) 25% 48% 68% Acute GVHD developed following 9 MA-allo [Grade III-IV (n=1)] and 8 RIC-allo [Grade III-IV (n=1)]. Chronic GVHD developed following 7 MA-allo [limited (n=5), extensive (n=2)] and 5 RIC-allo [limited (n=2), extensive (n=3)]. Conclusion: We confirm that autologous HSCT achieves some long term responses even in heavily pretreated patients. Allogeneic HSCT induces very long term disease control and may cure WM. Specially, the RIC-allo gives impressive results on disease control in a set of older patients, with refractory disease, mostly heavily pretreated.

We have previously reported that the incidence of acute graft-versus-host disease (GVHD) after myeloablative peripheral blood stem cell transplantation correlates more strongly with the blood donor CD34+ cell count after G-CSF mobilization than with the dose of CD34+ cells infused to the recipient (Dhedin et al. Exp Hematol 2006). The aim of this study was to confirm this finding in non myeloablative transplantation. We studied 92 patients transplanted with HLA-identical sibling donor after a conditioning regimen associating 2GY total body irradiation and fludarabine. The median blood donor CD34+ cell count on day 5 of G-CSF administration was 70/μl (range 9–210/μl). The median infused CD34+ and CD3+ cell doses per kilogram of recipient bodyweight were respectively 6.4 × 106 (range 1.3–22.6) and 275 × 106 (range 88–839). The cumulative incidence rates of grade II–IV aGVHD and grade III–IV aGVHD were respectively 34.4% (se=0.05) and 9.9% (se=0.03) on day 100. The cumulative incidence rates of all GVHD and extensive cGVHD at 24 months were respectively 60.5% (se=0.06) and 36.2% (se=0.06). Donor and recipient characteristics, the doses of infused CD34+ and CD3+ cells, and the donor CD34+ cell count after G-CSF mobilization were analyzed as potential risk factors for GVHD. No correlation was found between these parameters and the occurrence of acute GVHD. As in several previous studies, the CD34+ cell dose tended to influence the incidence of extensive cGVHD, but the correlation was not statistically significant (p=0.14). In contrast, the blood donor mobilized CD34+ cell count, divided into quartiles, was the only factor significantly associated with extensive chronic GVHD: In univariate analysis, the incidence of extensive cGVHD was significantly higher in the quartile of patients (N=24) whose donors had the highest mobilized CD34+ cell counts (quartile n°4: >109 CD34+ cells/ml at day 5 of G-CSF mobilization), compared to the three other quartiles (cumulative incidence of extensive cGVHD in quartile n°4 was 58.9% compared to respectively 20.8, 37.5 and 25% in the third, second and first quartiles (p=0.03)). In multivariate analysis, the donor CD34+ cell count was the only variable associated with the risk of extensive cGVHD: the hazard ratio associated with the highest quartile was 2.59 (95% CI [1.30–5.18], p=0.007).In conclusion, we confirm in non myeloablative transplants, that donor response to G-CSF is a better prognosis factor of GVHD, than the dose of CD34+ cell infused. “Outstanding mobilizers” seemed to have greater alloreactive potential. These findings do not support limiting the dose of CD34+ cells infused to prevent GVHD. They have also direct implications for transplant management, and especially for the modalities of GVHD prophylaxis.

We have previously reported that the incidence of acute graft-versus-host disease (GVHD) after myeloablative peripheral blood stem cell transplantation correlates more strongly with the blood donor CD34+ cell count after G-CSF mobilization than with the dose of CD34+ cells infused to the recipient (Dhedin et al. Exp Hematol 2006). The aim of this study was to confirm this finding in non myeloablative transplantation. We studied 92 patients transplanted with HLA-identical sibling donor after a conditioning regimen associating 2GY total body irradiation and fludarabine. The median blood donor CD34+ cell count on day 5 of G-CSF administration was 70/μl (range 9–210/μl). The median infused CD34+ and CD3+ cell doses per kilogram of recipient bodyweight were respectively 6.4 × 106(range 1.3–22.6) and 275 × 106(range 88–839). The cumulative incidence rates of grade II–IV aGVHD and grade III–IV aGVHD were respectively 34.4% (se=0.05) and 9.9% (se=0.03) on day 100. The cumulative incidence rates of all GVHD and extensive cGVHD at 24 months were respectively 60.5% (se=0.06) and 36.2% (se=0.06). Donor and recipient characteristics, the doses of infused CD34+ and CD3+ cells, and the donor CD34+ cell count after G-CSF mobilization were analyzed as potential risk factors for GVHD. No correlation was found between these parameters and the occurrence of acute GVHD. As in several previous studies, the CD34+ cell dose tended to influence the incidence of extensive cGVHD, but the correlation was not statistically significant (p=0.14). In contrast, the blood donor mobilized CD34+ cell count, divided into quartiles, was the only factor significantly associated with extensive chronic GVHD: In univariate analysis, the incidence of extensive cGVHD was significantly higher in the quartile of patients (N=24) whose donors had the highest mobilized CD34+ cell counts (quartile n°4: >109 CD34+ cells/ml at day 5 of G-CSF mobilization), compared to the three other quartiles (cumulative incidence of extensive cGVHD in quartile n°4 was 58.9% compared to respectively 20.8, 37.5 and 25% in the third, second and first quartiles (p=0.03)). In multivariate analysis, the donor CD34+ cell count was the only variable associated with the risk of extensive cGVHD: the hazard ratio associated with the highest quartile was 2.59 (95% CI [1.30–5.18], p=0.007).In conclusion, we confirm in non myeloablative transplants, that donor response to G-CSF is a better prognosis factor of GVHD, than the dose of CD34+ cell infused. “Outstanding mobilizers” seemed to have greater alloreactive potential. These findings do not support limiting the dose of CD34+ cells infused to prevent GVHD. They have also direct implications for transplant management, and especially for the modalities of GVHD prophylaxis.

Introduction: HSCT has been developed in few Wm cases and is nowadays challenged by other innovative approaches. However, high dose therapy followed by autologous HSCT (HD-auto) produces high response rate and some long term responses while allogeneic HSCT performed after either myeloablative (MA-allo) or reduced intensity conditioning (RIC-allo) regimens may be cure of Wm (Dreger 1998, Tournilhac 2003, Maloney 2006).