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Allogeneic hematopoietic stem cell transplantation can efficiently treat patients with severe hematological diseases. A human leukocyte antigen-compatible donor is required for performing transplantation. The occurrence of unexpected acute severe diseases in a donor can compromise the feasibility of allogeneic hematopoietic stem cell transplantation. However, when a severe health problem occurs in a donor while the recipient has already received a conditioning regimen, hematologists have to find the best solutions for the recipient, while the team in charge of the donor has to find the best medical solutions for the donor. We describe here the occurrence of psychiatric acute complications in an unrelated donor while the myeloablative conditioning regimen had already been given to the recipient. We report the successive decisions that were made in an emergency based upon the expertise of physicians specialized in hematology, apheresis, cell therapy, and psychiatry to preserve the donor’s health and recipient’s life.

β-Thalassemia is a genetic disease caused by a defect in the production of the β-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of four nucleotides in the first exon of β-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the β-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (nine generations). In order to determine whether this variant arose in this region of Northern Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare β-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.

This study analysed the effects of growth factor on outcome after haematopoietic stem-cell transplantation (HSCT) with9 years follow-up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)-identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P 0·0001), but reduced platelet counts (P = 0·0002). Graft-versus-host disease (GVHD)-free survival (no acute GVHD grade II-IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD-free survival were seen in patients with or without conditioning with total body irradiation (TBI). Non-relapse mortality (NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [HR = 1·48; 95% confidence interval (CI): 1·15-1·9; P = 0·002; HR = 1·59; 95% CI: 1·07-2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse (HR = 0·96; 95% CI: 0·78-1·18; P = 0·71). Leukaemia-free survival (LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls (HR = 0·70; 95% CI: 0·60-0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS 10 years after HSCT, regardless of conditioning with TBI.

hma.2011.0608 Auteur(s) : Chantal Bauchetet, Dominique Bordessoule, Philippe Casassus, Joel Ceccaldi, Morgane Cheminant, Christian Bastard, Philippe Colombat, Diane Damotte, Eric Fiat, Dominique Jaulmes, Jean-Pierre Jouet, Sandra Malak, Genevieve Margueritte, Sarah Morin, Alice Polomeni, Henri Rochant, Jean-Jacques Sotto JJSotto@chu-grenoble.fr, Marc Zandecki, Robert Zittoun Commission d’ethique de la Societe francaise d’hematologie Tires a part : J. Sotto Notre pratique quotidienne [...]

We analyzed risk factors influencing outcomes after related (R) human leukocyte antigen-identical cord blood transplantation (CBT) for 147 patients with malignancies reported to Eurocord–European Group for Blood and Marrow Transplantation. CBT has been performed since 1990; median follow-up was 6.7 years. Median patient age was 5 years. Acute leukemia was the most frequent diagnosis (74%). At CBT, 40 patients had early, 70 intermediate, and 37 advanced disease. CB grafts contained a median of 4.1 × 107/kg total nucleated cells (TNCs) after thawing. The cumulative incidence (CI) of neutrophil recovery was 90% at day +60. CIs of acute and chronic graft-versus-host disease (GVHD) were 12% and 10% at 2 years, respectively. At 5 years, CIs of nonrelapse mortality and relapse were 9% and 47%, respectively; the probability of disease-free survival (DFS) and overall survival were 44% and 55%, respectively. Among other factors, higher TNCs infused was associated with rapid neutrophil recovery and improved DFS. The use of methotrexate as GVHD prophylaxis decreased the CI of engraftment. Patients without advanced disease had improved DFS. These results support banking and use of CB units for RCBT. Cell dose, GVHD prophylaxis not including methotrexate, and disease status are important factors for outcomes after RCBT.

Introduction: B-ALL with t(4;11)(q21;q23) (t(4;11) B-ALL) is a well characterized adult B-ALL subtype associated with an unfavorable prognosis, mainly due to a high relapse risk, which is followed by a poor outcome. In order to prevent relapse during frontline treatment, alloHCT in CR1 is recommended by many cooperative groups, although the specific outcome and prognostic factors related to this procedure have been scarcely analyzed. Patients and Methods: We searched in the ALWP-EBMT database all adult patients (pts) (i.e., ≥18 year-old) with B-ALL reported to harbor a t(4;11) translocation who underwent an alloHCT in CR1 from a matched related or unrelated (10/10 or 9/10) donor during the 2000-2016 period, and analyzed their outcome. The prognostic value of the MRD status at the time of transplant, as reported by centers, was specifically addressed. In addition, a comparative analysis with analogous pts with normal karyotype B-ALL (NK B-ALL) was performed, adjusting for main significant variables including the pre-transplant MRD status. Results: Overall, we identified 151 pts with t(4;11) B-ALL and 567 with NK B-ALL. Compared to NK B-ALL, pts with t(4;11) B-ALL were older (median age, 38.1 vs. 33.8, p=0.028), presented with a higher WBC count (114 vs. 7.9x109/L¸ p MRD at the time of alloHCT was undetectable in 62 (69%) of the 90 pts with available information, and showed a strong favorable impact on outcome, with a lower RI (21 vs. 45% at 2 years, p=0.003) and higher LFS (67 vs. 27%, p=0.00004), OS (81 vs. 26%, p=0.000005)and GRFS (47 vs. 24%, p=0.01) compared to pts with detectable MRD at transplant. The prognostic value of the pre-transplant MRD status was confirmed in a multivariate analysis (performed among patients with known MRD status), in terms of RI (HR=0.23, CI: 0.09-0.55; p=0.0011), NRM (HR=0.16, 0.05-0.52; p=0.0023), LFS (HR=0.20, 0.10-0.40; p=10-5), OS (HR=0.14, 0.07-0.30; p Comparison between t(4;11) B-ALL and NK B-ALL showed a strong impact of the MRD status. In univariate analysis, outcome after alloHCT in both t(4;11) B-ALL and NK B-ALL groups was similar in pts without detectable MRD at transplant, with comparable RI (21 vs. 26%, p=0.35), NRM (12 vs. 18.5%, p=0.37), LFS (67 vs. 56%, p=0.14), and OS (81.4 vs. 69%, p=0.069). In contrast, among pts with detectable MRD at alloHCT, LFS and OS were superior in NK B-ALL compared to t(4;11) B-ALL pts (50 vs. 27%, p=0.02; and 62 vs.26%, p=0.01, respectively). In multivariate analysis, and considering MRD-negative NK B-ALL as the reference category, t(4;11) B-ALL pts allografted without detectable MRD showed a better LFS (HR=0.624,0.335-0.978; p=0.04) and OS (HR=0.523,0.296-0.925; p=0.02). On the contrary, MRD-positive t(4;11) pts showed a worse outcome compared to the remaining MRD-stratified subgroups, with higher RI (HR=3.28,1.63-6.60; p=.0009), and shorter LFS (HR=2.42,1.65-4.93; p=0.00017) and OS (HR=3.51,2-6.18; p=1x10-5) (Figure 1). Conclusions: Outcome of adult pts with t(4;11) B-ALL who received an alloHCT in CR1 is favorable, especially in those with a negative MRD status pre-alloHCT. These results, when compared to previously reported results in non-allografted pts, strongly suggest a neat beneficial effect of alloHCT for this adult B-ALL subset. Nonetheless, further studies should evaluate the magnitude of this benefit in comparison with contemporary non-allograft post-CR strategies, as well as the optimal management for pts failing to achieve a MRD-negative status. Disclosures Socié: Alexion Pharmaceuticals, Inc.: Consultancy. Schmid: Celgene: Research Funding, Speakers Bureau; MoilMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding, Speakers Bureau. Mohty: Sanofi: Honoraria, Speakers Bureau.

Summary Background Cord blood transplantation is used to treat patients with malignant and nonmalignant hematopoietic diseases. This study assessed the feasibility of collecting cord blood for eventual transplantation to a sibling with such a disease. Methods We studied the records of 47 infants from whom cord blood was collected for siblings from 1993 through 1999. Results During the study, cord blood was collected for 47 potential recipients: 37 (80.4%) with malignant disease and 9 (19.6%) with nonmalignant disease. Delivery was induced before 39 weeks of gestation. The mean volume collected was 107 ± 39 mL and the number of nucleated cells was 11.52 × 108. Problems making collection difficult included: impossibility of collecting cord blood because of spontaneous delivery (n = 1), the cytomegalovirus-positive serologic status of donor (n = 7), and an inadequate number of nucleated cells (n = 16). Weekday collection was possible for 60% of the donors. To date, only 7 of these cord blood collections have been used for stem cell transplantations. Conclusion This retrospective study demonstrates the practical difficulties in collecting cord blood for transplantation to siblings, difficulties that may decrease the likelihood of success.

HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P = .046, hazard ratio [HR] = 1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival (P = .003, HR = 1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P = .002, HR = 2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino’s classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. “Missing killer cell immunoglobulin-like receptor (KIR) ligand” evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

Donor T cells expressing lymph node homing receptors are the foremost initiators of acute graft-vs-host disease (aGVHD), and a high proportion of CD4(+)CCR7(+) T cells in human leukocyte antigen-matched allografts has been shown to confer a high risk of aGVHD without interfering in other outcomes.Naïve, central memory (T(CM)), effector memory (T(EM)), and terminally differentiated effector memory (T(TD)) subsets, further subdivided by CD28 expression, were compared in 52 bone marrow and 37 granulocyte colony-stimulating factor-mobilized peripheral blood harvests.CCR7(+) cells (naïve and T(CM)) predominated in the CD4(+) population, whereas CD8(+) memory cells were chiefly CCR7(neg) in the grafts. Donor age, antecedent of chronic infections, and graft type were independent factors influencing graft composition. CD8(+) naïve cells negatively correlated and CD8(+) T(EM) positively correlated with age. Cytomegalovirus seropositivity was associated with more CD8(+) T(TD) and diminished CD28 expression. Toxoplasmosis seropositivity was associated with more CD4(+) T(CM) (p = 0.021). Marrow grafts comprised more CD28(+) cells within CD8(+) T(TD), but the percentage of CD4(+)CCR7(+) cells did not differ significantly between the two graft sources. Each of the four CD4(+) subsets and the percentage of CD4(+)CCR7(+) cells (p0.001) were correlated between graft and venous blood analyzed in 42 donors before harvest procedures.This study provides reference values for CD4(+) and CD8(+) naïve and memory subsets within allografts applicable to the healthy donor population and indicates that beforehand analysis of a whole-blood sample can help evaluating the risk of aGVHD conferred by each donor and, when possible, choosing the one conferring the lowest risk.

We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17 days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3·5 years, the 5-year overall survival (OS) was 60·7%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score ≥80 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases.

The purpose of this study was to evaluate the impact of enteral nutrition on early outcome of patients after myeloablative allogeneic stem cell transplantation (allo-SCT). From January 2001 to January 2003, 22 patients agreed to receive enteral nutrition via a nasogastric feeding tube; the remaining 23 patients received parenteral nutrition (n=22) or standard oral feeding (n=1). Early complications and factors influencing 100-day overall survival (OS) were investigated. Patients who received enteral nutrition developed less often acute-grade III/IV graft-versus-host disease (18%) than those who did not (35%) (P=0.011). In addition, this group showed lower mortality from infection during the first 100 days after transplantation. In multivariate analyses, only the absence of enteral nutrition was found to adversely influence 100-day OS with a hazard ratio of 8.3. Enteral nutrition is a safe and effective method for feeding allo-SCT patients. A randomized trial is warranted to confirm its advantage on early patient outcome.

The most commonly used grading system for acute graft-versus-host disease (aGVHD) was introduced 30 years ago by Glucksberg; a revised system was developed by the International Bone Marrow Transplant Registry (IBMTR) in 1997. To prospectively compare the 2 classifications and to evaluate the effect of duration and severity of aGVHD on survival, we conducted a multicenter study of 607 patients receiving T-cell-replete allografts, scored weekly for aGVHD in 18 transplantation centers. Sixty-nine percent of donors were HLA-identical siblings and 28% were unrelated donors. The conditioning regimen included total body irradiation in 442 (73%) patients. The 2 classifications performed similarly in explaining variability in survival by aGVHD grade, although the Glucksberg classification predicted early survival better. There was less physician bias or error in assigning grades with the IBMTR scoring system. With either system, only the maximum observed grade had prognostic significance for survival; neither time of onset nor progression from an initially lower grade of aGVHD was associated with survival once maximum grade was considered. Regardless of scoring system, aGVHD severity accounted for only a small percentage of observed variation in survival. Validity of these results in populations receiving peripheral blood transplants or nonmyeloablative conditioning regimens remains to be tested. (Blood. 2005;106:1495-1500)

Results of unrelated cord blood transplantation (UCBT) in childhood acute myeloid leukemia (AML) have not been previously reported. We analyzed 95 children receiving UCB transplants for AML (20 in first complete remission [CR1], 47 in CR2, and 28 in more advanced stage). Poor prognosis cytogenetic abnormalities were identified in 29 cases. Most patients received a 1 or 2 HLA antigens-mismatched UCB transplants. The median number of collected nucleated cells (NCs) was 5.2 x 107/kg. Cumulative incidence (CI) of neutrophil recovery was 78% +/- 4%, acute graft-versus-host disease (GVHD) was 35% +/- 5%, and 100-day transplantation-related mortality (TRM) was 20% +/- 4%. In multivariable analysis, a collected NC dose higher than 5.2 x 107/kg was associated with a lower 100-day TRM. The 2-year CI of relapse was 29% +/- 5% and was associated with disease status. The 2-year leukemia-free survival (LFS) was 42% +/- 5% (59% +/- 11% in CR1, 50% +/- 8% in CR2, and 21% +/- 9% for children not in CR). Children with poor prognosis cytogenetic features had similar LFS compared with other patients (44% +/- 11% vs 40% +/- 8%). In CR2, LFS was not influenced by the length of CR1 (53% +/- 11% in CR1 < 9.5 months compared with 50% +/- 12% in later relapses). We conclude that UCBT is a therapeutic option for children with very poor-prognosis AML and who lack an HLA-identical sibling.

The use of peripheral blood stem cells (PBSCs) is rapidly growing in the allogeneic transplantation setting as an alternative to bone marrow (BM). We previously reported a higher incidence of chronic graft-versus-host disease (cGVHD) associated with allogeneic PBSC transplantation in a randomized trial. In this follow-up report, we analyzed the evolution of cGVHD in the patients (n = 101) enrolled on this study. At a median follow-up of 45 months (range, 31-57 months), we found that the 3-year cumulative incidence of cGVHD was 65% (95% confidence interval [CI] 51%-78%) in the PBSC group and 36% (95% CI 23%-49%) in the BM group (P = .004). We also found that extensive cGVHD was more frequent in the PBSC group (44% [95% CI 30%-58%] vs 17% [95% CI 7%-27%];P = .004). The prevalence of cGVHD was always higher in the PBSC arm. Ocular involvement was more frequent in PBSC recipients (P = .02). Cutaneous and liver involvement was similar among BM and PBSC recipients. Chronic GVHD required multiple courses of immunosuppressive therapy in addition to cyclosporine and corticosteroids during longer periods (P = .03). Altogether, this translated into longer periods of hospitalization after transplantation in the PBSC group (P = .04). Finally, we also confirm that cGVHD after PBSC transplantation is associated with an antileukemic effect that is at least as potent as after BM. However, to date, this has not translated into a survival difference, possibly due to the early-stage leukemic status of these patients or to the relatively small size of the study population.

Summary. The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Societe Francaise de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft-versus-host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD ≥ 2 at 3 months which was higher in group I (65 ± 10%) than in group II (38 ± 5%; P = 0·01). Moreover, disease-free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 ± 10% vs. 41 ± 6%; P = 0·005)(95% CI) and (41 ± 10% vs. 55 ± 6%; P = 0·002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.

A careful prognostic evaluation of patients referred for high-dose therapy (HDT) is warranted to identify those who maximally benefit from HDT as well as those who clearly fail current HDT and are candidates for more innovative treatments. In a series of 110 patients with myeloma who received HDT as first-line therapy, times to event (disease progression and death) were studied through proportional hazard models, in relation to different prognostic factors, including a chromosome 13 fluorescence in situ hybridization (FISH) analysis using a D13S319 probe. Delta13 was detected in 42 patients (38%). Follow-up time among surviving patients and survival time were 48 +/- 3 and 51 +/- 7 months, respectively (median +/- SE). In the univariate analysis, Delta13 was the most powerful adverse prognostic factor for all times to event, especially for the survival time (P.0001) and was followed by beta2-microglobulin (beta2m) levels 2.5 mg/L or higher (P =.0001). The comparison of survival prognostic models including beta2m 2.5 mg/L or greater and another factor favored the Delta13/beta2m combination. In 22 patients (20%) with no unfavorable factor, the median survival time was not reached at 111 months. In contrast, among 55 patients (50%) with one unfavorable factor and 33 patients (30%) with 2 unfavorable factors, median survival times were 47.3 +/- 4.6 months and 25.3 +/- 3.2 months, respectively (P.0001). We conclude that delta13, adequately detected by FISH analysis, is a very strong factor related to poor survival, especially when associated with a beta2m level of 2.5 mg/L or higher. Routine FISH Delta13 assessment is strongly recommended for patients considered for HDT.

We report a case of nodular granulomatous Pneumocystis carinii pneumonia following bone marrow transplantation. The patient was a 40-year-old man who had undergone bone marrow transplantation for myeloblastic acute leukemia. He presented with fever, dyspnea and bilateral diffuse nodular infiltration of the lungs. Bronchoalveolar lavage was negative. Open lung biopsy was performed. Histological examination revealed a granulomatous reaction with central necrosis surrounded by epithelioid and giant cells. Toluidine blue and Gomori-Grocott stains identified a few P. carinii. Mycobacterial and fungal cultures were negative. A granulomatous reaction is rarely observed and almost only in HIV-infected patients. To our knowledge this is the first description in a bone marrow transplant recipient.

Several prospective randomized trials in acute myelocytic leukemia (AML) documented a lower relapse rate with autologous bone marrow transplantation (ABMT) than with conventional chemotherapy. However, they also identified some transplant difficulties, such as failure to collect sufficient numbers of stem cells, slow kinetics of engraftment, and a high transplant-related mortality that diminished or negated positive impact on overall survival. Data for ABMT are inconclusive in acute lymphocytic leukemia (ALL) in adults. We retrospectively analyzed patients with acute leukemia autografted with marrow purged with mafosfamide after January 1983 in our institution. The population comprised 229 consecutive patients; 165 with AML [123 in first remission (CR1), 32 in second remission (CR2)]; 61 with ALL (46 in CR1, 4 in CR2); and 3 with undifferentiated acute leukemia. All patients were autografted with marrow purged with mafosfamide. Mafosfamide was given at a constant dose of 50 μg/mL in 103 and adjusted individually to produce a CFU-GM LD 95 (5% residual CFU-GM post purging) in 126. The outcome was analyzed for correlation with patient characteristics, the disease including cytogenetics, and the graft itself. Prognostic factors identified by multivariate analysis were used to derive a prognostic classification. Patients receiving higher doses of marrow submitted to purging (>5.46 × 10 4 CFU-GM/kg) experienced a lower treatment-related mortality (RR = 0.11, p=0.005) and a higher leukemia-free (RR = 0.5, p=0.005) and overall survival (RR = 0.4, p=0.001). Patients receiving 5.46 × 10 4 CFU-GM/kg and doses actually infused post purging of ≤0.02 × 10 4 /kg had a treatment-related mortality of only 2 ± 2%, a leukemia-free survival of 70%, and an overall survival of 77 ± 7% at 10 years. In this study of autotransplantation for acute leukemia using mafosfamide-purged marrow, the stem cell dose used for purging and the intensity of purging were the most important factors predicting outcome.

A prospective study of autologous bone marrow or peripheral blood stem cell transplantation after intensive chemotherapy in myelodysplastic syndromes

Agnogenic myeloid metaplasia is a rare indication for allogeneic bone marrow transplantation (BMT). We have retrospectively studied 12 patients allografted for this disease within the French BMT group. Prior to BMT, the mean age was 40 years (range 14-49). Diagnosis was based on the Polycythaemia Vera Study Group criteria. Before BMT, 10 patients had been splenectomized, eight required transfusions, and four had received at least two lines of chemotherapy. Cyclophosphamide and total body irradiation was the main conditioning regimen used (n=8). The donor was an HLA-identical sibling except in one case where there was one HLA-DR mismatch. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A. 11 patients engrafted with median times to achieve absolute neutrophil count > 0.5 x 10(9)/l and platelet count > 50 x 10(9)/l of 17 (range 12-44) and 29 (range 12-196) days respectively. One primary graft failure occurred. 10 patients developed grade II-IV acute GVHD, four developed extensive chronic GVHD. One patient relapsed 16 months post-BMT and was untreated and well 14 months later. Three patients died from the BMT procedure. In May 1996 the median follow-up was 25 months and the 4-year overall and event-free survivals were 71% and 59%, respectively. Thus, we conclude that extensive myelofibrosis is not associated with delayed engraftment, and that HLA-identical sibling allogeneic BMT can be considered in a small proportion of patients with agnogenic myeloid metaplasia.

From March 1988 to March 1991, 19 French bone marrow transplant (BMT) centers participated in a prospective randomized trial comparing two conditioning regimens for patients with chronic myeloid leukemia transplanted in first chronic phase with an HLA identical sibling donor. A total of 120 consecutive patients were randomized to receive either 120 mg/kg of cyclophosphamide followed by total body irradiation (CY-TBI; n = 55) or 16 mg/kg of busulfan followed by 120 mg/kg of CY (BU-CY; n = 65). Two different TBI regimens were used. Thirteen patients received a 10-Gy single-dose TBI (SDTBI), and 42 received a fractionated TBI (FTBI). Median time between diagnosis and BMT was 315 days. Overall 5-year actuarial survival was 62.9% (65.8% +/- 12.5% for CY-TBI and 60.6 +/- 11.7% for BU-CY; P = .5), and overall disease-free survival was 55% (51% +/- 14% for CY-TBI and 59.1% +/- 11.8% for BU-CY; P = .75). All patients conditioned with CY-TBI experienced sustained engraftment; in contrast, 4 of 65 patients conditioned with BU-CY rejected the graft (P = .18). There was no significant statistical difference between the two groups regarding transplant-related mortality (29% for CY-TBI and 38% for BU-CY; P = .44). So far, with a median follow up of 42 months, 11 patients have relapsed; 9 relapses occurred after CY-TBI, mostly after FTBI (8 of 9) and 2 after BU-CY (P = .02). The actuarial risk of relapse was 4.4% +/- 6.7% after BU-CY, 11.1% +/- 20.8% after SDTBI, and 31.3% +/- 18.1% after FTBI (P = .039). In addition, independently of the conditioning regimen, the increase of posttransplant immunosuppression in 16 patients with an anti- interleukin-2 receptor monoclonal antibody (MoAb) in addition to a short course of methotrexate and cyclosporine was shown to increase the actuarial risk of relapse (57% +/- 30% with MoAb v 9% +/- 7.3% without MoAb; P = .001). We conclude that BU is an acceptable alternative to TBI for patients with chronic myeloid leukemia in first chronic phase receiving BMT from HLA identical sibling donors. Both BU-CY and CY-TBI regimens gave similar transplant-related mortality, and the antileukemic efficiency of BU-CY regimen was either similar or even higher than that of CY-TBI.

Between January 1985 and July 1989 we diagnosed asymptomatic stage I multiple myeloma according to Durie and Salmon [Durie and Salmon: Cancer 36:842, 1975] in 91 patients. All patients were followed without chemotherapy. Disease progression occurred in 41 patients and the median time to progression for all patients was 48 months. In the Cox multivariate regression analysis, hemoglobin levels 25% (P or = 30 g/l for Ig G or > or = 25 g/l for Ig A (P < .01) were the only significant prognostic factors for progression. The 38 patients without any harmful factor remained free of progression for a median of more than 50 months. The 18 patients with two or three of these characteristics (high-risk group) had the shortest median time to progression of 6 months. Despite different times to progression, the response rate and survival after chemotherapy were similar for all groups of patients. Patients in the high-risk group for progression have to be frequently monitored for disease progression and might benefit from early treatment.

Purpose To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT). Patients and Methods The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months. Results Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors. Conclusion Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.

The outcomes were analyzed retrospectively of 59 cases of non-Hodgkin lymphoma (NHL) that included prominent splenic involvement (LPS). Forty-three patients had low-grade NHL, and 16 had intermediate or high-grade NHL. Forty of the 59 patients underwent splenectomy. Four patients died postoperatively before any treatment, and 10 others received no chemotherapy or radiation therapy. Twenty-nine splenectomized and 16 patients whose spleens were not removed received chemotherapy or radiation therapy. One or more cytopenias were present in 45 patients (77%). Five (18%) of the 28 patients who initially were cytopenic underwent splenectomies that did not correct their blood disorders. The median actuarial survival was 108 months in splenectomized patients and 24 months in those not treated surgically (P = 0.0001). For the 40 splenectomized patients, a normal postoperative platelet count, an initial hemoglobin level of 110 g/l or more, and a postoperative hemoglobin level 110 g/l or more were associated with prolonged survival. These results suggest that cytopenias are frequent in LPS and that their reversal is observed after early splenectomy in 82% of cases. The absence of cytopenia after early splenectomy is associated with prolonged survival. Cancer 1993; 71:207-15.

In 1992, we reported the results of the first randomized trial comparing the combination of cyclophosphamide (CY) (120 mg/kg) and total body irradiation (TBI) (CYTBI) versus CY and busulfan (BU) (BUCY) as preparation for an allogeneic bone marrow transplantation (BMT) for adult patients with acute

Purpose This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. Patients and Methods We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). Results The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. Conclusion Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.

Imatinib is a promising candidate for the treatment of fibrotic diseases. This retrospective study evaluated the use of imatinib for the treatment of refractory sclerotic chronic graft-versus-host disease in 14 patients with different hematologic malignancies. Imatinib was started at a median of 44 months after transplantation (range, 16-119 months after transplantation) and was administered for a median of 5.9 months from time of initiation (range, 2.1-74 months from time of initiation). With a median overall follow-up of 11.6 months from time of initiation (range, 4.1-74 months from time of initiation) of imatinib, 4 patients (29%) had to stop imatinib because of drug intolerance. All other adverse reactions were of mild-to-moderate grade and could be managed symptomatically. Overall, 7 patients responded to imatinib (50%; 95% confidence interval, 24%-76%) with 4 patients improving their Rodman score more than or equal to 90%. In addition, imatinib therapy allowed for a significant reduction of corticosteroid dosage. Despite its limited size, this cohort suggests some beneficial activity of imatinib in sclerotic chronic graft-versus-host disease, warranting further prospective investigations.

Donation is one of the crucial points for allogeneic stem cells transplantation. Bone marrow harvesting or, more often now, peripheral blood stem cells collection must be safe for donor and contre-indications strictly observed. As familial transplantations are less and less performed, national registries have to be strengthened.

Over a period of 14 years, we treated 70 cases of acute promyelocytic leukemia (APL) with 3 different chemotherapy protocols. In protocol 1, patients received high dose daunorubicin (DNR) alone for induction, followed by regular reinduction courses and continuous maintenance therapy with 6 mercaptopurine (6 MP) and methotrexate (MTX) during 3 years. In protocol 2, induction with high dose DNR and Ara C was also followed by regular reinduction courses, but without continuous maintenance therapy. Protocol 3 randomized high dose Amsacrine (AMSA) or Rubidazone in association with Ara C, for induction and consolidation, this was followed by reinduction courses and continuous maintenance therapy with 6 MP and MTX. During the induction all patients received, prophylactic heparinization and platelet transfusions. Fifty six patients (80%) achieved complete remission (CR), 13 patients (18.5%) had early death (ED) or hypoplastic death (HD), and 1 patient had true resistant leukemia. Only two patients died of hemorrhage. Median actuarial disease free survival (DFS) was 16.5 months and a plateau at 29.1% was reached after 29 months. Patients with fever at diagnosis had a significantly lower CR rate while age below 20 years and circulating blasts above 0.5 × 10(9)/1 were associated with shorter DFS. The CR rate did not significantly differ between protocols 1, 2 and 3 (87.5%, 80% and 60% respectively) but 9 of the 30 patients on protocols 2 or 3 had ED or HD, compared to 4 of the 40 treated with protocol 1 (p < 0.05). DFS was significantly shorter in protocol 2, which included no continuous maintenance chemotherapy, than in protocols 1 and 3. Median actuarial survival was significantly shorter in patients treated with protocols 2 or 3, compared to protocol 1. These results suggest that high dose DNR alone, associated with adequate prophylaxis of disseminated intravascular coagulation, gives very high CR rates in APL, with short periods of aplasia and limited toxicity. Combinations of an anthracycline or AMSA at the doses used with regular dose Ara C may be too toxic. Although this was not a randomized trial, our findings also suggest a possible benefit of prolonged continuous maintenance therapy with 6 MP and MTX in APL.

Allogeneic stem cell transplantation has become standard therapy for hematologic malignancies through the positive immunologic graft-versus-leukemia effect. Initial immune recovery relies on peripheral expansion of infused T cells, which switch to a memory-like phenotype. This study prospectively investigated whether changes in subset composition precedes complications after myeloablative HLA-matched transplantation for hematologic malignancies. Of 80 allograft recipients, 18 were still free of clinical complication throughout 395 to 1564 days of follow-up. Compared with this complication-free subgroup, patients who developed chronic graft-versus-host disease (cGVHD) without relapsing recovered similar numbers of circulating T cells with predominance of CD8+ T cells lacking CC-chemokine receptor-7 and CD28 expression throughout the first year after transplantation. Conversely, poor CD8+ T cell recovery with diminished numbers of CD28neg CD8+ T cells (approximately 1/4th of that of relapse-free patients) preceded occurrence of malignant relapse. In multivariate analysis, lower CD28neg CD8+ T cell counts by day 60 postallograft were associated with a greater risk of subsequent relapse (hazard ratio [HR] 0.33; 95% confidence interval [CI]: 0.14-0.76; P = .01). Enumeration of CD28neg CD8+ T cells in patients could assist in predicting risk of relapse and help build an algorithm for accelerating the immune recovery by reducing the immunosuppressive treatment and considering the introduction of preemptive donor lymphocyte infusions.

We studied two cases of chronic myelogenous leukemia (CML) with unusual variant Philadelphia (Ph) translocation (22;22)(q11;q13). Southerr, blot analysis showed a chromosomal break in the BCR gene within the 5.8-kilobase (kb) breakpoint cluster region (bcr), between bcr exons 2 and 3 and between bcr exons 3 and 4, respectively. Chimeric bcr-abl mRNA was detected using polymerase chain reaction (PCR) which amplified, according to the respective bcr breakpoints, bcr exon 2- abl exon II and bcr exon 3- abl exon II junction products. These results further support the involvement, even when not cytogenetically detectable, of the 9q34 chromosomal region in all variant Ph translocations and that BCR-ABL gene fusion products are causally involved in the development of Ph positive CML.

We report on 37 adults aged 50 years or less with de novo myelodysplastic syndrome (MDS) (excluding cases secondary to chemo or radiotherapy), who represented 6.7% of our total cases of adult MDS. Median age was 42 (range 18–50). At diagnosis, there were 9 RA, 6 RAEB, 13 RAEB-T, 9 CMML but no RARS. Five patients had a familial history of MDS, and 3 a history of occupational exposure to potential carcinogens. Twenty-one patients received intensive chemotherapy (at diagnosis or during the evolution) but only 8 (38%) achieved complete remission (CR), and median CR duration was 10 months. Five patients were allografted (3 of them as first line therapy): 2 remained disease free after 12 and 10 months, and 3 died of transplant related complications. Median actuarial survival of the 37 patients was 21 months. Significantly shorter survival was seen in patients who had circulating blasts, Bournemouth score >1 or 2, abnormal karyotype (especially monosomy 7) and RAEB or CMML. When compared with our MDS aged more than 50, our MDS aged 50 or less were characterized by more familial cases, more cases of RAEB-T and less cases of RAEB and RARS, more frequent abnormal karyotype and monosomy 7, more frequent progression to AML, identical overall survival but longer survival in RAEB-T and shorter survival in CMML. MDS in younger adults seem relatively often familiar or associated to occupational exposure. They have a poor prognosis with conventional therapeutic approaches and therefore require allografting, whenever possible.

Josy Reiffers nous a quittes le 21 septembre 2015.Josy avait ete nomme professeur de medecine en hematologie a l’universite Bordeaux Segalen en 1982. Apres avoir ete doyen d’une des facultes de medecine de Bordeaux, Josy Reiffers avait ete president de l’universite Bordeaux Segalen de 1997 a 2002. Il fut directeur adjoint du cabinet du ministre de la Jeunesse, de l’Education nationale et de la Recherche, charge de l’Enseignement superieur et de la Recherche entre 2002 [...]

Purpose To investigate the influence of donor type (human leukocyte antigen [HLA] -identical sibling donor versus HLA-A–, HLA-B–, HLA-Cw–, HLA-DRB1–, and HLA-DQB1–identical unrelated donors, or so-called 10/10) on the outcome of patients who underwent allogeneic stem-cell transplantation (alloSCT), adjusting for other prognostic factors, in patients with standard-risk hematologic malignancy. Patients and Methods Between March 2000 and January 2003, we prospectively investigated the outcome of 236 consecutive patients with standard-risk malignancy from 12 French centers. Fifty-five patients underwent alloSCT from an unrelated HLA-identical donor at the allelic level, whereas 181 patients received an alloSCT from an HLA-identical sibling. Diagnoses included acute leukemia (n = 175), chronic myeloid leukemia (n = 43), and myelodysplastic syndrome (MDS; n = 18). All patients received unmodified marrow graft following myeloablative conditioning with cyclophosphamide and total-body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short-course methotrexate in all patients. Results In multivariable analysis, overall survival and transplantation-related mortality were adversely influenced by recipient cytomegalovirus (CMV) -positive serology, age of donor older than 37 years, and the occurrence of acute grade ≥ II GVHD. Event-free survival rates were lower for patients with recipient CMV-positive serology. Acute grades II to IV GVHD rates were higher for patients with chronic myeloid leukemia (CML). No factor was found to influence either relapse or acute grades III to IV GVHD. The effect of donor type was nonsignificant for all criteria. Conclusion In patients with standard-risk malignancy, transplantation from unrelated HLA-allellically matched donors led to outcomes similar to those from HLA-identical sibling donors.

Cord blood transplantation is used to treat patients with malignant and nonmalignant hematopoietic diseases. This study assessed the feasibility of collecting cord blood for eventual transplantation to a sibling with such a disease.We studied the records of 47 infants from whom cord blood was collected for siblings from 1993 through 1999.During the study, cord blood was collected for 47 potential recipients: 37 (80.4%) with malignant disease and 9 (19.6%) with nonmalignant disease. Delivery was induced before 39 weeks of gestation. The mean volume collected was 107+/-39 mL and the number of nucleated cells was 11.52 x 10(8). Problems making collection difficult included: impossibility of collecting cord blood because of spontaneous delivery (n=1), the cytomegalovirus-positive serologic status of donor (n=7), and an inadequate number of nucleated cells (n=16). Weekday collection was possible for 60% of the donors. To date, only 7 of these cord blood collections have been used for stem cell transplantations.This retrospective study demonstrates the practical difficulties in collecting cord blood for transplantation to siblings, difficulties that may decrease the likelihood of success.

Contains fulltext : 50336.pdf (Publisher’s version ) (Closed access) In this multicenter retrospective study, the outcomes of 836 patients with myelodysplastic syndrome (MDS) who underwent transplantation with a human leukocyte antigen (HLA)-identical sibling donor were analyzed according to 2 types of conditioning: reduced-intensity conditioning (RIC) in 215 patients, and standard myeloablative (or high-dose) conditioning (SMC) in 621 patients. In multivariate analysis, the 3-year relapse rate was significantly increased after RIC (hazard ratio [HR], 1.64; 95% confidence interval [95% CI], 1.2-2.2; P = .001), but the 3-year nonrelapse mortality (NRM) rate was decreased in the RIC group (HR, 0.61; 95% CI, 0.41-0.91; P = .015). The 3-year probabilities of progression-free and overall survivals were similar in both groups (39% after SMC vs 33% in RIC; multivariate P = .9; and 45% vs 41%, respectively; P = .8). In conclusion, the lower 3-year NRM after RIC is encouraging, since these patients were older (age > 50 years in 73% RIC vs 28% in SMC, P < .001) and had more adverse pretransplantation variables. However, based on the higher risk of relapse, patients with no contraindications for SMC should not receive RIC outside of prospective randomized trials, which are needed to establish the position of RIC-based transplantation in the treatment of patients with MDS.

Background The use of monoclonal antibodies against interleukin-2 receptor (IL-2R)-alpha chains could be an effective treatment of acute graft-versus-host disease (GvHD). Experimental model and clinical studies have reported various results. Methods Inolimomab is a murine anti-IL-2R. Eighty-five patients were evaluated retrospectively for the safety and efficacy of inolimomab given for the treatment of steroid-resistant acute GvHD (aGvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Diseases were immune deficiency, hematological malignancies, or solid tumors. Seventy-six percent of the patients received a myeloablative regimen. The source of HSCT was bone marrow for 45 patients, peripheral blood for 36 patients, and cord blood for 4 patients. Donors were 49 siblings and 36 unrelated. Acute GvHD was diagnosed within a median of 28 days after transplantation (grade II, 26 patients; grade III, 26 patients; grade IV, 33 patients). Inolimomab was administered in the event of steroid-resistant aGvHD with a median dose of 0.468 mg per kg (median period of treatment: 18 days). Results Twenty-five complete responses and 29 partial responses (total response rate: 63%) were observed with no side effects. There was no correlation between aGvHD grading and quality of response. Better responses were observed in cutaneous aGvHD. The overall survival probability was 26% (median follow-up: 20 months). Fifty-seven percent of patients died of toxicity related mortality, mostly aGvHD. Response to inolimomab seemed sustained (11% relapse in responders). Conclusion Inolimomab is well-tolerated and effective for severe steroid-resistant aGvHD. The optimum regimen remains to be defined.

Background The purpose of this study was to evaluate the impact of the global diagnostic approach on the outcome of patients suspected of having acute (a) gastrointestinal (GI) graft-versus-host disease (GVHD). Methods Ten consecutive patients with suspected aGI-GVHD were prospectively explored with an exhaustive approach including video-capsule endoscopy (VCE). Images observed with VCE were compared with results obtained with other GI investigations including duodenal biopsies. RESULTS.: Five patients had a normal VCE examination: four were successfully treated symptomatically, but one died as a result of toxoplasmosis. VCE disclosed aGI-GVHD lesions in all five remaining patients, and two of the five were considered normal by upper GI endoscopy. All of these patients experienced improvement in their GI symptoms within 2 weeks of adjustments to their immunosuppressive treatment. Conclusions This approach has enhanced the authors' ability to adapt immunosuppressive treatments in patients suffering from suspected aGI-GVHD. Further investigation of the apparently high negative predictive value of VCE will be of great interest, particularly with a view to avoiding unnecessary immunosuppressive treatment.

We evaluated the effect of individual and collective factors on the outcome of allogeneic haematopoietic stem cell transplantation (HSCT) at 35 French centres. Individual factors included patient and transplantation characteristics. Collective factors were related to the period and centre in which HSCT was performed. Two centre factors were studied: centre experience (ie number of HSCT performed during the study period) and the type of centre (paediatric or adult). All patients receiving a first allogeneic HSCT in France between 1st January 1993 and 31st December 1997 were included in the study. The follow-up period ended on 31st December 1997. The final sample included 2756 subjects. We analysed overall survival (OS) and transplant-related mortality (TRM). Prognostic factors were identified by univariate and multivariate analysis, using Cox models. We found that centre experience had no significant effect on outcome. However, survival rates, whether determined on the basis of OS or TRM, were significantly higher in paediatric centres than in adult centres. Residual heterogeneity was found between adult centres. Survival rates were significantly higher for HSCT performed after 1st January 1996 than for those performed before this date.

Various transplantation strategies have been designed to improve the poor prognosis of adult (ages 15 to 60 years) acute lymphoblastic leukemia (ALL). The GOELAL02 trial evaluated the impact of early allogeneic bone marrow transplantation (alloBMT) or delayed unpurged autologous stem cell transplantation (ASCT) for patients who had no human leukocyte antigen (HLA)-matched sibling donor or who were older than 50 years. Inclusion criteria included at least one of the following: age older than 35 years; non-T-ALL; leukocytosis greater than 30 x 10(9)/L; t(9;22), t(4;11), or t(1; 19); or failure to achieve complete remission (CR) after one induction course. Among 198 patients, the median age was 33 years. The CR rate was 80% with vincristine, idarubicine, L-asparaginase, and randomized intravenous injection or oral steroids (P = nonsignificant [ns]). AlloBMT was performed after 2 consolidation courses while ASCT was delayed after 1 additional reinduction. Intensified conditioning regimen before transplantation included etoposide, cyclophosphamide, and total body irradiation (TBI). Median follow-up was 5.1 years. The median overall survival (OS) was 29 months, with a 6-year OS of 41%. On an intent-to-treat analysis for patients younger than 50 years, alloBMT significantly improved the 6-year OS (75% versus 40% after ASCT; P = .0027). Randomized interferon-alpha maintenance had no effect on relapse or survival after ASCT. In conclusion, the outcome of adult ALL is better after early alloBMT than after delayed ASCT.

Purpose Granulocyte colony-stimulating factor (G-CSF) is given after bone marrow transplantation (BMT) to shorten the neutropenic phase. Its effects have not been evaluated in a large patient population. Patients and Methods We studied 1,789 patients with acute leukemia receiving BMT and 434 patients receiving peripheral-blood stem cells (PBSCs) from HLA-identical siblings from 1992 to 2002 and reported the findings to the European Group for Blood and Marrow Transplantation. Among the BMT and PBSC patients, 501 (28%) and 175 (40%), respectively, were treated with G-CSF during the first 14 days after the transplantation. The outcome variables were entered into a Cox proportional hazards model. Results BMT and PBSC patients treated with G-CSF had a faster engraftment of absolute neutrophils greater than 0.5 × 109/L (P < .01), but platelet engraftment ( > 50 × 109/L) was slower (P < .001). In the BMT patients, acute graft-versus-host disease (GVHD) grades II to IV was 50% ± 5% (± 95% CI) in the G-CSF group versus 39% ± 3% in the controls (relative risk [RR], 1.33; P = .007, in the multivariate analysis). The incidence of chronic GVHD was also increased (RR, 1.29; P = .03). G-CSF was associated with an increase in transplantation-related mortality (TRM; RR, 1.73; P = .00016) and had no effect on relapse but reduced survival (RR, 0.59; P < .0001) and leukemia-free survival rates (LFS; RR, 0.64; P = .0003). No such effects of G-CSF were seen in patients receiving PBSC. Conclusion After BMT, platelet engraftment was delayed, and GVHD and TRM were increased. Survival and LFS were reduced. This suggests that G-CSF should not be given shortly after BMT.

PURPOSE: Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. PATIENTS AND METHODS: One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. RESULTS: Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade ≥ 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. CONCLUSION: Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.

During a 13-year period, 5200 autografts, 1039 HLA-identical sibling transplants without acute or chronic graft-vs.-host disease (GVHD) and 67 twins were reported to the European Group for Blood and Marrow Transplantation EBMT. Follow-up time was a median of 32 months. Diagnoses were acute myeloid leukaemia (AML, 4521) and acute lymphoblastic leukaemia (ALL, 1785) in first complete remission. The probability of relapse at 5 years was 51 +/- 1% in the autografts, 45 +/- 8% in the twins and 34 +/- 2% among the HLA-identical siblings (auto vs. sibs, P < 0.0001). In multivariate analyses, the following factors were significantly associated with an increased risk of relapse: ALL vs. AML M3 [relapse rate (RR) 2.29, P < 0.0001], AML non-M3 vs. AML M3 (RR 1.8, P < 0.0001), autograft vs. sibling transplant (RR 1.76, P < 0.0001), interval diagnosis to transplantation < 261 d (RR 1.45, P < 0.001) and other conditioning vs. total body irradiation (RR 1.16, P = 0.001). Transplant-related mortality was the same in the three groups at approximately 10% at 2 years. Five-year leukaemia-free survival was 42 +/- 1% in the autografts, 44 +/- 8% in the twins and 58 +/- 2% among the siblings (auto vs. sibs, P < 0.0001). The factors significant for relapse were also significant in multivariate analyses for leukaemia-free survival. In addition, children had a significantly better leukaemia-free survival than adults (RR 0.82, P < 0.0001). Recipients of bone marrow from HLA-identical siblings without GVHD had a lower risk of relapse and a better leukaemia-free survival than recipients of autografts. This may be as a result of a graft-vs.-leukaemia effect in the absence of GVHD.