Related and unrelated nonmyeloablative hematopoietic stem cell transplantation for malignant diseases

Patients with advanced hematological malignancies ineligible for conventional myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to advanced age or medical contraindications were enrolled in multi-center study to investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total body irradi ation (TBI)-based regimen. A total of 192 patients (median age 55) were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts, and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated donor (URD) HSCT (PBSC graft, n = 48; marrow graft, n = 15). Diagnoses included multiple myeloma (n = 61), myelodysplastic syndrome (n = 55), chronic myeloid leukemia (n = 31), non-Hodgkin lymphoma (n = 31), acute myeloid leukemia (n = 28), chronic lymphocytic leukemia (n = 24), Hodgkin Disease (n = 14). The conditioning regimen was fludarabine 30 mg/m2/d x 3 days and 2 Gy TBI. Ninety-five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting immunosuppression was combined mycophenolate mofetil an cyclosporine. Transplants were well tolerated with a median of 0 days of hospitalization in the first 60 days for eligible patients. For related HSCT recipients, median follow-up was 289 (100-1,188) days. Nonfatal graft rejection occurred in 6.8%. Of those with sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33% grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%. Overall, 59% (114/192) of patients were alive. The relapse/disease progression mortality was 18%, and non-relapse mortality was 22%. The projecte 2-year survival and progression-free survival were 50% and 40%. For the URD HSCT recipients, median follow-up was 190 (100-468) days. Graft rejection occurred in 27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic GVHD requiring therapy occurred in 50% of patients. Of the 63 URD HSCT patients, 54% were alive, 37% in CR, 3% PR, and 14% with disease progression or relapse. Related and unrelated nonmyeloablative HSCT is feasible and potentially curative in patients with advanced hematological malignancies who have no other treatment options.     

Related and unrelated nonmyeloablative hematopoietic stem cell transplantation for malignant diseases

Patients with advanced hematological malignancies ineligible for conventional myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) due to advanced age or medical contraindications were enrolled in a multi-center study to investigate the safety and efficacy of nonmyeloablative HSCT using a 2 Gy total body irradiation (TBI)-based regimen. A total of 192 patients (median age 55) were treated with HLA-matched sibling peripheral blood stem cell (PBSC) grafts, and 63 patients (median age 53) received a 10 of 10 HLA-antigen matched unrelated donor (URD) HSCT (PBSC graft, n=48; marrow graft, n=15). Diagnoses included multiple myeloma (n=61), myelodysplastic syndrome (n=55), chronic myeloid leukemia (n=31), non-Hodgkin lymphoma (n=31), acute myeloid leukemia (n=28), chronic lymphocytic leukemia (n=24), Hodgkin Disease (n=14). The conditioning regimen was fludarabine 30 mg/m²/d × 3 days and 2 Gy TBI. Ninety-five related HSCT patients received 2 Gy TBI without fludarabine. Postgrafting immunosuppression was combined mycophenolate mofetil and cyclosporine. Transplants were well tolerated with a median of 0 days of hospitalization in the first 60 days for eligible patients. For related HSCT recipients, median follow-up was 289 (100–1188) days. Nonfatal graft rejection occurred in 6.8%. Of those with sustained engraftment, graft-versus-host disease (GVHD) occurred in 49% (33% grade II, 11% grade III, 5% grade IV). Day-100 non-relapse mortality was 6%. Overall, 59% (114/192) of patients were alive. The relapse/disease progression mortality was 18%, and non-relapse mortality was 22%. The projected 2-year survival and progression-free survival were 50% and 40%. For the URD HSCT recipients, median follow-up was 190 (100–468) days. Graft rejection occurred in 27% (17/63) of patients, mostly in recipients of marrow grafts (9/15). Acute GVHD occurred in 63% (50% grade II, 13% grade III) of 46 engrafted patients. Chronic GVHD requiring therapy occurred in 50% of patients. Of the 63 URD HSCT patients, 54% were alive, 37% in CR, 3% PR, and 14% with disease progression or relapse. Related and unrelated nonmyeloablative HSCT is feasible and potentially curative in patients with advanced hematological malignancies who have no other treatment options.     

Long-term results of allogeneic hematopoietic stem cell transplantation after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin

Reduced-intensity conditioning (RIC) is widely used for allogeneic stem cell transplantation (SCT). Here we present our long-term experience with RIC regimen consisting of fludarabine (30 mg/m2/day on days -10 to -5), busulfan (4mg/kg/day on days -6 and -5) and antithymocyte globulin (ATG Fresenius, 10 mg/kg/day on days -4 to -1) (Flu-Bu-ATG) in a cohort of 71 patients with various hematological malignancies including chronic myeloid leukemia (24 patients), acute myeloid leukemia (19 patients), lymphoma (20 patients), multiple myeloma (3 patients), myelodysplastic syndrome (3 patients), and myelofibrosis (2 patients). The median age was 50 years. The overall response rate was 87%, including 83% CR and 4% PR. The incidence of acute and chronic GVHD was 35% and 52% and the cumulative incidence of non-relapse mortality at 1 year and 4 years was 8% and 14%. With the median follow-up of 55.0 months, the 2- and 4-year event-free survival (EFS) was 49.0% and 40.3%, and the overall survival (OS) was 73.2% and 62.6%, respectively. Gender, age at SCT, type of donor, disease status at SCT, previous autologous transplantation, and complete chimerism by day +100 did not significantly influence EFS and OS. In a multivariate analysis, no presence of chronic GVHD (p=0.029, HR: 2.5),and diagnosis other than CML (p=0.018, HR: 4.6), and CD34+ dose < 5x106/kg (p=0.010, HR: 2.8) were significant predictors of poor OS. Flu-Bu-ATG protocol is a RIC regimen that combines effective disease control with low non-relapse mortality and acceptable toxicity profile. Keywords: reduced-intensity conditioning, fludarabine, busulfan, antithymocyte globulin.     

Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia

We report the feasibility and efficacy of a fludarabine/busulfan-based dose-reduced conditioning regimen followed by stem cell transplantation from related ( n=19) or unrelated HLA-matched donors ( n=18) in 37 patients with myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine (120-180 mg/m(2)), busulfan (8 mg/kg p.o. or 6.4 mg/kg i.v.), and antithymocyte globulin ( n=25). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine ( n=36) and a short course of methotrexate ( n=29) or mycophenolate mofetil ( n=3). The median age of the patients was 55 years (range: 23-72). The reasons to perform a dose-reduced conditioning were reduced performance status ( n=14), age ( n=12), prior autologous ( n=5) or allogeneic ( n=1) transplantation, or prior/active fungal infection ( n=5). Diagnoses at transplantation were refractory anemia (RA) ( n=8), refractory anemia with excess of blasts (RAEB) ( n=6), RAEB in transformation (RAEB-T) ( n=13), chronic myelomonocytic leukemia (CMML) ( n=3), and sAML ( n=7). Stem cell sources were peripheral blood stem cells (PBSC) ( n=29) or bone marrow ( n=8). One patient received a T-cell-depleted peripheral stem cell graft. Two primary graft failures were observed (6%). Engraftment of leukocytes (>1.0x10(9)/l) and platelets (>20x10(9)/l) was seen after a median of 14 days. Acute GVHD grade II-IV was seen in 37%, while severe grade III/IV GVHD was observed in six patients (17%). Chronic GVHD was seen in 13 patients (48%). There were ten deaths (27%) due to treatment (TRM). The probability of TRM was higher in patients with unrelated donors (45 vs 12%, p=0.03) and in patients with poor cytogenetics in comparison to those with a low or intermediate karyotype (75 vs 20%, p=0.009). During follow-up 12 patients relapsed (32%). Patients without chronic GVHD had a significantly higher probability of relapse compared to those with chronic GVHD (70 vs 15%, p=0.02). After a median follow-up of 20 months, the 3-year estimated disease-free survival (DFS) is 38% [95% confidence interval (CI): 21-55%] and the overall survival (OS) is 39% (95% CI: 22-56%). The OS and DFS after related and unrelated transplantations was 45% (95% CI: 19-71%) vs 31% (95% CI: 9-53%) (n.s.) and 51% (95% CI: 29-73%) vs 25% (95% CI: 4-47%) (n.s.), respectively. We conclude that dose-reduced conditioning followed by allogeneic stem cell transplantation from related or unrelated donors is an effective treatment approach in patients with MDS/sAML and might cure a substantial number of patients who are not eligible for a standard allogeneic transplantation.     

Standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia.

BACKGROUND AND OBJECTIVES: To analyze the results of standard versus alternative myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for high-risk acute leukemia. DESIGN AND METHODS: From October 1986 to February 2000, 104 consecutive patients (male: n = 63; median age: 21, range 1.3-44.2 years) with high-risk acute leukemia underwent a non-T-cell depleted graft from an HLA-identical sibling following a standard or alternative myeloablative conditioning regimen. Sixty patients were affected by acute lymphoblastic leukemia (ALL) and 44 by acute myeloid leukemia (AML); the phase at transplant was >= 2nd complete remission (CR) in 76, untreated 1st relapse with < 20% blasts in 11, refractory leukemia or overt resistant relapse in 17. Pre-transplant regimens consisting of either 12 Gy fractionated total body irradiation (TBI) or 16 mg/kg busulphan (BU) combined with cyclophosphamide (CY) were defined standard (n = 38), whereas all other myeloablative regimens (TBI plus 60 mg/kg etoposide and three-drug combinations) were considered alternative (n = 66). RESULTS: No significant differences in terms of baseline characteristics, incidence and severity of either acute or chronic graft-versus-host disease (GVHD) were observed between the two groups, but a significantly higher proportion of patients prepared with an alternative regimen were not evaluable for chronic GVHD (36% vs 16%) (p = 0.026). Sixty-six patients died, 38 of relapse, 26 of transplant-related mortality (TRM) and 2 of other causes. Thirty-eight patients are still alive with a follow-up ranging from 0.7 to 13.8 years (median, 7.1 years); only 1 of 39 patients who relapsed after transplant is alive in CR at 5.7 years from relapse. At the median follow-up, the actuarial probabilities of overall survival, relapse and TRM for patients conditioned with standard and alternative regimens are respectively 52% vs 25% (95% CI, 36-68% vs 13-37%; p = 0.0163), 34% vs 58% (95% CI, 18-51% vs 43-73%; p = 0.0377) and 25% vs 32% (95% CI, 9-40% vs 19-44%; p = ns). After adjustment for diagnosis, age, period, leukemia phase, duration of 1st CR, GVHD prophylaxis and donor-recipient sex combination, the multivariate analysis showed that alternative regimens are associated with a significantly worse survival (hazard ratio 2.31; p = 0.0071) and relapse rate (hazard ratio 2.75; p = 0.0187). INTERPRETATION AND CONCLUSIONS: From this retrospective analysis we can conclude that the alternative myeloablative conditioning regimens we used did not improve the outcome of patients transplanted for high-risk acute leukemia.     

Fludarabine/i.v. BU conditioning regimen: myeloablative, reduced intensity or both?

In this study, we utilized a conditioning regimen with fludarabine and myeloablative dose i.v. BU (12.8 mg/kg) (FluBU) in 36 adult patients (median age: 44 years, range: 18-61) with myeloid or lymphoid malignancies at standard risk (n=10) or high risk of relapse (n=26), who received an allogeneic hematopoietic SCT (HSCT) from HLA-matched related (n=16) or unrelated (n=20) donors. The source of hematopoietic stem cells was peripheral blood in 28 and marrow in 8 cases. Rabbit-antithymocyte globulin at 7 mg/kg was utilized in 21 patients. Acute GVHD grade II-IV was observed in 19% of the patients (grade III-IV in 14% of patients) and chronic GVHD in 11 of 30 evaluable patients (37%). At median follow-up of 737 days (range: 152-1,737) for alive patients, overall survival rates in standard- and high-risk patients were 80 and 35%, respectively, and event-free survival rates were 70 and 31%, respectively. TRM was 10% in standard-risk and 19% in high-risk patients. Post transplant relapse was observed in 20% standard-risk and in 46% high-risk patients. FluBU conditioning regimen is associated with a limited hematologic and extrahematologic toxicity and with an antitumor activity comparable to other standard myeloablative regimens.     

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2

A regimen of busulfan and cyclophosphamide (BuCy2) is regarded as the standard myeloablative regimen for SCT. This study evaluated the hypothesis that fludarabine can replace cyclophosphamide for myeloablative allogeneic SCT. Ninety-five patients underwent allogeneic SCT from HLA-identical donors, following BuCy2 (n=55) or busulfan+fludarabine (BF, n=40). The efficacy of fludarabine compared to cyclophosphamide was retrospectively evaluated. The BF group exhibited a shorter duration until engraftment (P=0.001), lower incidence of acute and chronic GVHD (P<0.001 and P=0.003, respectively), and non-relapse mortality (NRM) (P=0.039). Furthermore, the event-free survival and overall survival were significantly higher for the BF group compared to the BuCy2 group (P=0.004 and 0.002, respectively). After adjusting for age, the risk status of disease, GVHD prophylaxis and donor type, the BF regimen was found to be an independent favorable risk factor for event-free survival (hazard ratio (HR), 0.181; 95% confidence interval, 0.045-0.720; P=0.016) and overall survival (HR, 0.168; 0.035-0.807; P=0.026). The replacement of cyclophosphamide with fludarabine for myeloablative conditioning seems to be more effective in terms of short-term NRM, and GVHD compared to BuCy2 regimen in allogeneic transplantation.     

Cyclosporine and mycophenolate mofetil prophylaxis with fludarabine and melphalan conditioning for unrelated donor transplantation: a prospective study of 22 patients with hematologic malignancies

In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.     

Hematopoietic stem cell transplantation for childhood myeloid malignancies after high-dose thiotepa, busulfan and cyclophosphamide

Seventeen children with advanced myeloid malignancies (induction failure, relapse, myelodysplasia, secondary AML, or CR >1) received thiotepa 750 mg/m2 i.v., busulfan 12 mg/kg or 640 mg/m2 p.o., and cyclophosphamide 120 mg/kg i.v. as a preparative regimen for allogeneic or autologous hematopoietic stem cell (HSC) transplantation. Of the 15 allogeneic transplants, eight were from matched siblings, one was from a mismatched sibling, and six were from unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Regimen-related toxicity was common but tolerable, affecting mainly the skin and gastrointestinal tract. Three patients died early and were not evaluable for engraftment; engraftment occurred in the remaining patients. Nine patients with active disease at the time of transplant were evaluable for response; all achieved remission. With a median follow-up of 40 months (range, 10-71 months), nine patients are alive and disease-free. The 3-year actuarial event-free survival was 51% (95% confidence interval (CI) 27-76%). Seven patients died of transplant-related complications: infection (n = 4), chronic GVHD (n = 1), veno-occlusive disease, VOD, (n= 1) and pulmonary alveolar hemorrhage (n = 1). Only one patient had leukemia relapse and died. We conclude that the use of high-dose thiotepa, busulfan and cyclophosphamide is an effective conditioning regimen for childhood myeloid malignancies and may be tested in patients with less advanced disease (eg CR1).     

Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation

The graft-versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively (P < 0.001), and was 39% vs. 29%, respectively (P = 0.043), for grades 2-4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2.16 [95% confidence interval (CI): 1.52-3.07], P < 0.0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively (P = 0.084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3.3 (95% CI: 1.42-8.08), P = 0.0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0.007). Duration of immunosuppression was shorter among allo-RIC patients (35.5% vs. 68.8% required systemic immunosuppression 36 months after transplant, P = 0.028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning.     

A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.     

Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long-term efficacy in chronic myeloid leukaemia (CML), although high non-relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 × 14 g/m² and fludarabine 5 × 30 mg/m², in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92·5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non-haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2·5%). The incidence of grade II–IV acute graft-versus-host disease (GVHD) was 22·5% and extensive chronic GVHD, 14%. The 2-year probability of overall survival, leukaemia-free survival and NRM was 85%, 82·5% and 15% respectively. At 1 year post-transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low-toxicity regimen with high anti-leukaemic potential that seems feasible in CML patients referred for alloHSCT.     

Cyclosporine A and mycophenolate mofetil vs cyclosporine A and methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings

The combination of Cyclosporin A (CSA) and Methotrexate (MTX) is considered to be the standard regimen for the prevention of graft-versus-host disease (GVHD) after stem cell transplantation (SCT) from HLA-identical siblings. Mycophenolate Mofetil (MMF) has been widely used for GVHD prophylaxis after nonmyeloablative SCT, but experience following myeloablative therapy is still limited. We retrospectively compared CSA/MTX and CSA/MMF in 93 patients (median age 35 years, range 17-59 years, male subjects 48, female subjects 45) with acute myeloid leukemia (n=33), myelodysplastic syndrome (MDS) (n=3), acute lymphoblastic leukemia (ALL) (n=20) or chronic myeloid leukemia (n=37) who received CSA/MMF (n=26) or CSA/MTX (n=67) as GVHD prophylaxis following high-dose therapy and allogeneic SCT from HLA-identical siblings. No statistically significant differences were found in overall survival, relapse rate, treatment-related mortality and acute or chronic GVHD. Time to myeloid recovery was significantly shorter in patients who received CSA/MMF. We conclude that the combination of CSA/MMF appears equivalent to CSA/MTX for GVHD prophylaxis in patients receiving conventional-intensity SCT from HLA-identical siblings.     

In vivo T cell depletion with pretransplant anti-thymocyte globulin reduces graft-versus-host disease without increasing relapse in good risk myeloid leukemia patients after stem cell transplantation from matched related donors

One-hundred and two patients with good risk myeloid leukemia (CML first chronic phase or AML first CR) were transplanted from HLA-related donors after conditioning with (n = 45) or without anti-thymocyte globulin (ATG) (n = 57). One graft failure was observed in the non-ATG and none in the ATG group. The median time to leukocyte engraftment (> 1 x 10(9)/l) was 16 (range 12-33) in the ATG group and 17 days (range 11-29) in the non-ATG group (NS) and for platelet engraftment (> 20 x 10(9)/l) 24 and 19 days (P = 0.002), respectively. Acute GVHD grade II-IV was observed in 47% of the non-ATG and in 20% of the ATG group (P = 0.004). Grade III/IV GVHD occurred in 7% of the ATG and in 32% of the non-ATG group (P = 0.002). Chronic GVHD was seen in 36% and 67% (P = 0.005), respectively. After a median follow-up of 48 months (range 2-128), the 5-year estimated OS is 66% (95% KI: 51-81%) for the ATG group and 59% (95% KI: 46-72%) for the non-ATG group (NS). The 5-year estimated DFS is 64% (95% KI: 50-78%) for ATG and 55% (95% KI: 43-67%) for the non-ATG regimen (NS). The 5-year probability of relapse was 5% in the ATG and 15% in the non-ATG group (NS). ATG as part of the conditioning regimen leads to a significant reduction in GVHD without increase of relapse in patients with myeloid leukemia after stem cell transplantation from HLA-related donors.     

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases

There is a significant amount of morbidity and mortality following myeloablative umbilical cord blood transplantation (UCBT). Reduced intensity (RI) conditioning offers an alternative to myeloablative conditioning before UCBT. We investigated RI-UCBT in 21 children and adolescents with malignant (n=14), and non-malignant diseases (n=7). RI conditioning consisted of fludarabine (150-180 mg/m2) with either busulfan (< or = 8 mg/kg)+rabbit antithymocyte globulin (R-ATG; n=16) or cyclophosphamide+R-ATG+/-etoposide (n=5). Human leukocyte antigen match: 4/6 (n=13), 5/6 (n=5) and 6/6 (n=3). The median total nucleated cell and CD34+ cell dose per kilogram were 3.58 x 10(7) and 2.54 x 10(5), respectively. The median time for neutrophil and platelet engraftment was 17.5 and 52 days, respectively. There were six primary graft failures (chronic myelogenous leukemia (CML), beta-thalassemia, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS)). The probability of developing grade II to grade IV acute graft-versus-host disease (GVHD) and chronic GVHD was 28.6 and 16.7%, respectively. Incidence of transplant-related mortality (TRM) was 14%. The 5 years overall survival (OS) in all patients was 59.8%. The 5 years OS for patients with average versus poor-risk malignancy was 77.8 versus 22.2% (P=0.03). RI-UCBT may result in graft failure in specific high-risk chemo-na?ve patients (CML, beta-thalassemia, HLH and MDS), but in more heavily pretreated pediatric and adolescent recipients results in rapid engraftment and may be associated with decreased severe GVHD and TRM.     

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18‐50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty‐eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow‐up of 48 months, 2‐year overall survival was 39%, 95% confidence interval (CI) (24‐53) in the myeloablative group versus 33%, 95% CI (21‐45) in the sequential groups (P = .39), and 2‐year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II‐IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21‐0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.     

Allogeneic hematopoietic stem cell transplantation after rituximab-containing myeloablative preparative regimen for acute lymphoblastic leukemia

We explored the safety and efficacy of rituximab administered in combination with the standard transplant conditioning regimen of cyclophosphamide (Cy) 120 mg/kg and total body irradiation (TBI) 12 Gy for adult patients with acute lymphoblastic leukemia (ALL). Patients were eligible if their disease expressed CD20. Rituximab was administered at 375 mg/m2 weekly for four doses beginning on day -7 of the conditioning regimen. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-five patients undergoing matched sibling (n = 23) or unrelated donor (n = 12) transplantation were studied, with a median age of 30 years (range 15-55 years). At 2 years, progression-free survival, treatment-related mortality, and overall survival were 30, 24, and 47%, respectively. There was no delay in engraftment or increased incidence of infection. The cumulative incidence of grade II-IV acute GVHD was 17%, and limited and extensive chronic GVHD was 43% at 2 years. The addition of rituximab to the standard Cy/TBI transplant conditioning regimen in ALL was safe and well tolerated, and there was a suggestion of decreased incidence of acute GVHD when compared to historically reported GVHD rates for this group of patients.     

Cord blood transplantation for acute myelogenous leukemia using a conditioning regimen consisting of granulocyte colony-stimulating factor-combined high-dose cytarabine, fludarabine, and total body irradiation

The cytotoxic effect of cytarabine (Ara-C) on myeloid leukemic cells is enhanced by concomitant use of granulocyte colony-stimulating factor (G-CSF) in vitro. The feasibility of a conditioning regimen consisting of G-CSF-combined 24 g/m2 Ara-C, 90 mg/m2 fludarabine, and 12 Gy total body irradiation was studied for five patients with acute myelogenous leukemia in cord blood transplantation (CBT). Graft vs. host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. After the conditioning regimen, 2.48 x 10(7)/kg (2.28-3.53) of cord blood nucleated cells was infused. Neutrophil counts consistently >0.5 x 10(9)/L was achieved 24 d (22-32) after CBT. Grade I stomatitis and gastrointestinal toxicities occurred in all patients. Grades I and II acute GVHD occurred in one and four patients, respectively, which resolved without steroid therapy. Sepsis and aspergillosis occurred in two and one patients, respectively. All patients were alive without leukemia relapse at a follow up of 15 months (12-43) after CBT. This conditioning regimen could avoid the toxicities of high-dose cyclophosphamide but might enhance the cytotoxic effect of Ara-C. Large-scale studies will be needed to determine the efficacy and safety of the conditioning regimen in CBT.     

Idarubicin-intensified BUCY2 regimens may lower relapse rate and improve survival in patients undergoing allo-SCT for high-risk hematological malignancies: a retrospective analysis

We conducted a retrospective study to evaluate the outcome of 94 consecutive patients with high-risk hematological malignancies who received allo-PBSCT, following idarubicin (IDA)-intensified BUCY2 (IDA-BUCY2) myeloablative conditioning regimens (n=53) and BUCY2 conditioning regimens (n=41). IDA 15?mg/m(2) once daily was administered by continuous infusion on days -11 to -9, followed by BU, 3.2?mg/kg in divided doses daily, on days -6 to -4, and i.v. injection of CY, 1.8?g/m(2) once daily on days -3 to -2 in the IDA-BUCY2 group. The relapse rate in patients in the IDA-BUCY2 and BUCY2-conditioning regimens group was 18.9 and 39%, respectively (P=0.030). There was no significant difference in terms of TRM. The cumulative probabilities of OS and disease-free survival at 2 years for patients conditioned with the IDA-BUCY2 and BUCY2 regimens were 65.3% vs 46.8% (P=0.038), and 63.5% vs 43.4% (P=0.025), respectively. Multivariate analysis showed that IDA-BUCY2 regimens and limited chronic GVHD were the only two factors resulting in improved survival and reduced relapse rate. This retrospective study suggests that IDA-intensified BUCY2 may be substituted for BUCY2 as conditioning regimen for patients with high-risk hematological malignancies.     

Association between pretransplant Thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors

A matched cohort study was designed to test the efficacy of polyclonal rabbit antiserum specific for human T cells (Thymoglobulin), administered in vivo on days 1-5 (2 mg/kg/day) before T cell-replete unrelated donor marrow transplantation. Thymoglobulin was given to 52 leukemic patients at Huddinge Hospital. Control patients matched for diagnosis, disease stage, age and treated with a similar regimen, apart from the omission of Thymoglobulin, were selected in Seattle during the same period (n = 104). All received conditioning with cyclophosphamide and TBI. In the study group all patients received 10 Gy single dose TBI, while the controls were given 12-14.4 Gy fractionated TBI. GVHD prophylaxis was cyclosporine and methotrexate. Patients were treated for grade I acute GVHD in the study group, and for grade II GVHD in the control group. Multivariable analyses were adjusted for patient and donor age and CMV serology, HLA matching, donor gender and marrow cell dose. Non-relapse mortality was lower in the study patients (hazard ratio = 0.30, 95% CI 0.12-0.75, P value = 0.005). The 5-year cumulative incidence of non-relapse mortality was 19% in the study cohort, and 35% in the control cohort. Overall mortality was also lower in study patients (hazard ratio 0.51, 95% CI 0.27-0.97, P value = 0.03). No significant difference in the risk of relapse was seen (P = 0.63). This suggests that Thymoglobulin during conditioning may reduce non-relapse mortality after unrelated donor marrow transplantation.