| 2021 | Haploidentical Stem Cell Transplantation With a Novel Conditioning Regimen in Older Patients: A Prospective Single-Arm Phase 2 Study. | Front Oncol | Haploidentical stem cell transplantation (haplo-SCT) has demonstrated encouraging results in younger patients. There is also an increasing need for haplo-SCT in older patients. However, the high risk of treatment-related mortality (TRM) in older patients is still a major concern. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-SCT in older patients. This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia or MDS; (2) without MSD and MUD, and with HID available; and (3) age ≥55 years. The Bu/Flu/Cy/ATG regimen consisted of the following agents: Ara-C (2 g/m/day, injected i.v.) on days-10 and-9; BU (9.6 mg/kg, injected i.v. in 12 doses) on days-8,-7, and-6; Flu (30 mg/m/day, injected i.v.) from day-6 to day-2; Cy (1 g/m/day, injected i.v.) on days-5 and-4; semustine (250 mg/m, orally) on day-3 and antithymocyte globulin (ATG) [2.5 mg/kg/day, rabbit, SangStat (Lyon, France)] on days-5,-4,-3, and-2. The primary endpoint was 1-year TRM. From April 1, 2018 to April 10, 2020, a total of 50 patients were enrolled. All patients achieved neutrophil engraftment with complete donor chimerism. The cumulative incidence of grade 2-4 aGVHD at day-100 was 22.0%. The cumulative incidences of CMV viremia and EBV viremia on day 100 were 68.0 and 20.0%, respectively. The cumulative incidence of TRM at 1-year was 23.3%. and the cumulative incidence of relapse (CIR) at 1 year after transplantation was 16.5%. The overall survival (OS) and leukemia-free survival (LFS) at 1 year were 63.5 and 60.2%, respectively. The outcomes were also comparable with patients who received Bu/Cy/ATG regimen using a propensity score matching method. In conclusion, this study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for older patients. The study was registered as a clinical trial. www.ClinicalTrials.gov, identifier: NCT03412409. |
| 2020 | Outcomes of Haploidentical Stem Cell Transplantation using Total Body Irradiation (600 cGy) and Fludarabine with Antithymocyte Globulin in Adult Patients with Severe Aplastic Anemia: A Prospective Phase II Study. | Biol Blood Marrow Transplant | The aim of this study was to verify the feasibility of rabbit antithymocyte globulin (ATG; 5 mg/kg) in combination with 600 cGy of fractionated total body irradiation (fTBI; 3 doses of 200 cGy) and fludarabine (Flu; 150 mg/m) as a conditioning regimen for haploidentical stem cell transplantation from a related mismatched donor (haplo-SCT) in adult patients with severe aplastic anemia (SAA). We analyzed 47 consecutive patients who underwent haplo-SCT, including 24 patients from our previous pilot report. The median age was 36.0 years (range, 17 to 61 years), and 25 patients (53%) were very severe aplastic anemia (VSAA) at transplantation. All patients achieved primary engraftment. The cumulative incidence of grade ≥II acute graft-versus-host disease (GVHD) and chronic moderate or greater GVHD was 27.7% at 100 days and 13.5% at 3 years, respectively. With a median follow-up of 32.3 months, the 3-year probability of overall survival and failure-free survival was 91.0% and 88.6%, respectively. The 3-year GVHD- and failure-free survival (GFFS) was 71.6%. Offspring donor and lower comorbidity index were independent factors correlated with higher GFFS in multivariate analysis. In conclusion, the outcomes of haplo-SCT with fTBI 600 cGy/Flu/ATG-5 indicate that haplo-SCT can be an effective alternative option when a fully matched donor is not available or a patient with VSAA needs an urgent transplantation. |
| 2020 | Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children. | J Korean Med Sci | This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) ( = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; = 0.001) and GFFS (85.7% vs. 35.7%; = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued. |
| 2020 | Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy. | Int J Hematol | Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m), MEL (100 mg/m), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies. |
| 2019 | Feasibility of salvage cord blood transplantation using a fludarabine, melphalan, and low-dose anti-thymocyte globulin conditioning regimen. | Int J Hematol | Primary graft failure (PGF) is a lethal complication that occurs early after allogeneic stem cell transplantation (allo-SCT). Cord blood transplantation (CBT) is a potential re-transplantation option. Total body irradiation (TBI) is often incorporated into the pre-salvage CBT conditioning regimen following PGF; however, patients experiencing PGF are not always amenable to TBI, and non-TBI regimens for salvage CBT should be established. Here, we report five patients with hematologic malignancies who received salvage CBT for PGF following a non-TBI regimen using fludarabine (Flu), melphalan (Mel), and low-dose anti-thymocyte globulin (ATG). The median intervals between the failed allo-SCT and salvage CBT, as well as between the diagnosis of PGF and salvage CBT, were 37 days and 8 days, respectively. The median neutrophil recovery period was 21 days (range 18-21 days). Four of five patients achieved neutrophil engraftment following salvage CBT; all four exhibited sustained engraftment with complete donor chimerism. Three of the five patients were alive after a median follow-up time of 907 days (range 315-909 days) post-salvage CBT; two patients died of causes unrelated to recurrence. These data suggest that CBT following the non-TBI regimen described here is feasible in patients with PGF. |
| 2019 | Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy. | Mol Genet Metab Rep | The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution.Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m), melphalan (140 mg/m) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1).Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement.Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement. |
| 2018 | Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. | Lancet Haematol | In patients with recently diagnosed multiple myeloma, the HOVON-50 phase 3 trial showed improved event-free survival for thalidomide-containing induction and maintenance regimens (in conjunction with high-dose melphalan and autologous stem cell transplantation [auto-SCT]) after a median of 52 months of follow-up, by comparison with regimens containing classical cytotoxic drugs. In this follow-up analysis, we aimed to determine the long-term effects of thalidomide in induction and maintenance therapy in multiple myeloma.In this open-label, phase 3 randomised controlled trial, patients with recently diagnosed multiple myeloma were recruited from 44 Dutch and Belgian hospitals. Participants had been diagnosed with multiple myeloma of Durie-Salmon stage II or III and were aged 18-65 years. Patients were randomly assigned (1:1) either to receive three 28-day cycles of vincristine (0·4 mg, intravenous rapid infusion on days 1-4), doxorubicin (9 mg/m, intravenous rapid infusion on days 1-4) and dexamethasone (40 mg, orally on days 1-4, 9-12, and 17-20; control group); or to receive the same regimen, but with thalidomide (200-400 mg, orally on days 1-28) instead of vincristine (thalidomide group). No masking after assignment to intervention was used. Patients were randomly assigned to groups, stratified by centre and treatment policy (one vs two courses of high-dose melphalan and auto-SCT). After stem cell harvest, patients received one or two courses of 200 mg/m melphalan intravenously with auto-SCT. Patients with at least a partial response to high-dose melphalan and auto-SCT were eligible for maintenance therapy, starting 2-3 months after high-dose melphalan. Patients in the control group received maintenance therapy with interferon alfa (3 × 10 international units, subcutaneously, three times weekly). Patients in the thalidomide group received thalidomide as maintenance therapy (50 mg, orally, daily). Maintenance therapy was given until relapse, progression, or the occurrence of adverse events. The primary endpoint of the study was event-free survival (EFSc; censored at allogeneic stem cell transplantation), analysed by intention to treat. The study is closed for enrolment and this Article represents the final analysis. This trial was registered with the Netherlands Trial Register, number NTR238.Between Nov 27, 2001 and May 31, 2005, 556 patients were enrolled in the study, of whom 536 (96%) were eligible for evaluation and were randomly allocated (268 [50%] to the control group and 268 [50%] to the thalidomide group). These 536 patients were assessed for the primary endpoint of EFSc. At an extended median follow-up of 129 months (IQR 123-136), EFSc was significantly longer in the thalidomide group compared with the control group (multivariate analysis hazard ratio [HR] 0·62, 95% CI 0·50-0·77; p<0·0001). Thalidomide maintenance was stopped because of toxicity in 65 (42%) of 155 patients in the thalidomide group (neuropathy in 49 [75%] patients, skin reactions in four [6%] patients, fatigue in two [3%] patients, and as other symptoms [such as abdominal pain, pancreatitis, and dyspnoea] in ten [15%] patients). 24 (27%) of 90 patients in the control group discontinued protocol treatment during maintenance therapy with interferon alfa because of toxicity (five [21%] patients with psychiatric side-effects, five [21%] patients with flu-like symptoms, four [17%] patients with haematological toxicity [thrombocytopenia and leucocytopenia], three [13%] patients with skin reactions, and seven [29%] patients with other symptoms [such as infections, cardiomyopathy, and headache]). The frequency of second primary malignancies was similar in both groups. There were 23 second primary malignancies in 17 patients in the control group and 29 second primary malignancies in 24 patients in the thalidomide group. There were 19 treatment-related deaths in the control group, and 16 treatment-related deaths in the thalidomide group.Our data indicate that thalidomide-based treatment could be a treatment option for patients with multiple myeloma who are eligible for auto-SCT who live in countries without access to proteasome inhibitors or lenalidomide. However, careful follow-up and timely dose adjustments are important to prevent the development of thalidomide-induced neurotoxicity.The Dutch Cancer Foundation. |
| 2018 | Optimal conditioning regimen for haplo-identical stem cell transplantation in adult patients with acquired severe aplastic anemia: Prospective de-escalation study of TBI and ATG dose. | Am J Hematol | This prospective study explored an optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with severe aplastic anemia (SAA) who received haplo-identical stem cell transplantation from a related mismatched donor (Haplo-SCT). We explored a safe and sufficient dose of rabbit ATG (Thymoglobulin) in combination with 800 cGy total body irradiation (TBI) and fludarabine (Flu, 30 mg/m /day) for 5 days using step-by-step dose de-escalation. The dose of ATG was de-escalated from 10 mg/kg (group 1), to 7.5 mg/kg (group 2), to 5 mg/kg (group 3), and the TBI dose was reduced to 600 cGy (group 4) beginning in October 2014. If one patient developed transplant-related mortality (TRM) with engraftment in a group, we moved to the next lower dose group. Thirty-four patients were enrolled in groups 1-3 (n = 10) and 4 (n = 24). All patients achieved primary engraftment. The incidence of acute GVHD (grade ≥ 2) and chronic GVHD (≥ moderate) was 29.4% and 14.7%, respectively. With a median follow-up of 56.6 and 21.8 months in groups 1-3 and group 4, respectively, the 2-year probability of overall survival (91.7% in group 4 vs 70% in groups 1-3, P = 0.155) and GVHD-free survival (78.4% in group 4 vs 50% in groups 1-3, P = 0.115) was shown tended to be better in group 4. This study explored an optimal conditioning with step-by-step de-escalation dosage of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/intermediate-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA. |
| 2018 | The pharmacokinetics and pharmacodynamics of busulfan when combined with melphalan as conditioning in adult autologous stem cell transplant recipients. | Ann Hematol | Busulfan (Bu) is an alkylating agent widely used in conditioning regimes prior to stem cell transplantation (SCT), most commonly in combination with cyclophosphamide (Bu-cy) or fludarabine (Bu-flu) as myeloablative conditioning prior to allograft or with high-dose melphalan (Bu-mel) prior to autologous SCT. Despite many decades of Bu use, initially orally but now intravenously (IV), a paucity of pharmacokinetic (PK) and pharmacodynamic (PD) data exists to inform evidence-based guidelines as how best to balance the efficacy and toxicity of this agent. This is a non-randomized retrospective real-world study at three hospitals investigating the role of PK guidance in dosing Bu in the setting of IV Bu-mel autologous SCT. The primary intent was to examine how effectively PK assessment could be used to achieve a desirable drug exposure and to evaluate factors, particularly, age, sex, actual weight, body mass index (BMI), body surface area (BSA), disease, number of prior treatments, renal function, and the use of concomitant medications that may influence Bu exposure. All patients underwent PK analysis on a test dose of Bu (1.6 mg/kg, i.e., 50% of the first dose) on D-7 and subsequently received a second 1.6 mg/kg dose on D-6. Bu dose was calculated using actual body weight (ABW) if patients were less than ideal body weight (IBW), or adjusted ideal body weight (AIBW) if ABW was greater than IBW. Thereafter, at the discretion of the investigator, the group was divided into two; a weight-based cohort at two hospitals and a PK-guided cohort at the third hospital. Thirty-seven patients received PK-adjusted dosing guided by the results of the initial PK results, targeting a specific Bu exposure expressed as the area-under-the-concentration-versus-time curve (AUC) of between 4000 and 5000 μmol min/day (median 4800). The remaining 27 patients received unadjusted weight-based doses with a further three doses of 3.2 mg/kg of Bu infused over 180 min (D-5 to - 3) irrespective of their initial PK results. For the purposes of the analysis, we selected a target AUC of 4800 μmol min/day in this group, equivalent to the median targeted AUC in the PK-adjusted group. All patients subsequently had repeated PK analysis on D-5 after receiving their "therapeutic" Bu dose. Mel (140 mg/m or 100 mg/m) IV was given on D-2. Sixty-four adult patients were enrolled. Patients who received PK-guided Bu dosing received a higher median Bu dose than the unadjusted weight-based cohort (3.5 mg/kg vs 3.2 mg/kg respectively, p = 0.007). Eighty-one percent (30/37) of patients in the PK-guided group achieved their target AUC (± 15%) compared with 56% (15/27) in the weight-based cohort (p = 0.027). The respective median AUCs of 5064 μmol min/day (range 3639-6157 μmol min/day) and 4854 μmol min/day (range 3251-6305 μmol min/day) were not significantly different (p = 0.16). Multivariate analysis identified ABW as the only independent variable that affected the relationship between Bu dosing and exposure (p = 0.02) with heavier patients achieving lower than anticipated AUCs for the dose they received. On D-5, within the weight-based cohort, the mean AUCs were 12% higher than anticipated based on initial D-7 PK. No correlation between AUC and grade 3-4 transplant-related toxicities were observed, although only three patients had AUCs > 6000 μmol min/day. These results suggest that PK-directed Bu dosing may be of benefit in achieving a target level of drug exposure, with larger studies needed to determine the clinical significance of this strategy. |
| 2018 | The impact of individual comorbidities on non-relapse mortality following allogeneic hematopoietic stem cell transplantation. | Leukemia | Comorbidity burden is a well-established risk factor for non-relapse mortality (NRM) following allogeneic stem cell transplantation (allo-SCT). We evaluated whether individual comorbidities could better characterize NRM risk. Furthermore, given differing toxicity profiles of conditioning agents, we hypothesized that the hazard of comorbidities is exerted in a regimen-specific manner. This retrospective study included 875 adults treated with an allo-SCT. Six conditioning regimens were considered. Across the entire cohort and within each regimen, the hazard ratio (HR) for NRM associated with individual comorbidities was assessed using multivariable Cox regressions. In the overall population, renal dysfunction, hypoalbuminemia, and severe hepatic disease were associated with the highest risk of NRM (HR 2.1, HR 1.9, HR 1.7, respectively). The risk associated with specific comorbidities was modified by the conditioning regimen and was not correlated with intensity. In patients conditioned with fludarabine/busulfan (Flu/Bu4), NRM risk was increased with cardiac disease (HR 5.54). Severe pulmonary disease and a pre-existing infection were associated with increased NRM risk in patients receiving fludarabine/melphalan (HR 4.9) and fludarabine/treosulfan (HR 3.6), respectively. Comorbidities may exert effects unique to particular conditioning regimens, suggesting that regimen selection should be driven in part by specific comorbidities. |
| 2018 | Community-acquired respiratory infections are common in patients with non-Hodgkin lymphoma and multiple myeloma. | Support Care Cancer | Available data suggest that respiratory infections are associated with increased morbidity and mortality in patients hospitalized due to acute leukemia and allogeneic stem cell transplantation (allo-SCT). However, the precise incidence, risk factors, and severity of respiratory infection, mainly community-acquired, in patients with lymphoma and multiple myeloma (MM) are not fully determined. The current study aimed to investigate risk factors for respiratory infections and their clinical significance in patients with B cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) in the first year of diagnosis.Data of consecutive patients diagnosed with NHL or MM and treated at the Rambam Hematology Inpatient and Outpatient Units between 01/2011 and 03/2012 were evaluated. Information regarding anticancer treatment, incidence and course of respiratory infections, and infection-related outcomes was analyzed.One hundred and sixty episodes of respiratory infections were recorded in 103 (49%) of 211 (73-MM, 138-NHL) patients; 126 (79%) episodes were community-acquired, 47 (29%) of them required hospitalization. In univariate analysis, age < 60 years, MM diagnosis, and autologous SCT increased the respiratory infection risk (P = 0.058, 0.038, and 0.001, respectively). Ninety episodes (56% of all respiratory episodes) were examined for viral pathogens. Viral infections were documented in 25/90 (28%) episodes, 21 (84%) of them were community-acquired, requiring hospitalization in 5 (24%) cases. Anti-flu vaccination was performed in 119 (56%) patients. Two of the six patients diagnosed with influenza were vaccinated.Respiratory infections, including viral ones, are common in NHL and MM. Most infections are community-acquired and have a favorable outcome. Rapid identification of viral pathogens allows avoiding antibiotic overuse in this patient population. |
| 2017 | Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India. | J Glob Oncol | Purpose There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML). Patients and Methods We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%). The 5-year overall survival (OS) and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1), second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively ( P < .001). From 2007, reduced intensity conditioning (RIC) with fludarabine and melphalan (Flu/Mel) was used in a majority of patients in CR1 (n = 67). Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38). Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% ( P = .003) and 63.8 ± 6.4% versus 32.3 ± 7.9% ( P = .002), respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients. |
| 2017 | Incidence and risk factor of hemorrhagic cystitis after allogeneic transplantation with fludarabine, busulfan, and anti-thymocyte globulin myeloablative conditioning. | Transpl Infect Dis | Hemorrhagic cystitis (HC) is a complication of allogeneic stem cell transplantation (SCT), associated with factors such as BK polyomavirus reactivation, age, conditioning regimen, and presence of graft-versus-host disease (GVHD). The incidence and impact of HC in patients receiving fludarabine (Flu), busulfan (Bu), and anti-thymocyte globulin (ATG) conditioning is unknown.We conducted a case-control study of patients undergoing SCT at our center between January 1, 2003 and Dec 31, 2012, to determine the incidence of HC and its effect on patient outcomes including overall survival (OS), relapse, non-relapse mortality (NRM), GVHD, and healthcare resource use.In total, 94 cases of HC were identified and matched to controls based on age, donor type, disease type, and disease status at transplantation. The total incidence of HC was 17.7% (117 of 661 patients). Cases had a higher rate (43.6% vs 27.1%, P=.0394) of acute GVHD (Grade II-IV), and chronic GVHD requiring systemic steroids (34.9% vs 18.6%, P=.004). Male gender was found to be a risk factor (hazard ratio [HR]=1.725, P=.017). OS and progression-free survival did not differ between cases and controls (OS HR=1.128, 95% confidence interval [CI] 0.7807-1.639; progression-free survival HR=0.8809, 95% CI 0.6320-1.234), however the rate of NRM was higher in cases (HR=1.632, 95% CI 1.007-2.830). Median length of hospitalization was longer for patients with HC than matched controls (65.5 days vs 40.5 days, P<.0001).HC is common in patients undergoing allogeneic SCT with FluBuATG conditioning, and affects the duration of hospitalization. Rate of GVHD is higher among patients with HC. While OS is not affected, an association was seen with higher NRM in our study. Improvement in treatment for HC may lead to reductions in morbidity and healthcare resource utilization. |
| 2017 | Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy. | Bone Marrow Transplant | Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting. |
| 2016 | Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning. | Bone Marrow Transplant | Allogeneic stem cell transplantation from HLA-matched siblings (MSD-SCT) for elderly patients with severe aplastic anemia (SAA) is not a widely accepted first-line treatment. Recently, fludarabine, lower-dose cyclophosphamide and antithymocyte globulin conditioning (Flu/lower-dose Cy/ATG) with lower toxicities has been investigated. To determine whether this regimen can overcome the negative effects of age, we analyzed 117 adult patients with SAA who received MSD-SCT using Flu/lower-dose Cy/ATG, and compared outcomes between 63 younger age group (YAG; ⩽40 years) and 54 older age group (OAG; >40 years) patients. No primary graft failure was observed. Neutrophil engraftment was significantly faster in the YAG compared with the OAG (12 vs 13 days; P=0.04). The incidences of acute grade II-IV (9.5% vs 9.3% at day 100; P=0.42) and chronic GVHD (8.1% vs 9.5% at 5 years; P=0.80), secondary graft failure (20.8% vs 7.9% at 5 years; P=0.11) and transplant-related mortality (5.4% and 11.1% at 5 years; P=0.91) were not significantly different between the YAG and OAG. In addition, failure-free (73.7% vs 81.0% at 5 years; P=0.73) and overall survival rates (93.7% vs 88.9% at 5 years; P=0.20) were comparable. Our results suggest that MSD-SCT using Flu/lower-dose Cy/ATG may be a feasible first-line treatment even in older patients with SAA. |
| 2016 | Four decades of stem cell transplantation for Fanconi anaemia in the Netherlands. | Br J Haematol | This article presents the haematopoietic stem cell transplantation (SCT) results of the complete Dutch Fanconi anaemia (FA) patient cohort. Sixty-eight Dutch FA patients have been transplanted since 1972. In total, 63 (93%) patients engrafted, 54 after first SCT and 9 after second SCT. Fludarabine (FLU)-based conditioning was associated with decreased graft failure (odds ratio 0·21, P = 0·01), decreased early mortality (hazard ratio 0·25, P = 0·01) and improved 5-year overall survival (FLU 87·8% [standard error (SE) 5·1%] versus non-FLU 59·3% [SE 9·5%], P = 0·01). Late mortality was mainly caused by squamous cell carcinoma. Twenty-two patients were treated with the current Dutch FA conditioning regimen (FLU 150 mg/m(2) and cyclophosphamide 30 mg/kg ± anti-thymocyte globulin - no irradiation). Stem cell donors were matched related (n = 8) or alternative donors (n = 14). Stable engraftment after first SCT was achieved in 19 (86%) patients. At a median follow-up of 3·9 years 20 (91%) patients are alive. Our study provides a unique overview of a nation-wide SCT cohort illustrating the major improvements in treatment regimen and patient outcome in recent years. It shows that a non-irradiation and busulfan-free conditioning regimen can be used successfully, also in alternative donor SCT. Furthermore, it underlines the importance of late cancer screening and comprehensive care for this complex disorder. |
| 2016 | Long-Term Outcomes after Treatment with Clofarabine ± Fludarabine with Once-Daily Intravenous Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and Myelodysplastic Syndrome. | Biol Blood Marrow Transplant | Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu. In a preliminary report, we previously showed the safety and efficacy of Clo ± Flu with i.v. Bu in 51 patients with high-risk AML, CML, and MDS. The study has now been completed, and we present long-term follow-up data on the entire 70-patient population, which included 49 (70%), 8 (11%), and 13 (19%) patients with AML, MDS, and CML, respectively. Thirteen patients (19%) were in complete remission, and 41 patients (59%) received matched unrelated donor grafts. Engraftment was achieved in all patients. Sixty-three patients (90%) achieved complete remission. There were no deaths reported at day +30, and the 100-day nonrelapse mortality rate was 4% (n = 3). Thirty-one percent of patients (n = 22) developed grades II to IV acute graft-versus-host disease, and the median overall survival and progression-free survival times were 2.4 years and .9 years, respectively. Our results confirm the safety and overall and progression-free survival advantage of the arms with higher Clo doses and lower Flu doses, which was most prominent in the AML/MDS group. |
| 2016 | Fludarabine, idarubicin, and cytarabine regimen together with TKI followed by haploidentical hematopoietic stem cell transplantation, a success for relapsed Ph+ acute lymphoblastic leukemia. | Clin Case Rep | In this report, a case of relapsed Ph+ ALL was remedied by reinduction, and consolidation regimen of TKI and Flu+ Ara-C+ IDA (FLAI) combination, followed by haploidentical SCT. Results suggest that FLAI together with TKI and subsequently with haploidentical SCT could be applied for relapsed Ph+ ALL. |
| 2016 | Hematopoietic stem cell transplantation for homozygous β-thalassemia and β-thalassemia/hemoglobin E patients from haploidentical donors. | Bone Marrow Transplant | Thalassemia-free survival after allogeneic stem cell transplantation (SCT) is about 80-90% with either matched-related or -unrelated donors. We explored the use of a mismatched-related ('haplo- ') donor. All patients received two courses of pretransplant immunosuppressive therapy (PTIS) with fludarabine (Flu) and dexamethasone (Dxm). After two courses of PTIS, a conditioning regimen of rabbit antithymocyte globulin, Flu and IV busulfan (Bu) was given followed by T-cell-replete peripheral blood progenitor cells. GvHD prophylaxis consisted of cyclophosphamide (Cy) on days SCT +3 and +4 (post-Cy), and on day SCT +5 tacrolimus or sirolimus was started together with a short course of mycophenolate mofetil. Thirty-one patients underwent haplo-SCT. Their median age was 10 years (range, 2-20 years). Twenty-nine patients engrafted with 100% donor chimerism. Two patients suffered primary graft failure. Median time to neutrophil engraftment was 14 days (range, 11-18 days). Five patients developed mild to moderate, reversible veno-occlusive disease, while nine patients developed acute GvHD grade II. Only five patients developed limited-chronic GvHD. Projected overall and event-free survival rates at 2 years are 95% and 94%, respectively. The median follow up time is 12 months (range, 7-33 months). |
| 2016 | Two pregnancies shortly after transplantation with reduced intensity conditioning in chronic myeloid leukemia. | Pediatr Transplant | POI is a relevant late complication after HSCT and occurring more frequently after MAC than after RIC regimens. Reports on the frequency of POI after RIC in a large pediatric and adolescent population are lacking. In this study, we describe a girl affected by CML diagnosed at the age of 15 yr and treated with oncarbide and interferon followed by imatinib and dasatinib. She had two pregnancies shortly after RIC performed according to the CML-SCT I-BFM protocol including TT, FLU, and MEL. Hypergonadotropic hypogonadism occurred four months after HSCT; menstruations resumed regularly six months after HSCT. Eight and 20 months after HSCT, the patient became pregnant and then delivered, respectively, two babies at term by cesarean section. Both newborns had no neonatal complications. Donor chimerism at time of two pregnancies and five yr after transplantation demonstrated complete donor engraftment. These findings suggest that I-BFM CML-SCT protocol could be a promising treatment option for adolescents or young adults with CML eligible for HSCT. |
| 2015 | Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia--The CMC Experience. | J Assoc Physicians India | This is a single centre experience on the use of immunosuppressive therapy (IST) and stem cell transplantation (SCT) in patients with aplastic anaemia. Between 1985 and December 2013, 530 patients underwent IST while 214 underwent allogeneic SCT. Overall response rate with the use of IST was 58% with higher responses seen in adults (65.1%) compared to children (35.8%) [p = 0.001]. At a median follow up of 34 months (range: 1 - 264), 5 year KM estimates for OS for the entire group is 68.2 ± 2.2%. Loss of response or relapse was seen in 27 responders while clonal evolution to PNH was seen in 8 patients and transformation to MDS or AML was seen in 3. The 5 yr OS for children (45.7 ± 4.7%) was significantly lower than the OS of age groups 16-30 (75.6 ± 3.6%), 31-50 years (76.2 ± 4.2%) and > 50 years (73.0 ±4.2%) (p = 0.0001). SCT was performed in 214 patients with engraftment seen in 91%. The incidence of grade II-IV acute graft versus host disease (GVHD) was 38.4% with grade III-IV GVHD in 11.7%. Chronic GVHD was seen in 47.5% of evaluable patients with majority (73%) being limited chronic GVHD. At a median follow up of 32 months (range: 1 - 244), the 5 year KM estimates of OS for the entire cohort is 64.8 ± 3.3%); The 5 yr OS was significantly higher with the use of Flu/Cy (5 yr OS of 73.8 ± 3.6%) compared to Cy/ATG (5 yr OS of 44.4 ± 9.6%) or Flu/Bu conditioning (5 yr OS of 52.4 ± 8.9%) [p = 0.001]. Imp: SCT and IST offer good response rates and survival in Indian patients with AA except in children receiving IST. |
| 2016 | Outcomes of Haploidentical Stem Cell Transplantation for Lymphoma with Melphalan-Based Conditioning. | Biol Blood Marrow Transplant | Haploidentical transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PTCy) is increasingly utilized for the treatment of lymphoma and almost exclusively with the nonmyeloablative fludarabine (Flu)/cyclophosphamide/total body irradiation (TBI) conditioning regimen. We present early results of a reduced-intensity (RIC) regimen utilizing fludarabine and melphalan (FM) for the treatment of advanced lymphoma. All patients with a diagnosis of lymphoma or chronic lymphocytic leukemia (CLL) who received Haplo-SCT at the University of Texas MD Anderson Cancer Center between 2009 and 2014 were reviewed (N = 22). Patients received Flu 160 mg/m(2) and melphalan 100 mg/m(2) to 140 mg/m(2) with thiotepa 5 mg/kg or 2 Gy TBI. Because of concerns of increased treatment-related mortality (TRM) with the melphalan 140 mg/m(2) regimen (FM140), a RIC regimen with melphalan 100 mg/m(2) (FM100) was devised. Rituximab was included for CD20(+) disease. Graft-versus-host disease prophylaxis consisted of PTCy 50 mg/kg on days +3 and + 4, tacrolimus, and mycophenolate mofetil. Sixty-eight percent of all patients were not in complete remission at the time of transplantation. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire cohort were 54%, 1-year TRM was 19%, and the cumulative incidence of relapse at 2 years was 27%. Two-year PFS for Hodgkin lymphoma, non-Hodgkin lymphoma, and CLL/small lymphocytic lymphoma were 57%, 51%, and 75%. Patients treated with FM100 compared to FM140 had equivalent PFS (71% versus 37%, P = .246) and OS (71% versus 58%, P = .32). These early results establish Flu and melphalan 100 mg/m(2) with 2 Gy TBI or thiotepa 5 mg/kg as a very promising conditioning regimen for the treatment of advanced lymphoma with Haplo-SCT and PTCy. |
| 2015 | Leukemia cell mobilization with G-CSF plus plerixafor during busulfan-fludarabine conditioning for allogeneic stem cell transplantation. | Bone Marrow Transplant | We hypothesized that during conditioning chemotherapy for allogeneic stem cell transplant (allo-SCT), the disruption of stromal-leukemia interactions using G-CSF in combination with the CXCR4-specific inhibitor, plerixafor, may promote the release of leukemic cells from the niche and increase tumor elimination. In a phase 1/2 investigation, we treated 45 AML/myelodysplastic syndrome (MDS)/CML patients (34 AML, 7 MDS and 4 CML) with G-CSF (10 μg/kg daily for 6 days starting on day -9) plus plerixafor (doses of 0, 80, 160 or 240 μg/kg daily for 4 days starting on day -7) along with the busulfan-fludarabine (Bu-Flu) conditioning regimen. In the phase 1 part, we determined that G-CSF plus plerixafor is safe in this setting. We compared the clinical effects and outcomes of AML/MDS study patients (n=40) with 164 patients from a historical data set who received Bu-Flu alone before allo-SCT by stratifying on cytogenetics and disease status to correct for bias. Study patients had increased myeloid chimerism and lower rates of GvHD. There was no significant difference in relapse-free survival or overall survival. The G-CSF plus plerixafor combination increased circulating WBCs, CD34+ cells and CXCR4+ cells, and preferentially mobilized FISH+ leukemic cells. |
| 2015 | Paediatric reduced intensity conditioning: analysis of centre strategies on regimens and definitions by the EBMT Paediatric Diseases and Complications and Quality of Life WP. | Bone Marrow Transplant | The aim of this analysis was to explore the diversity of reduced intensity conditioning (RIC) in paediatric allo-SCT in daily practice across Europe. Data from the European Group for Blood and Marrow Transplantation (EBMT) Promise database from 1994 to 2008 were supplemented by a survey of EBMT centres performing paediatric allo-SCT on the current policy asking for the underlying diseases and for the drug combinations. Records from 161 centres from 30 countries were analysed and 139 various RIC regimens were reported. More centres applied RIC for malignant rather than for non-malignant diseases. In general, fludarabine (FLU)-based regimens predominated except for BU-based regimens in myeloid malignancies and haemoglobinopathies. Treosulfan (TREO) was mainly applied for unspecified malignant diseases and for haemophagocytic diseases. FLU-based regimens revealed the greatest number of different combinations. Correlating the number of regimens with the number of treating centres revealed the lowest variety in FLU and the highest variety in TBI and TREO. FLU/melphalane and FLU/CY were the most frequent combinations. This extreme heterogeneity in RIC may influence both the efficacy and the safety of the procedures, which requires further investigation. Optimization and standardization of RIC is the final goal to provide a platform for future prospective studies. |
| 2014 | Evans syndrome after unrelated bone marrow transplantation for refractory cytopenia of childhood. | Pediatr Transplant | Post-transplant ES, which is often resistant to therapies, has seldom been described. This report describes a case of ES after UBMT for RCC. A five-yr-old boy developed RCC with no evidence of monosomy 7. Because no matching family donors were available for SCT and immunosuppressive therapy was ineffective, UBMT was performed when he was six yr old. The conditioning regimen included TAI (3 Gy) and administration of FLU, CY, and rabbit antithymocyte globulin. The recovery of blood cells was good. He displayed grade II acute GVHD involving only the skin. ES developed on day 66, with positive results for Epstein-Barr virus DNA and HHV 6. Cytopenia was resolved with treatment with RTX, GCV, an escalated dose of steroids, high-dose gammaglobulin, and romiplostim. No relapse has occurred since discontinuing steroids on day 177 and romiplostim on day 268. Post-SCT ES after UBMT is rare, and the risk factors and therapies are unclear. Prospective analysis and collection of cases from multiple centers are required for clarification. |
| 2014 | Peripheral T-cell lymphoma: the role of hematopoietic stem cell transplantation. | Crit Rev Oncol Hematol | Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs). Whereas the incidence of the disease appears to increase during last decades and the prognosis remains dramatically poor, so far no standard treatment has been established. High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) has been proven effective in relapsed PTCL, while retrospective studies have shown a survival benefit as first-line treatment in some subsets of PTCL patients. However, given disease rarity, there is a paucity of randomized trials in both upfront and relapse setting. Here, we critically evaluated eligible prospective and retrospective studies that address the role of ASCT in treatment of PTCL, with respect to quality of design and performance. Additionally, the role of allogeneic transplantation has been reviewed. The comparison of ASCT with novel agents that emerge or the combination of both, are to be ascertained via prospective randomized trials in this field. |
| 2013 | Serum citrulline levels as a marker of enterocyte function in patients after allogeneic hematopoietic stem cells transplantation - a pilot study. | Med Sci Monit | Citrulline is an amino acid produced by enterocytes. Serum citrulline concentration has been proposed as a marker of enterocyte mass and function. Our study focused on evaluation of citrulline levels in patients with diarrhea related to toxic intestinal damage (mucositis), intestinal graft versus host disease (GVHD), and other etiology of diarrhea (e.g., dysmicrobia) after allogeneic stem cells transplantation (SCT).This was a prospective study in 11 adults (18 blood samples) with diarrhea developed after allogeneic SCT in 4/2011-1/2012 compared to twenty healthy control samples.The median (interquartile range) of citrulline levels was significantly lower in the transplanted patients group compared to healthy controls: 9.3 (3.62-15.38) vs. 33.3 (26.82-36.23) µmol/L, p<0.0001. The median values of citrulline in patients with post-transplant toxic intestinal mucositis (n=8, days 1-22 post-transplant) vs. intestinal GVHD (n=7, day 43-142) vs. other etiology of diarrhea (e.g., dysmicrobia) (n=3, day 120-127) were: 9.55 (2.95-12.03) vs. 5 (3.85-9.05) vs. 15.6 (15.45-18.3) mol/L resp. Serum citrulline levels were significantly higher in other (eg, dysmicrobic) etiology of diarrhea in comparison with mucositis (p=0.0336) and GVHD (p=0.0152).Citrulline levels are very low shortly after the myeloablative FLU/MEL or BuCY2 conditioning allogeneic SCT due to the toxic intestinal damage. Significantly low levels of citrulline were also in patients with intestinal GVHD later on. Other observations in larger groups of patients are necessary before any specific recommendation for citrulline levels monitoring in intestinal GVHD can be made. |
| 2012 | Outcome of allogeneic haematopoietic stem cell transplantation in aplastic anaemia. | J Coll Physicians Surg Pak | To analyze factors associated with survival, rejection and graft versus host disease in aplastic anaemia patients undergoing allogeneic haematopoietic stem cell transplantation (SCT) from HLA matched sibling donors.Analytical study.Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan from July 2001 to June 2010.Consecutive aplastic anaemia (AA) patients undergoing haematopoietic stem cell transplantation from HLA-matched sibling donors at this centre were included in this study. Potential factors affecting overall survival, rejection, disease-free survival and graft versus host disease were analyzed. Survival analysis was done by Kaplan-Meier method. Cox regression model was applied for multivariate analysis.Ninety male and thirty-five female patients with AA were included in the study. Median age was 18 years. Conditioning regimens used were cyclophosphamide (Cy) plus antilymphocyte globulin (ALG) or antithymocyte globulin (ATG), fludarabine (FLU) +Cy+ATG, Campath 1-H +Cy in 89, 30 and 6 cases respectively. GVHD prophylaxis used was ciclosporin (CSA) plus prednisolone and short methotrexate in 81 while 44 received CSA plus prednisolone. At a median follow-up of 1185 days OS and DFS were 84% and 78% respectively. Factors associated with better OS were male sex, Flu/Cy/ATG conditioning and use of bone marrow as stem cell source.Flu/Cy/ATG conditioning regimen, bone marrow as stem cell source and CSA, prednisolone and short methotrexate regimen were associated with better survival in AA. |
| 2012 | Matched sibling donor stem cell transplantation for Fanconi anemia patients with T-cell somatic mosaicism. | Pediatr Transplant | SCT from HLA-identical sibling donors is generally associated with an excellent survival in FA patients if performed prior to the development of MDS or leukemia. However, the optimal conditioning regimen has not been defined. We report here our experience with 15 Japanese FA patients who underwent HLA-matched sibling donor SCT. The aim of this study is to compare radiation-based conditioning to Flu-based conditioning for FA patients in a Japanese population where the T-cell somatic mosaicism is higher than in the Caucasian population. Eight patients (a-group) received a radiation-based conditioning (500-600 cGy of thoracoabdominal/TBI) with CY dose modification (20-120 mg/kg), and ATG; two patients exhibited rejection. Seven patients (b-group) received CY (40 mg/kg), 150-180 mg/m(2) of Flu, and ATG. Durable engraftment was demonstrated in all patients. In FA patients, Flu-based conditioning may allow stable engraftment in matched sibling donor transplantation without radiation, even in patients with T-cell somatic mosaicism. |
| 2011 | Comparison of new flu-bu12-tg conditioning with the standard bu-cy myeloablative regimen in patients undergoing allogeneic stem cell transplantation for acute myeloid leukemia. | Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub | This study compares the outcomes of patients with high-risk acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (SCT) after conditioning combining busulfan (16 mg/kg orally) and cyclophosphamide (120 mg/kg intravenously) (BU-CY) with those allografted after administration of fludarabine (150 mg/m(2) intravenously), busulfan (12 mg/kg orally) and thymoglobulin (6 mg/kg intravenously) (FLU-BU12-TG).SCT after BU-CY and FLU-BU12-TG was performed in 21 and 10 AML patients. There were no significant differences between groups in number of patients treated in complete disease remission, gender, age, donors, CD34+, mononuclear cell (MNC) count in the graft and follow-up period. However, significantly more SCTs from unrelated (90% vs. 19%; p=0.00018) and HLA-mismatched donors (50% vs. 0%; p=0.0004) were performed in the FLU-BU12-TG group. The Cox proportional hazards model was used to assess the risk of post-transplant AML relapse and non-relapse mortality (NRM). The probability of post-transplant 2-year event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method.No significant differences were found between the FLU-BU12-TG and BU-CY groups in risk of AML relapse (HR=1.036; 95% CI [0.102 - 10.47]; p=0.9), post-transplant NRM (HR=0.25; 95% CI [0.031 - 1.96]; p=0.18), 2-year EFS (89% vs. 43%; p=0.19) or OS (79% vs. 57%; p=0.23).These pilot results demonstrate the efficacy of the new FLU-BU12-TG conditioning regimen in patients allografted for high-risk AML. This conditioning might become an alternative approach in patients at high risk of severe post-transplant complications after the standard BU-CY myeloablative regimen. |
| 2012 | Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity. | Bone Marrow Transplant | Treatment of relapse of hematological malignancies following allogeneic hematopoietic SCT (allo-HSCT) remains very challenging and relies usually on the readministration of chemotherapy combined with donor lymphocyte infusion (DLI). To enhance DLI effectiveness, lymphodepletion (LD) with fludarabine (Flu) and/or CY before the injection of lymphocytes is an attractive modality to modify the immune environment, leading possibly to suppression of regulatory T cells (T(reg)) and exposing the patient to cytokine activation. However, LD before DLI may lead to induction of deleterious GVHD. To avoid inducing overwhelming toxicity, we proceeded by escalating doses of both LD and DLI. Eighteen patients with various non-CML hematological malignancies who relapsed following allo-HSCT were treated with chemotherapy and LD-DLI or LD-DLI upfront. T-cell subpopulation and DC levels as well as cytokine plasma levels (IL-7, IL-15) were measured before and following LD-DLI. Cumulative incidence of acute grade II-IV GVHD was 29.4% similar to that reported in patients receiving DLI without LD. In addition, Flu alone with low dose of DLI was not associated with severe GHVD. CY/Flu at the respective doses of 600 mg/m(2) on day 1 and Flu 25 mg/m(2)/day on days 1-3 did not result in a marked decrease of T(reg) cells, nor in endogenous IL-7 and IL-15 production. However, a peripheral expansion of DCs was observed. These findings suggest that the escalated dose procedure appears safe and prevent overwhelming toxicity. A dose-limiting toxicity has not yet been reached. |
| 2011 | Significant oral graft-versus-host disease after allogeneic stem cell transplantation with the FLU/MEL conditioning regimen. | Med Sci Monit | Oral graft-versus-host disease (GVHD) is a significant complication after allogeneic stem cell transplantation (SCT) and there is no consistent information about its characteristics in patients after reduced-intensity conditioning regimen FLU/MEL (fludarabine 120 mg/m² and melphalan 140 mg/m²).This was a single-centre prospective observational study of patients after allogeneic SCT with FLU/MEL conditioning performed during the period 1/2005-12/2007. Characteristics of oral GVHD were observed in 71 patients. The observation was discontinued due to death, donor lymphocyte infusion (DLI) or new chemotherapy administration.In 10/2010, the median duration of the observation of the cohort of the patients was 13 (0.2-69) months, and 42 (35-69) months in the still-ongoing 20/71 (28%) patients. Oral acute GVHD had sporadic 7% incidence, whereas oral chronic GVHD was observed in 33% of patients and persisted with median duration of 188 (11-665) days. Clinical and histopathological features were similar in both acute and chronic oral GVHD and included mucosal lichenoid changes, erythema, ulcerations and pseudomembranes, satellite necrosis, apoptotic bodies and lichenoid interface inflammation.It is necessary to consider complex clinical symptomatology and pathological correlations when classifying the oral GVHD, because local oral symptoms and histopathological features in both acute and chronic oral GVHD forms can be similar. Even though the oral chronic GVHD was mild in the majority of patients, it can be considered as clinically significant due to its incidence, duration and symptomatology. The FLU/MEL conditioning regimen should not be considered as low-risk protocol in this context. |
| 2012 | The Saudi experience in fludarabine-based conditioning regimens in patients with Fanconi anemia undergoing stem cell transplantation: excellent outcome in recipients of matched related stem cells but not in recipients of unrelated cord blood stem cells. | Biol Blood Marrow Transplant | Low-dose cyclophosphamide (CY) is now considered the backbone of many of the conditioning regimens used in patients with Fanconi anemia undergoing allogeneic stem cell transplantation (SCT). To reduce the risk of rejection and improve results, CY is usually used in combination with other agents/modalities, such as antithymocyte globulin (ATG), busulfan, radiation, and, more recently, fludarabine (Flu). In this study, we used a uniform Flu-based conditioning regimen (ie, CY, Flu, ATG) in 26 pediatric patients with Fanconi anemia undergoing SCT. The median patient age at the time of SCT was 7.8 years, and the stem cell source was an HLA-matched related donor in 19 patients and partially HLA-matched unrelated cord blood in 7 patients. The CY, Flu, ATG regimen was well tolerated overall, with a remarkably low incidence of graft-versus-host disease and hemorrhagic cystitis. All 19 patients in the matched related donor group engrafted and were alive and transfusion-independent at a median follow-up time of 19 months, compared with only 2 of 7 patients in the unrelated cord blood group. We conclude that the combination of CY, Flu, and ATG in the doses used in this study is well tolerated, and that the proclaimed positive effect of adding Flu to the conditioning regimens of patients with Fanconi anemia undergoing SCT is most pronounced in recipients of HLA-matched related transplants. Its value in unrelated cord blood transplantation probably depends on other factors, such as the degree of HLA matching and the cell dose. |
| 2012 | Oral cryotherapy can significantly reduce oral mucositis but not acute GVHD incidence in Flu/Mel conditioning allo-SCT. | Bone Marrow Transplant | |
| 2011 | Long-term results of allogeneic hematopoietic stem cell transplantation after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin. | Neoplasma | 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.reduced-intensity conditioning, fludarabine, busulfan, antithymocyte globulin. |
| 2011 | Successful reduced-intensity SCT from unrelated cord blood in three patients with X-linked SCID. | Bone Marrow Transplant | We describe three males with X-linked SCID (X-SCID) who were successfully treated by reduced-intensity SCT from unrelated cord blood (CB). Mean age at transplant was 5.7 months (range, 3-9 months). Pre-transplant conditioning for all patients consisted of fludarabine (FLU) (30 mg/m(2) per day) from day -7 to day -2 (total dose 180 mg/m(2)) and BU 4 mg/kg per day from day -3 to day -2 (total dose 8 mg/kg). All CB units were serologically matched at HLA-A, B and DR loci. Although two patients had suffered from fungal or bacterial pneumonia before transplantation, there were no other infectious complications during transplantation. All patients engrafted and achieved 100% donor chimerism. We also confirmed full donor chimerism of both T and B cells. Only one patient developed acute GVHD grade III, which was resolved by increasing the dose of oral corticosteroid. None of the patients has developed chronic GVHD during follow up for 21-77 months. None of the patient received i.v. Ig replacement post transplant, or showed delay in psychomotor development. Reduced-intensity conditioning consisting of FLU and BU and transplantation from unrelated CB was an effective and safe treatment for these patients with X-SCID. |
| 2010 | Stem cell transplantation using non-myeloablative conditioning regimen with fludarabine for hematological malignancies. | J Nippon Med Sch | Stem cell transplantation (SCT) is a useful treatment for hematological malignancies, but it is limited to younger patients because of its high treatment-related mortality. Fludarabine (Flu), a novel anticancer agent with potent immunosuppressive activity, used as a conditioning regimen (reduced intensity transplantation; RIST), can decrease treatment-related mortality, as recently reported. However, the best drug combination and the best timing for RIST remain unknown. We herein report the SCT outcomes of 36 patients undergoing Flu treatment at our institution since December 2002 and retrospectively analyze the results. RIST conditioning with Flu was well-tolerated. No severe toxicity related conditioning regimens was observed in our patients, even though there were 10 patients with a history of autologous (n = 5) or allogeneic stem cell transplantation (n = 5). Hematological engraftment was found in 33 patients. The median times for reconstitution of WBCs, RBCs, and platelets were 16 days, 27.5 days and 34 days, respectively. Stable complete donor chimerism after SCT was present in all patients with WBC engraftment, and no patients experienced late rejection. Thirty-two patients were evaluated for acute graft versus host disease (aGVHD). Nine patients had no aGVHD. The incidence of grade I/II and III/IV aGVHD was 78% and 22%, respectively. Skin lesions were the major sites of involvement. Gut involvement was present in 9 patients. All 4 patients with grade IV GVHD had stage four hepatic GVHD. Twenty-two patients were analyzed for chronic GVHD (cGVHD). Twelve patients had no cGVHD, 6 had limited type and 4 had extended type. The overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in all patients over 7 years were found to be 41.7%, 20.1%, and 34.6%, respectively. Induction failures were present in 5 cases of AML and 1 case of NHL. Disease progression was the primary cause of death, which occurred in 12 of 21 patients. Six patients died of grade IV GVHD (n = 2) or complicated fungal infection contracted during the GVHD treatment (n = 4). One patient died of secondary MSD, which originated from donor hematopoietic cells. Two patients died of cerebral bleeding and cardiac rapture, respectively. We found that the patients' state on SCT was the most important factor in long-term survival. The OS of standard risk and high risk patients with hematological malignancies were 75% and 30.3%. We concluded that stem cell transplantation using a non-myeloablative conditioning regimen with Flu was a useful therapeutic approach for patients with hematological malignancies. |
| 2011 | Clofarabine ± fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. | Biol Blood Marrow Transplant | Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I-Clo:Flu 10:30 mg/m(2), Arm II-20:20 mg/m(2), Arm III-30:10 mg/m(2), and Arm IV-single-agent Clo at 40 mg/m(2). The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo ± Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v. Bu as pretransplant conditioning therapy are warranted. |
| 2010 | Favorable outcomes of intravenous busulfan, fludarabine, and 400 cGy total body irradiation-based reduced-intensity conditioning allogeneic stem cell transplantation for acute myelogenous leukemia with old age and/or co-morbidities. | Int J Hematol | Traditional transplant conditioning regimens have a limiting factor regarding co-morbidities or old age. Therefore, reduced-intensity conditioning (RIC) regimens have been increasingly used. To define the role of RIC in AML with old age (>or=55 years) and/or co-morbidities (HCT-CI scores >or=2), we analyzed patients who received allogeneic stem cell transplantation (SCT) with Flu/Bu/TBI 400 cGy/+/-antithymocyte globulin (ATG) conditioning regimen. Seventeen men and 15 women were enrolled. The median age was 45 years (range 17-65 years). All patients were in first (n = 25) or second (n = 7) complete remission before undergoing allogeneic SCT. Patients were transplanted from HLA-mismatched unrelated donors (n = 5), matched unrelated donors (n = 10), and matched sibling (n = 17). Calcineurin inhibitor and a short course of standard dose methotrexate were used to prevent graft-versus-host disease (GVHD). All patients achieved engraftment. At a median follow-up of 18 months (range 4-40) for survivors, the estimated 2-year rates of overall survival, event-free survival, transplantation-related mortality, and relapse were 66, 63, 26, and 16%, respectively. The incidence of acute (grades II-IV) and chronic GVHD by NIH consensus criteria was 34.4 and 62.5%. This study suggests that the Flu/Bu/TBI 400 cGy or Flu/Bu/TBI 400 cGy/ATG-based conditioning regimens maybe a feasible therapeutic approach for AML with old age and/or co-morbidities. |
| 2010 | Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients. | Am J Hematol | Reduced intensity conditioning (RIC) regimens are widely used in allogeneic stem cell transplantation (SCT). In this study, we retrospectively investigated the clinical outcomes of RIC with fludarabine (Flu; 180 mg/m(2)), intravenous busulfan (BU; 6.4 mg/kg) or oral BU (8 mg/kg), and low-dose total body irradiation (TBI; 4 Gy) (Flu-BU2-TBI) in 66 patients (median age: 54.5 years) with various hematological malignancies. Thirty-eight patients (58%) were high-risk patients (median age: 56 years). The overall survival rate at 2 years of the high-risk patients was 64.5%, which was comparable to the survival rate of 70.9% in standard-risk patients (P = 0.68). The relapse rates at 2 years in the standard-risk and high-risk patients were 16 and 28%, respectively, and day 100 treatment-related mortality rates were 0 and 6%, respectively. The Flu-BU2-TBI regimen for high-risk patients showed therapeutic effects equivalent to those for standard-risk patients and favorable outcomes compared with those of other previous RIC regimens. |
| 2010 | HLA-matched sibling transplantation with BM and CD34(+)-purified PBSCs in adult patients with high-risk severe aplastic anemia to overcome graft rejection without an increase in GVHD. | Bone Marrow Transplant | The transplantation of a large number of stem cells can overcome graft rejection but with the increased risk of GVHD. In this study, we analyzed the outcome of 32 adult patients with acquired severe aplastic anemia (SAA) who were at a high risk for graft rejection, including multiple transfusions (median 147 units, range 20-680) and long disease duration (median 67 months, range 3-347), and who had received both BM and CD34(+)-purified PBSCs from an HLA-matched sibling donor to reduce graft rejection. T cells in PBSCs were depleted using a magnetic-activated cell sorting method (CliniMACS system). Conditioning regimens consisted largely of CY and antithymocyte globulin (ATG) with fludarabine (FLU) or procarbazine (PCB). With a median follow-up of 89 months, the 8-year probability of survival was 87.5%. Neutrophils and plts promptly recovered, and none of the patients developed graft failure. The cumulative incidences of acute and chronic GVHD were 9.4 and 18.0%, respectively. Sustained engraftment and excellent survival without an apparent increase in the rate of GVHD in high-risk patients using the current approach showed that high-dose SCT with both BM and CD34(+)-purified PBSCs may yield better outcomes in heavily transfused and/or allo-immunized patients with SAA. |
| 2010 | Low nonrelapse mortality and prolonged long-term survival after reduced-intensity allogeneic stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma: report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire. | Biol Blood Marrow Transplant | Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have a very poor prognosis. However, they may achieve long-term survival by undergoing allogeneic stem cell transplantation (SCT). The purpose of this study was to assess the outcome of all adult patients with DLBCL whose treatment included a reduced-intensity conditioning (RIC) regimen for allogeneic SCT and whose data were reported in the French Society of Marrow Transplantation and Cellular Therapy registry. Sixty-eight patients (median age: 48 years) were transplanted from October 1998 to January 2007. They had received a median of 2 regimens of therapy prior to allogeneic SCT, and 54 (79%) had already undergone SCT. Prior to transplantation, 32 patients (47%) were in complete remission (CR). For all patients but 1, conditioning regimens were based on fludarabine (Flu), which was combined with other chemotherapy drugs in 50 cases (74%) and with total body irradiation (TBI) in 17 (25%). For 56 patients (82%), the donor was an HLA-matched sibling, and peripheral blood was the most widely used source of stem cells (57 patients, 84%). With a median follow-up of 49 months, estimated 2-year overall survival (OS), progression-free survival (PFS), and the cumulative incidence of relapse were 49%, 44%, and 41%, respectively. The 1-year cumulative incidence of nonrelapse mortality (NRM) was 23%. According to multivariate analysis, the patients in CR before transplantation had a significantly longer PFS and a lower CI of relapse than patients transplanted during partial remission or stable or progressive disease. These results suggest that reduced-intensity allergenic transplantation is an attractive therapeutic option for patients with high-risk DLBCL. |
| 2009 | High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma. | Biol Blood Marrow Transplant | We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma. |
| 2010 | Reduced-intensity conditioning using fludarabine with either antithymocyte globulin and BU, or low-dose TBI allowing allogeneic hematopoietic SCT. | Bone Marrow Transplant | In a single-center study, we analyzed the outcomes of 66 patients with advanced hematological malignancies receiving two reduced-intensity conditioning regimens for allogeneic transplantation: fludarabine and low-dose TBI (flu/TBI, n=25), or fludarabine, antithymocyte globulin and BU (flu/ATG/BU, n=41). The selection criteria were based on the hypothesis that flu/TBI patients were expected to achieve autologous recovery in the event of non-engraftment. Sixty-three patients (95%) engrafted. Regimen-related mortality at day 100 and 1 year was 6 and 15%, respectively. With median follow-up of 50.4 months, survival did not differ by regimen. Multivariate analysis confirmed that the type of regimen did not affect relapse. In patients achieving full donor chimerism by day 30, those conditioned with flu/TBI showed greater overall survival (P=0.02). Engraftment failure occurred in two patients (3%), both of whom received flu/TBI. We conclude that conditioning with flu/TBI or flu/ATG/BU yields comparable survival and remission outcomes. By contrast to our hypothesis, patients receiving flu/TBI who subsequently failed engraftment did not achieve autologous recovery. Yet, rapid attainment of full donor chimerism after flu/TBI is associated with greater survival than after flu/ATG/BU. Further, larger prospective randomized studies are required to define the advantage of one regimen over the other. |
| 2009 | Comparison of Tacrolimus and Sirolimus (Tac/Sir) versus Tacrolimus, Sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. | Biol Blood Marrow Transplant | Previous studies have shown that adding sirolimus to a tacrolimus/mini-methotrexate regimen (Tac/Sir/MTX) as graft-versus-host disease (GVHD) prophylaxis produces low rates of acute GVHD (aGVHD) after reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). To assess whether posttransplantation methotrexate MTX can be safely eliminated altogether, we conducted a prospective clinical trial testing the combination of T and Sir alone (tac/sir) as GVHD prophylaxis after RIC SCT from matched related donors. We compared the results with patients who received (Tac/Sir/MTX) as GVHD prophylaxis after RIC SCT from matched related donors in a previous prospective study. Patients in both groups received i.v. fludarabine (Flu) 30 mg/m(2)/day and i.v. busulfan (Bu) 0.8 mg/kg/day on days -5 to -2 as conditioning, followed by transplantation of unmanipulated filgrastim-mobilized peripheral blood stem cells (PBSCS). After transplantation, patients in both groups received Tac and Sir orally starting on day -3, with doses adjusted to achieve trough serum levels of 5 to 10 ng/mL and 3 to 12 ng/mL, respectively. The patients in the Tac/Sir/MTX group also received mini-MTX therapy (5 mg/m(2) i.v.) on days +1, +3, and +6. Filgrastim 5 microg/kg/day s.c. was started on day +1 and continued until neutrophil engraftment. Twenty-nine patients received the Tac/Sir regimen, and 46 patients received the Tac/Sir/MTX regimen. The 2 groups were balanced in terms of age, sex, and disease characteristics. Engraftment was brisk and donor chimerism after transplantation robust in both groups. The cumulative incidence of grade II-IV aGVHD was similar in the 2 groups (17% for Tac/Sir versus 11% for Tac/Sir/MTX; P = .46). There also were no differences between the 2 groups in cumulative incidence of extensive chronic GVHD (cGVHD), treatment-related mortality (TRM), disease relapse, or survival. The Tac/Sir combination for GVHD prophylaxis is well tolerated and associated with a low incidence of aGVHD in matched related donor RIC SCT. The omission of mini-MTX from the Tac/Sir GVHD prophylaxis regimen appears to have no adverse effect on the development of aGVHD. |
| 2009 | Regimen-related mucosal injury of the gut increased the incidence of CMV disease after allogeneic bone marrow transplantation. | Biol Blood Marrow Transplant | Cytomegalovirus (CMV) infection is 1 of the major causes of morbidity in patients undergoing allogeneic stem cell transplantation (allo-SCT). The incidences of CMV antigenemia and CMV disease in 43 patients who received allogeneic bone marrow transplantation (BMT) using a reduced-intensity conditioning (RIC) regimen, which mainly consisted of fludarabine (Flu), busulfan (Bu), and total body irradiation (TBI), were compared with those in 68 patients who received a myeloablative conditioning (MAC) regimen, and risk factors for CMV antigenemia and CMV disease were identified. Before engraftment, grade 3-4 mucosal injury because of the conditioning regimen was significantly decreased in RIC patients (stomatitis: P = .02; diarrhea: P < .01). Rate of engraftment, incidences of acute graft-versus-host disease (aGVHD), and rate of corticosteroid administration were not different in RIC patients and MAC patients. Although the incidences of CMV antigenemia were not significantly different in RIC patients and MAC patients (64.1% versus 57.8%, log rank, P = .59), the incidence of CMV disease was significantly decreased in RIC patients (5.4% versus 20.3%, log rank, P = .04). CMV seropositivity in the patients (P < .01) and corticosteroid administration (P < .01) were revealed by multivariate analysis to be significant risk factors for CMV antigenemia. Grade II-IV aGVHD (P = .02) and grade 3-4 diarrhea before engraftment (P = .04) were revealed to be risk factors for CMV disease. The present study is the first study to show that severe diarrhea before engraftment is a significant risk factor for CMV disease. In summary, risk of CMV disease was significantly decreased in patients without severe mucosal injury of the gut because of the conditioning regimen before engraftment. |
| 2009 | The combined use of Flu/ATG in nonmyeloablative SCT for severe aplastic anemia with multiple earlier transfusions. | Bone Marrow Transplant | |
| 2008 | High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. | Biol Blood Marrow Transplant | Low plasma busulfan (Bu) area under the concentration-time curve (AUC) is associated with graft failure and relapsed leukemias, and high AUC with toxicities when Bu is used orally or i.v. 4 times daily combined with cyclophosphamide in myeloablative hematopoietic stem cell transplantation (SCT) conditioning regimens. We report Bu AUC and its association with clinical outcomes in 130 patients with hematologic malignancies given a once-daily i.v. Bu (3.2 mg/kg days -5 to -2) and fludarabine (Flu, 50 mg/m(2) days -6 to -2) regimen. Total-body irradiation (TBI) 200 cGy x 2 was added for 51 patients with acute leukemias. Plasma AUC varied 3.6-fold (2184-7794 microM.min, median 4699 microM.min). Patients with an AUC >6000 microM.min had lower overall survival (OS) than those with AUC < or =6000 microM.min at 12 months (38% versus 74%) and 36 months (23% versus 68%, P < .001). This effect was apparent in patients with standard-risk and high-risk disease, and persisted when potential confounders were considered (hazard ratio 3.2, 95% confidence interval 1.7-6.3). Nonrelapse mortality (NRM) at 100 days (6% versus 19%) and progression free survival (PFS; 58% versus 16%) at 3 years were better with AUC < or =6000 microM.min. These data support a role for therapeutic dose monitoring and dose adjustment with daily i.v. busulfan. |
| 2007 | In vitro effect of fludarabine, cyclophosphamide, and cytosine arabinoside on chromosome breakage in Fanconi anemia patients: relevance to stem cell transplantation. | Int J Hematol | Designing stem cell transplantation (SCT) conditioning regimens for Fanconi anemia (FA) has proved difficult because of hypersensitivity to the DNA cross-linking agents. We performed chromosome fragility tests with 56 FA patients and with 50 non-FA patients with severe aplastic anemia or myelodysplastic syndrome. We evaluated peripheral blood lymphocyte specimens cultured for 72 hours and treated with mitomycin C, diepoxybutane (DEB), cyclophosphamide (CY) metabolites, cytosine arabinoside (Ara-C), and fludarabine (Flu) metabolite (9-beta-D-arabinofuranosyl-2-fluoroadenine [2-F-Ara-A]). The DEB and CY metabolite tests were highly sensitive and specific for FA (P<10(-4)) for both tests), and the number of aberrations per cell for DEB correlated with that for the CY metabolite test (P < 10(-4)) but did not correlate with the number of aberrations per cell for the Ara-C and 2-F-Ara-A tests. The difference in breakage frequencies between FA and non-FA patients for cultures treated with 2-F-Ara-A was not statistically significant. Most of the breakages observed in cells treated with 2-F-Ara-A-and Ara-C were chromatid breaks. It may be possible to determine the appropriate CY dose in the preconditioning regimen for SCT in FA patients on the basis of the in vitro effects on fragility, and Flu or Ara-C may be a safer drug than high-dose CY for conditioning in FA patients. |
| 2002 | Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. | Biol Blood Marrow Transplant | The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 microM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for p.o. Bu. This regimen incorporating once-daily i.v. Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed. |
| 2002 | Allogeneic hematopoetic stem-cell transplantation for patients with relapsed or refractory lymphomas: comparison of high-dose conventional conditioning versus fludarabine-based reduced-intensity regimens. | Ann Oncol | Allogeneic hematopoetic stem-cell transplantation (alloHSCT) has curative potential for poor risk lymphoma patients due to the graft-versus-lymphoma effect. High non-relapse mortality with conventional high-dose conditioning indicates the necessity for less toxic transplant strategies.Between 1992 and 1999, 25 patients [median age 37 (20-60) years] with relapsed or refractory non-Hodgkin's lymphoma (NHL, n = 20) or Hodgkin's disease (HD, n = 5) received an alloHSCT in our institution. Patients were grafted from HLA matched (17) or mismatched (2) related, or matched unrelated donors (MUD) (6). NHL histological subtypes were lymphoblastic (6), high grade B/T-cell lymphomas (5), follicular (3), mantle cell (2) and CLL, immunocytic, composite lymphoma and panniculitic T-NHL in one patient each. Patients had received a median of four (range three to six) different therapies before alloHSCT, and 10 patients had relapsed after high-dose chemotherapy and autologous (9) or allogeneic (1) HSCT. Remission status prior to allogeneic SCT was CR1 (1), CR2 (1), relapse (11), partial remission (5) or primary refractory induction failure (7). Conventional myeloablative conditioning (cc) regimens contained total body irradiation 12 Gy (5), busulfan 16 mg/kg (7) or BCNU/VP16 (1). Twelve patients received reduced-intensity conditioning (ric) regimens with fludarabine (FLU) plus alkylating agents. Graft-versus-host disease prophylaxis consisted of cyclosporin A +/- prednisone or methotrexate. Six patients also received anti-T-lymphocyte globulin.Twenty-four patients engrafted. Best response after alloHSCT was complete remission in 16 of all patients [64%: 95% confidence interval (CI) 44% to 84%] and in 16 of 22 evaluable patients (73%: 95% CI 53% to 93%), partial remission in three of 25 (12%), and no change in three of 25 (12%) patients. Early death prevented response evaluation in three of 25 patients. Non-relapse mortality was 54% (95% CI 15% to 78%) in patients after cc and 17% (95% CI 0% to 41%) after FLU-based ric (P = 0.03). Six patients died due to progressive disease or relapse. Four patients with HD died, three in complete remission due to non-relapse mortality and one with progressive disease. Eleven of 25 patients are alive with a median follow up of 618 days (range 383-2815), with an overall survival of 44% (95% CI 23% to 65%) at 1 year for all patients, while eight of 12 (67%: 95% CI 35% to 98%) patients are alive after ric compared with three of 13 (23%; 95% CI 0% to 50%) after cc (P <0.02).AlloHSCT induces high rates of complete remission in advanced lymphoma patients, even when the tumor had relapsed after autologous HSCT. It should be considered earlier as part of the therapeutic options in poor risk patients to avoid non-relapse mortality associated with extensive pretreatment. Our novel reduced conditioning regimens show promising results, especially in heavily pretreated patients, and improve survival after allogeneic transplantation. |
| 2000 | Stem cell transplantation for the treatment of Fanconi anaemia using a fludarabine-based cytoreductive regimen and T-cell-depleted related HLA-mismatched peripheral blood stem cell grafts. | Br J Haematol | We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD. |
| 1999 | In vitro and in vivo evaluation of the enhancing activity of glycyrrhizin on the intestinal absorption of drugs. | Pharm Res | The enhancing activity of dipotassium glycyrrhizinate (Grz) on the intestinal absorption of drugs has been demonstrated in an in vitro study using Caco-2 cell monolayers and in an in vivo absorption study in rats.The hydrolysis of Grz by luminal content and mucosa of the rat colon was investigated. The absorption-enhancing activity of Grz and its hydrolysates was estimated by changes in transepithelial electrical resistance (TEER) and the permeation of sodium fluorescein (Flu-Na) in Caco-2 cell monolayers. It was further evaluated through the absorption of salmon calcitonin (sCT) in the rat colon.Grz was not hydrolyzed to glycyrrhetinylmonoglucuronide (GrMG) and glycyrrhetinic acid (GA) by colonic mucosa, but, rather by the beta-glucuronidase in colonic flora. The hydrolysis of Grz to GrMG was extremely slow and the GrMG produced was rapidly regenerated to GA. Grz and GrMG had no effect on TEER nor on the permeability of Flu-Na across Caco-2 cell monolayers. On the other hand, GA decreased TEER and increased the permeability of Flu-Na in a dose-dependent manner. However, Grz and GrMG enhanced the plasma calcium-lowering effect of sCT after administration in the rat colon. The coadministration of sCT and GA in the rat colon induced the strongest plasma calcium-lowering effect and the highest plasma concentration of sCT.The in vivo enhancing-activity of Grz in the absorption of drugs is dependent on GA, a hydrolysis product of Grz resulting from the action of beta-glucuronidase in intestinal flora. |