In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation

A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m(2) on days -7 to -3; and melphalan, 140 mg/m(2) on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor-mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.     

Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality

We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m(2)), melphalan (100-140 mg/m(2)), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P =.04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.     

Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program

Between April 1988 and July 1998, 510 patients with myelodysplastic syndromes (MDS) underwent unrelated donor bone marrow transplantation (BMT) facilitated by the National Marrow Donor Program. Median age was 38 years (range, <1-62 years). Several conditioning regimens and graft-versus-host disease (GVHD) prophylaxis methods were used, and T-cell depletion was used in 121 patients. Donors were serologically matched for HLA-A, -B, and -DRB1 antigens for 74% of patients. Of 437 patients evaluable for engraftment, 24 (5% cumulative incidence, with 95% confidence interval [CI] of 3%-7%) failed to engraft, and an additional 33 (8% cumulative incidence; 95% CI, 6%-10%) had late graft failure. Grades II to IV GVHD developed in 47% of patients (95% CI, 43%-49%), and limited and extensive chronic GVHD developed at 2 years in 27% (95% CI, 24%-30%). The incidence of relapse at 2 years was 14% (95% CI, 11%-17%). Greater relapse was independently associated with advanced MDS subtype and no acute GVHD. The estimated probability of disease-free survival (DFS) at 2 years was 29% (95% CI, 25%-33%). Improved DFS was independently associated with less advanced MDS subtype, higher cell dose, recipient cytomegalovirus (CMV) seronegativity, shorter interval from diagnosis to transplantation, and transplantation in recent years. Common causes of death were treatment-related complications accounting for 82% of fatalities. The 2-year cumulative incidence of treatment-related mortality (TRM) was 54% (95% CI, 53%-61%). Sixty-nine percent of TRM occurred within the first 100 days, and 93% occurred within the first year of transplantation. Higher TRM was independently associated with older recipient and donor age, HLA mismatch, and recipient CMV seropositivity. This study demonstrates that unrelated donor BMT cures a significant proportion of patients with MDS. TRM is the major problem limiting the success of unrelated donor BMT in MDS. The observations made in this study should facilitate the design of prospective trials aimed at improving the results of unrelated donor stem cell transplantation for MDS.     

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.     

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.     

Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases

Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m(2)/d from days -4 to -2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day -3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56(+) cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.     

Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m²) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465).     

Safety and outcome after fludarabine-thiotepa-TBI conditioning for allogeneic transplantation: a prospective study of 30 patients with hematologic malignancies

Fludarabine, thiotepa and total body irradiation (TBI) has been used as conditioning in haplo-identical transplantation. We studied this conditioning regimen in adults undergoing matched sibling transplantation and alternative donor transplantation. A total of 30 consecutive patients underwent matched related, haplo-identical related or matched unrelated donor transplantation with fludarabine, thiotepa and TBI conditioning. All but four had advanced hematologic malignancies. For haplo-identical transplant, ATG was added to the regimen. All patients received peripheral blood stem cells; these were T-cell depleted for 2-antigen or 3-antigen mismatched related transplantation. Additional graft-versus-host disease prophylaxis consisted of tacrolimus and mini-methotrexate. One recipient of haplo-identical transplant failed to engraft; all other evaluable patients had prompt engraftment. Four patients died of regimen-related toxicity. In all, 14 additional patients died of regimen-related causes including four from failure to thrive with persistent thrombocytopenia and four from delayed pulmonary toxicity. Six patients relapsed. Progression-free survival at 12 months was 47% (90% CI: 25-69%) for recipients of HLA-identical sibling transplants and 30% (90% CI: 14-46%) for all patients. Five of six long-term survivors have extensive chronic GVHD. As a result of the delayed complications and a relatively high recurrence rate, we abandoned this regimen.     

Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T-cell globulin

Despite improvements in HLA typing, graft-versus-host disease (GVHD) continues to impair the results after volunteer unrelated donor bone marrow transplantation (VUD-BMT) in adult patients compared with matched sibling BMT. Here, the outcome after VUD-BMT using a specific regimen with high-dose anti-T-lymphocyte globulin (ATG) was analysed. Fifty-five adult patients, median age 34 years (range 17-55 years), with acute or chronic leukaemia or myelodysplastic syndrome (MDS) were transplanted in first complete remission (CR1)/first chronic phase (CP1) (early disease) (n = 21) or in advanced (CR2/CP2, no remission) disease (n = 34) from an unrelated marrow donor. GVHD prophylaxis consisted of ATG-S (Fresenius) 60-90 mg/kg b.w. prior to transplantation, in addition to cyclosporin A and short-course methotrexate. Graft failure did not occur and white blood cell count (WBC) > 1.0 x 10(9)/l was reached at median day +16. The cumulative incidence of acute (a)GVHD grade II-IV was 15% [95% CI (8%, 28%)] and of chronic GVHD was 51% [95% CI (38%, 68%)]. The cumulative incidence of relapse within 1 year was 0% [95% CI (0%, 19%)] and 21% [95% CI (11%, 40%)] for patients with early and advanced disease respectively. With a median follow-up of 28 months (range 16-45 months), 2-year disease-free and overall survival for patients transplanted in CR1/CP1 was 81% and 81% [95% CI (64%, 98%)], respectively, and for patients with advanced disease was 33% [95% CI (17%, 50%)] and 40% [95% CI (23%, 57%)] respectively. Complete and persistent donor chimaerism was seen in 77.5% of 40 patients evaluated. All 14 chronic myeloid leukaemia (CML)-CP1 patients became bcr-abl negative within 250 d. High-dose ATG pretransplant results in a low incidence of severe aGVHD without compromising donor chimaerism or elimination of minimal residual disease. Our results are similar to data obtained after matched sibling donor transplantation.     

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.     

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.     

Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis

Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001).     

Polyoma viruria following T-cell-depleted allogeneic transplants using Campath-1H: incidence and outcome in relation to graft manipulation,donor type and conditioning

Haemorrhagic cystitis (HC) is an important cause of morbidity following stem cell transplantation (SCT) and has been associated with polyoma virus infection. We studied the incidence and outcome of polyoma virus infection in 58 T-cell-depleted SCT patients. T-cell depletion was carried out using Campath-1H, either 10 or 20 mg in vitro (n=33) or 50 or 100 mg in vivo (n=25) following conventional (n=35) or nonmyeloablative conditioning (n=23). A total of 21 patients (36%) had polyoma viruria at a median of 35 days (5-114); 30% among patients receiving Campath in vitro and 44% among those given in vivo. The only risk factor for polyoma viruria was graft-versus-host disease GVHD grade >or=2. The onset of polyoma viruria coincided with Cytomegalovirus (CMV) reactivation in all six patients who reactivated both viruses. Prolonged viruria (defined as polyoma viruria >2 weeks) was documented in 10 patients (17%) and this was associated with GVHD >or=grade 2. HC occurred in four patients. Prolonged viruria was associated with HC only in patients receiving unrelated donor grafts following conventional conditioning. HC was not observed following nonmyeloablative conditioning despite a higher incidence of prolonged viruria. Thus, HC was uncommon in patients with polyoma viruria following T-cell depletion with Campath, particularly after reduced intensity conditioning.     

Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes

Outcomes of 159 young patients with inherited metabolic disorders (IMDs) undergoing transplantation with partially HLA-mismatched unrelated donor umbilical cord blood were studied to investigate the impact of graft and patient characteristics on engraftment, overall survival (OS), and graft-versus-host disease (GVHD). Patients received myeloablative chemotherapy (busulfan, cyclophosphamide, ATG) and cyclosporine-based GVHD prophylaxis. Infused cell doses were high (7.57 x 10(7)/kg) because of the patients' young age (median, 1.5 years) and small size (median, 12 kg). Median follow-up was 4.2 years (range, 1-11 years). The cumulative incidences of neutrophil and platelet engraftment were 87.1% (95% confidence interval [CI], 81.8%-92.4%) and 71.0% (95% CI, 63.7%-78.3%). A total of 97% achieved high (> 90%) donor chimerism. Serum enzyme normalized in 97% of patients with diseases for which testings exist. Grade III/IV acute GVHD occurred in 10.3% (95% CI, 5.4%-15.2%) of patients. Extensive chronic GVHD occurred in 10.8% (95% CI, 5.7%-15.9%) of patients by 1 year. OS at 1 and 5 years was 71.8% (95% CI, 64.7%-78.9%) and 58.2% (95% CI, 49.7%-66.6%) in all patients and 84.5% (95% CI, 77.0%-92.0%) and 75.7% (95% CI, 66.1%-85.3%) in patients with high (80-100) performance score. In multivariate analysis, favorable factors for OS were high pretransplantation performance status, matched donor/recipient ethnicity, and higher infused colony forming units.     

Nonmyeloablative allogeneic hematopoietic stem cell transplantation for treatment of Dyskeratosis congenita

We describe the treatment of a 10-year-old girl with autosomal recessive Dyskeratosis congenita (DC), neutropenia, thrombocytopenia and combined immunodeficiency by nonmyeloablative hematopoietic stem cell transplantation. The conditioning regimen consisted of fludarabine 30 mg/m(2)/day (days -5, -4, -3) and 2 Gy TBI (0.07 Gy/min; day 0). For graft-versus-host disease (GVHD) prophylaxis a course of intravenous MMF and CSA was administered. At 2 years after transplantation of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from a healthy 11-year-old HLA-identical brother, peripheral blood counts and T- and B-cell functions have completely normalized and donor chimerism was 100% in all cell lineages. No GVHD occurred. Neurological examination and lung function remained normal. The current transplantation regimen appears suitable, safe and efficacious in patients with DC.     

Mycophenolate mofetil combined with tacrolimus and minidose methotrexate after unrelated donor bone marrow transplantation with reduced-intensity conditioning

We evaluated the efficacy of a post-grafting immunosuppressive regimen consisting of tacrolimus, methotrexate, and mycophenolate mofetil (MMF) in 21 adults (median age, 55 years) with poor-risk hematologic malignancy who underwent unrelated bone marrow transplantation after fludarabine-based reduced-intensity conditioning (RIC). In combination with intravenous tacrolimus and minidose methotrexate (5 mg/m² on days 1, 3, and 6), MMF was orally administered at 30 mg/kg daily in three divided doses between days 7 and 27. All patients achieved neutrophil recovery with donor-type chimerism at a median of 19 days (range, 13–35). Cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) were 33% (95% CI, 15–53%) and 5% (95% CI, 0.3–20%), respectively. Five of 20 evaluable patients developed extensive chronic GVHD. Toxicities associated with the use of MMF were acceptable, although one patient experienced intractable GVHD immediately after the cessation of MMF. With a median follow-up of 24 months, overall survival at 3 years was 38% (95% CI, 14–63%). No late graft failure was observed. In conclusion, post-transplant MMF combined with tacrolimus and methotrexate was well tolerated and conferred stable donor cell engraftment, low risk of severe acute GVHD, and encouraging overall survival in unrelated donor marrow transplantation after RIC regimens.     

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.     

Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study

We report results in 41 consecutive patients with chronic lymphocytic leukemia (CLL) who underwent allogeneic hematopoietic cell transplantation (HCT) after fludarabine, melphalan, and alemtuzumab conditioning. Donors were 24 HLA-matched siblings and 17 unrelated volunteers, 4 of them mismatched with recipients. All but 3 patients had initial hematologic recovery, but 5 more patients had secondary graft failure. Median intervals to neutrophil (greater than 0.5 x 10(9)/L) and platelet (greater than 20 x 10(9)/L) recovery were 14 days (range, 9-30 days) and 11 days (range, 8-45 days), respectively. Eleven (27%) patients had relapses and received escalated donor lymphocyte infusions, but only 3 of them had sustained responses. Acute and chronic graft-versus-host disease (GVHD) was observed in 17 (41%) and 13 (33%) patients, respectively. Seventeen (41%) patients have died, 5 of progressive disease. The 2-year overall survival and transplantation-related mortality (TRM) rates were 51% (95% confidence interval [CI], 33%-69%) and 26% (95% CI, 14%-46%), respectively. The alemtuzumabbased regimen was feasible and effective in patients with CLL with a relatively low rate of GVHD. However, TRM remains relatively high as a result of a variety of viral and fungal infections. Studies are ongoing to address the efficacy of reduced doses of alemtuzumab in this group of immunosuppressed patients.     

Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters

Hemorrhagic cystitis (HC) remains a common complication of allogeneic blood and marrow transplantation. Previous analyses of risk factors for this complication were performed in heterogeneous populations, with dissimilar diagnosis and conditioning regimens. We postulated that HC is more prevalent in matched unrelated donor (MUD) and unrelated cord blood (UCB) transplantations than in matched related donor (MRD) transplantations. We performed a retrospective study on 105 acute lymphocytic leukemia patients treated with 12 Gy total body irradiation-based regimens and allogeneic transplants (MUD, n = 38; UCB, n = 15; mismatched related, n = 20; MRD, n = 32). HC occurred in 16% of patients receiving MRD transplants, 30% of recipients of mismatched related, and 40% of MUD or UCB transplants (hazard ratio 2.9, 95% CI 1.0-7.9 for the comparison of MRD versus MUD). The excessive rate of HC among MUD and UCB patients became evident after the first 30 days after transplantation. Recipients younger than 26 years had a significantly higher incidence of HC (HR 2.5, 95% CI 1.1-5.8). This donor type and age effect was independent of platelet engraftment, development of graft-versus-host disease (GVHD), source of stem cells, use of anti-thymocyte globulin (ATG) or cyclophosphamide in the regimen, steroid use, or stem cell source. We concluded that HC is more prevalent in MUD and UCB transplantations.     

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.