Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan

Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60-3.04, P<0.0001 for grade II-IV acute GVHD; HR: 1.81, 95% CI: 1.32-2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23-2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.     

Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation.

We evaluated demographic characteristics and graft composition as risk factors for acute graft-versus-host disease (GVHD) in 160 adult recipients of HLA-identical allogeneic blood stem cell transplants. The patients received a median nucleated cell dose of 7.9 x 10(8)/kg and median C34(+) cell dose of 5.6 x 10(6)/kg. GVHD prophylaxis consisted of cyclosporine (CSA) and steroids, tacrolimus (FK506) and steroids, or FK506 and methotrexate. Grades 2 to 4 GVHD occurred in 31% (95% CI, 23% to 39%), and grades 3 to 4 GVHD in 14% (95% CI, 8% to 20%). In univariate analyses, GVHD prophylaxis with CSA and high CD34(+) cell doses were significant risk factors for grades 2 to 4 GVHD, but diagnosis, age, use of total body irradiation, donor sex, female donor for male recipient, donor parity, donor alloimmunization, viral serology, nucleated cell dose, CD3(+) cell dose, and CD56(+) cell dose did not alter the incidence of GVHD significantly. With a CD34(+) cell dose less than 8 x 10(6) CD34(+) cells/kg, the risk of grades 2 to 4 GVHD was significantly higher for those who received CSA (39%, 95% CI, 21% to 47%) in comparison with those on FK506 (18%, 95% CI, 10% to 26%) (P =.03), but GVHD prophylaxis regimen had less impact with a higher CD34(+) cell dose (overall grades 2 to 4 GVHD rate 52%, 95% CI, 37% to 67%). GVHD prophylaxis and CD34(+) cell dose are independent risk factors for acute GVHD after allogeneic blood stem cell transplantation.     

Early matched sibling hematopoietic cell transplantation for adult AML in first remission using an age-adapted strategy: long-term results of a prospective GOELAMS study

The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients.     

Allogeneic transplantation after reduced conditioning in high risk patients is complicated by a high incidence of acute and chronic graft-versus-host disease

Background and Objectives. We studied the toxicity and efficacy of reduced intensity conditioning followed by allogeneic stem cell transplantation in 50 patients over 50 years old or with relative contraindications against myeloablative regimens. Diagnoses were chronic myeloid leukemia (n=15), acute myeloid leukemia (n=9), myelodysplastic syndromes (n=9), lymphoma (n=11) and refractory solid tumors (n=6). Design and Methods. Donors were identical siblings (n=25), non-identical family members (n=6) and unrelated volunteers (n=19). Peripheral blood stem cells (n=36) or bone marrow (n=14) were transplanted. The conditioning regimen consisted of fludarabine 180 mg/m(2), busulphan 8 mg/kg and rabbit antithymocyte globulin 40 mg/kg (Fresenius). Graft-versus-host disease (GVHD) prophylaxis was carried out with cyclosporin A (CSA) alone (n=17) or in combination with methotrexate (n=18) or mycophenolate mofetil (n=15). Results. Neutrophil counts >0.5/nL and platelet counts > 20/nL were reached after 17 (range 0-66) and 19 days (range 0-111), respectively. Three graft failures occurred. Fever lasted for a median of 2 days (range 0-15). Six patients developed veno-occlusive disease of the liver. Acute GVHD grade II-IV occurred in 47% of the patients and chronic GVHD in 46%. The 1-year overall survival probability was 44% (95% CI: 30-58%). GVHD-related complications were a major cause of the probability of 1-year non-relapse mortality of 31% (95% CI: 16-46%). Interpretation and Conclusions. In conclusion, the regimen itself can be carried out safely in patients with relative contraindications against myeloablative conditioning. However, GVHD causes significant non-relapse mortality in high risk patients.     

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.     

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.     

Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia

Since the incidence of cytomegalovirus (CMV) infections after hematopoietic stem cell transplantation (HSCT) may depend on the intensity of the pretreatment, we studied the incidence of CMV infections after reduced-intensity compared to myeloablative conditioning. A total of 82 patients with matched related or unrelated donors were prospectively monitored for CMV infections after HSCT by CMV-PCR techniques, CMV-antigenemia and clinical observation. A total of 45 patients received reduced-intensity conditioning consisting of fludarabine, busulfan and ATG and 37 patients received myeloablative conditioning. Leukocyte engraftment occurred after a median of 15 vs 18 days (P=0.012) and platelet engraftment after 12 days vs 20 days (P=0.001), respectively. Acute graft-versus-host disease (GVHD) grade II-IV was observed in 58 vs 54% patients (P=0.737), respectively. The onset and peak values of CMV-antigenemia and DNAemia and the incidence of CMV infections did not differ statistically significantly between the two treatment groups. Multivariate analysis confirmed CMV seropositivity of the recipient (P=0.035), acute GVHD II-IV (P=0.001) but not the type of conditioning as significant risk factors for CMV-antigenemia. In conclusion, the kinetics of CMV-antigenemia and DNAemia and the incidence of CMV infections were not statistically different in patients who received HSCT after reduced-intensity conditioning with fludarabine, busulfan and ATG compared to myeloablative conditioning.     

Hyperacute GVHD: risk factors, outcomes, and clinical implications

Acute graft-versus-host disease (GVHD) is a major limiting factor in allogeneic hematopoietic stem cell transplantation (HSCT), and the timing of acute GVHD may affect patient outcomes. We evaluated the incidence, risk factors, clinical manifestations, and outcomes of hyperacute GVHD, defined as that occurring within 14 days after transplantation, among 809 consecutive HSCTs at the University of Texas M.D. Anderson Cancer Center. Of 265 patients with grade II-IV acute GVHD, 27% had biopsy-proven hyperacute GVHD. Skin involvement was significantly more common (88% versus 44%) and more severe (stage III-IV, 88% versus 66%) in the hyperacute group compared with acute GVHD diagnosed after day 14. On multivariate analysis, significant risk factors for hyperacute GVHD included a mismatched related or matched unrelated donor, a myeloablative conditioning regimen, more than 5 prior chemotherapy regimens, and donor-recipient sex mismatch. Hyperacute GVHD was associated with a significantly lower response rate to first-line therapy and a higher rate of nonrelapse mortality in patients with a mismatched related or matched unrelated donor graft. In conclusion, hyperacute GVHD accounts for a substantial proportion of grade II-IV acute GVHD after HSCT. Patients at high risk or with a diagnosis of hyperacute GVHD should be included in clinical studies.     

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.     

Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma

We investigated the efficacy and toxicity of the combination of busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL). Fifty-three patients with recurrent ( n=30), refractory ( n=20), or high-risk ( n=3) lymphoma were enrolled. The 10 patients with HD and 43 with NHL (median age: 46 years, range: 18-64) received busulfan (16 mg/kg), cyclophosphamide (120 mg/kg), and etoposide (30 or 45 mg/kg) followed by ASCT. A total of 50 patients (94%) were consolidated in complete ( n=25) or partial ( n=25) remission, whereas 3 patients had chemoresistant disease before Bu/Cy/VP-16. Thirty-five patients (66%) had received prior radiotherapy (RT) excluding total body irradiation (TBI) as part of the conditioning regimen. The main nonhematological toxicities (grade II-IV according to the Bearman score) in 52 evaluable patients were mucositis (79%) and hepatic toxicity (15%). Severe veno-occlusive disease (VOD) occurred in three patients (5.8%) including one treatment-related death caused by VOD. Overall, treatment-related mortality was 3.8%. After a median follow-up for surviving patients of 21 months (range: 6-118), 20 patients (38%) are in continuous complete remission, 8 patients (15%) are alive in relapse, and 25 patients (47%) died. Probabilities of relapse, event-free survival, and overall survival at 3 years were 63% [95% confidence interval (CI): 48-79%], 31% (95% CI: 17-46%), and 43% (95% CI: 27-59%), respectively. In conclusion, Bu/Cy/VP-16 is an effective and well-tolerated conditioning regimen in patients with HD and NHL. Both toxicity and outcome were not significantly different in patients treated with 30 mg/kg and 45 mg/kg etoposide, respectively. The observed long-term results are even comparable to those published for other established high-dose protocols, including TBI-based regimens. However, further investigations are necessary to evaluate the value of Bu/Cy/VP-16 as a high-dose protocol for malignant lymphoma, especially in patients who have already received extensive RT.     

Tacrolimus (FK506) and methotrexate as prophylaxis for acute graft-versus-host disease in pediatric allogeneic stem cell transplantation

Currently, limited data exist on the role of tacrolimus (FK506) in pediatric allogeneic marrow transplantation. Forty-one patients who received tacrolimus as prophylaxis were reviewed, with a median age of 9 years (range 0.2-16 years). Twenty-one patients underwent related donor transplants and 20 underwent unrelated donor transplants. All patients received tacrolimus beginning the day prior to transplant at a dose of 0.03 mg/kg/day by continuous i.v. infusion. When clinically possible, patients were switched to oral therapy in two divided doses, at four times the intravenous dose. Tacrolimus levels were monitored twice a week, and dosages adjusted to maintain serum levels 5-15 ng/ml. Common adverse effects included hypomagnesemia (98%), hypertension (49%), nephrotoxicity (34%), and tremors (32%). Less common side-effects (<10% cases) included seizures and hyperglycemia. The median time to ANC recovery (ANC >500 x 106/l) was 15 days. For the related donor group, the incidence of grade II-IV acute GVHD was 33%, and grade III-IV GVHD 19%. For the unrelated donor group, the incidence of grade II-IV acute GVHD was 55%, and grade III-IV GVHD 30%. Overall, tacrolimus therapy was well tolerated as prophylaxis for acute GVHD in pediatric patients undergoing allogeneic transplantation.     

High-dose weekly liposomal amphotericin B antifungal prophylaxis following reduced-intensity conditioning allogeneic stem cell transplantation

The use of high-dose corticosteroids for graft-versus-host disease (GVHD) treatment represents a major risk factor for long-term invasive fungal infections. The aim of this study was to investigate the safety and tolerance of weekly prophylactic administration of once-weekly high-dose (7.5 mg/kg) of liposomal amphotericin B (L-AmB) therapy in 21 adult patients receiving high-dose prednisone (2 mg/kg/day) for acute GVHD therapy after reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). Patients received a median of 4 (range, 1-8) infusions of L-AmB. Seven patients (33%; 95% confidence intervals (CI), 13-53%) discontinued taking the study drug owing to study drug-related adverse events, including elevated serum creatinine (>1.5 times from baseline values; n=5), hypotension and pain (n=1), and violent chest pain and arrhythmia (n=1). The overall frequency of infusion-related reactions was 29% (n=6; 95% CI, 10-48%), but these reactions were always transient and relieved by stopping the infusion. This safety data provide support for an efficacy study of this prophylaxis strategy, because this may help further improving the outcome of RIC or nonmyeloablative allo-SCT.     

Comparison of Myeloablative and Nonmyeloablative Hematopoietic Stem Cell Transplantation for Treatment of Chronic Myeloid Leukemia

This retrospective study compared outcomes for 81 chronic myeloid leukemia patients who underwent myeloablative or nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT). Sixty-five patients received myeloablative HSCT, and 16 patients received fludarabine (Fd), low-dose busulfan (Bu), and antithymocyte globulin (ATG) in nonmyeloablative HSCT. We determined overall survival (OS) and disease-free survival (DFS), as well as the occurrence of acute and chronic graft-versus-host disease (GVHD). The incidences of acute GVHD of grades II to IV were 14.0% and 18.7% for the myeloablative and nonmyeloablative groups, respectively. The incidence of chronic GVHD was significantly higher in the nonmyeloablative group (80% versus 66%). Five-year OS and DFS rates were significantly higher in nonmyeloablative group (70% for both), compared with 56% and 54%, respectively, for the myeloablative group. A univariate analysis, however, revealed a strong but statistically insignificant trend for enhanced overall OS and DFS in the nonmyeloablative group (P = .1 and .07, respectively). A multivariate analysis with the factors of treatment, age, sex, acute and chronic GVHD, and disease status at the time of transplantation revealed that both OS and DFS were significantly higher in the nonmyeloablative group than in the myeloablative group. These findings suggest that nonmyeloablative Fd/Bu/ATG treatment is at least not inferior (and quite probably superior) in terms of patient outcome compared with standard myeloablative therapy. Further larger-scale randomized clinical trials are warranted to clarify the efficacy of this treatment regimen.     

Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: differences in ATG dosage are key

Late-onset hemorrhagic cystitis (LOHC) is a common complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its cause remains obscure. More attention to risk factors for LOHC is needed. We retrospectively analyzed patients with advanced leukemia who had been treated with ATG-containing conditioning regimens to evaluate the influence of different doses of ATG on LOHC after haploidentical HSCT. Seventy-five patients undergoing haploidentical HSCT from January 2003 to February 2011 were evaluated. A total of 39 patients receiving transplantation before June 2008 were treated with high-dose ATG (10 mg/kg), whereas 36 patients received low-dose ATG (6 mg/kg) thereafter. LOHC occurred in 16.7 % of the patients with low-dose ATG, and in 38.5 % of the patients with high-dose ATG (P = 0.027). Univariate analysis showed high-dose ATG, male gender and cytomegalovirus reactivation to be significant risk factors for LOHC. However, only high-dose ATG (HR 2.96, 95 % CI 1.143–7.663, P = 0.025) and male gender (HR 4.033, 95 % CI 1.355–12.008, P = 0.012) were independent risk factors, as shown by multivariate analysis. In the setting of haploidentical HSCT, we concluded that LOHC is more prevalent in recipients of high-dose ATG and male patients. Future studies should focus on immune reconstitution and virus infection after haploidentical HSCT with 6 mg/kg or 10 mg/kg ATG.     

Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

We evaluated the effect of acute and chronic GVHD on relapse and survival after allogeneic hematopoietic SCT (HSCT) for multiple myeloma using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005, following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (aGVHD; grades I-IV) was 42% (95% confidence interval (CI), 35-49%) and of chronic GVHD (cGVHD) at 5 years was 59% (95% CI, 49-69%), with 70% developing extensive cGVHD. In multivariate analysis, aGVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42, P=0.016), whereas limited cGVHD significantly decreased the risk of myeloma relapse (RR=0.35, P=0.035) and was associated with superior EFS (RR=0.40, P=0.027). aGVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52, P=0.001). The reduction in relapse risk associated with cGVHD is consistent with a beneficial graft-vs-myeloma effect, but this did not translate into a survival advantage.     

Increased costs after allogeneic haematopoietic SCT are associated with major complications and re-transplantation

We wanted to evaluate factors associated with high costs after allogeneic haematopoietic SCT (HSCT). We collected all in-patient and outpatient costs during the first year after HSCT over 5 years, from 2003 to 2007. Mean 1-year costs per patient were \[euro]141,493 (95% confidence interval (95% CI)=125,019-157,967). Patients treated with non-myeloablative conditioning (NMC) had reduced costs, but patients treated with reduced-intensity or myeloablative conditioning had similar 1-year costs. Multivariate analysis showed that increased 1-year costs were seen in post-transplant complications: rejection (relative hazard (RH) 1.24, P<0.001), acute GVHD of grades III-IV (1.31, P<0.001) and invasive fungal infection (1.15, P=0.02). In addition, increased costs were associated with re-transplantation (1.21, P=0.001), mesenchymal stem-cell therapy (1.26, P<0.001), unrelated donor transplants (1.20, P=0.002) and the need for G-CSF treatment due to poor engraftment (1.12, P=0.047). In patients without any of these risk factors, mean 1-year costs were \[euro]84,773 (95% CI=71,145-98,400) (n=51). With three risk factors, the cost increased to \[euro]249,775 (95% CI=166,824-332,727) (n=14). To conclude, major complications increased the costs of HSCT. Unrelated donor transplants were more expensive than HLA-identical sibling transplants. Costs were reduced in patients treated with NMC.     

Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning

Reduced-intensity conditioning may reduce transplantation-related mortality in high-risk adults undergoing hematopoietic transplantation. We investigated unrelated donor umbilical cord blood (UCB) transplantation after such conditioning in 43 patients (median age, 49.5 years; range, 22-65 years) with a primary end point of donor engraftment. The first 21 patients received busulfan 8 mg/kg, fludarabine 200 mg/m2, and 200 cGy of total body irradiation (Bu/Flu/TBI). Subsequent patients (n = 22) received cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2, and 200 cGy TBI (Cy/Flu/TBI). UCB grafts (93%) were 1-2 HLA antigen-mismatched with the recipient and contained a median cryopreserved cell dose of 3.7 x 107 (range, 1.6 x 107-6.0 x 107) nucleated cells per kilogram of recipient body weight (NC/kg). Graft versus host disease (GVHD) prophylaxis was cyclosporin A to day 180 plus mycophenolate mofetil to day 30. The cumulative incidence of sustained donor engraftment was 76% (95% confidence interval [CI], 56%-96%) for Bu/Flu/TBI recipients and 94% (95% CI, 84%-100%) for Cy/Flu/TBI recipients. The median day of neutrophil recovery (at least 0.5 x 109/L) for engrafting Bu/Flu/TBI recipients was 26 days (range, 12-30 days) and for Cy/Flu/TBI recipients was 9.5 days (range, 5-28 days). Incidence of grades III-IV acute GVHD was 9% (95% CI, 1%-17%), and survival at 1 year was 39% (95% CI, 23%-56%). These data demonstrate that 0-2 antigen mismatched UCB is sufficient to engraft most adults after reduced-intensity conditioning and is associated with a low incidence of severe acute GVHD.     

Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study

Reduced-intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (SCT) have been shown to lead to engraftment of donor stem cells without the severe extra-haematological toxicities of traditional myeloablative transplants. Between December 1998 and December 2000, 76 patients underwent a RIC peripheral blood SCT in a prospective multicentre study. The median age was 53 years, and 57 patients were beyond the early phase of their disease. The conditioning regimens consisted of fludarabine (150 mg/m2) plus melphalan (140 mg/m2) or busulphan (10 mg/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A plus short-course methotrexate. The preparative regimens were well tolerated. All patients experienced severe pancytopenia, but haematological recovery was prompt in all but two cases (early deaths). The 100-d probability of developing grade II-IV acute GVHD was 32% (10% grade III-IV), and the 1-year probability of developing chronic extensive GVHD was 43%. Early complete donor chimaerism was observed in 52/68 patients, and 16 evaluable patients were in complete chimaerism 1 year post transplant. With a median follow-up of 283 d (355 in 48 survivors), the 1-year probability of transplant-related mortality was 20%, and the 1-year overall and progression-free survivals were 60% and 55% respectively. In conclusion, RIC regimens lead to low early toxicity after allografting, with stable donor haematopoietic engraftment, with an apparent low risk of acute GVHD. Chronic GVHD, however, develops in a significant proportion of patients.     

Allogeneic transplantation of CD34+-selected cells from peripheral blood in patients with myeloid malignancies in early phase: a case control comparison with unmodified peripheral blood transplantation

We compared fractionated total body irradiation (12 Gy)/cyclophosphamide (120 mg/kg) with busulfan (16 mg/kg)/cyclophosphamide (120 mg/kg) as preparative therapy in unrelated donor stem cell transplantation of CML patients. Fifty patients with CML (1.CP = 46; aP = 4) and a median age of 36 years (range 16-52) were enrolled in this sequential trial between 1994 and 1999. In both groups patients were well balanced with respect to age, disease status, stem cell source and CMV status. All patients received standard doses of cyclosporin A, methotrexate and anti-thymocyte globulin (ATG) as GVHD prophylaxis. No graft failures occurred in either group. The median day of leukocyte engraftment was earlier in the Bu/Cy than in the TBI/Cy group (day 15 vs 17; P = 0.006). The incidence of grade II-IV GVHD was 40% in the TBI/Cy and 36% in the Bu/Cy group, whereas severe grade III/IV GVHD was only observed in 12% of patients in both groups. The incidence of chronic GVHD (limited and extensive) at 1 year was higher in the Bu/Cy arm (65% vs 30%; P = 0.02). More toxicity grade I/II of the liver (88% vs 44%; P = 0.002) and more hemorrhagic cystitis (32% vs 8%; P = 0.02) were observed in the Bu/Cy regimen. Seven relapses in the TBI and no relapse in the Bu/Cy group were observed after a median follow-up of 44 and 15 months, respectively. The estimated 3 year OS and DFS was 72% (95% CI: 55-98%) and 58% (95% CI: 39-77%) in the TBI and 70% (95% CI: 51-89%) for DFS and OS in the Bu/Cy group. We conclude that the anti-leukemic effect of the Bu/Cy regimen seems to be at least as effective as the TBI/Cy combination in unrelated stem cell transplantation of CML patients, with no graft failures, but that it correlates with a higher incidence of liver toxicity, hemorrhagic cystitis and chronic GVHD. Longer follow-up is necessary to determine the late relapse rate and late toxicity.     

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.