HLA-Matched Sibling Stem Cell Transplantation Using Conditioning Regimen with Reduced Dose of Cyclophosphamide, ATG and Fludarabine in Patients with Severe Aplastic Anemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3296-3296
Author(s):  
Jong Wook Lee ◽  
Byung Sik Cho ◽  
Yoo Jin Kim ◽  
Seok Lee ◽  
Hee Je Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Cardiac Toxicity ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Dose ◽  
Matched Sibling

Abstract Background: We have reported the outcome of HLA-matched stem cell transplantation (SCT) using triple immunosuppressive agents with cyclophosphamide (CY, 200mg/kg), ATG and procarbazine for 113 adult patients with severe aplastic anemia (SAA) (Kim et al, BMT31:79, 2003). However, high dose CY (200mg/kg) causes serious cardiac toxicity in some cases which may lead to death within few weeks. To avoid high dose CY-associated cardiac toxicity we underwent HLA-matched sibling SCT using increasing dose of ATG and Fludarabine instead of reduced CY to half dose. Method: Between March 2002 and December 2007, fifty patients with adult SAA (six patients were AA/PNH syndrome) received matched sibling SCT. The median age of patients was 39 (16~53) and median interval between Dx and SCT was 19 months (1~352). The median number of transfusion prior to SCT was 34 units (2~680). Nineteen patients (38%) had a history of IST before SCT. The conditioning regimen consisted of Fludarabine (30mg/m2/day, 6 days), CY (50 mg/kg/day, 2 days) and ATG (Thymoglobulin 2.5mg/kg/day, 4 days). Stem cell sources were BM plus CD34+-selected PBSC (n=12), BM (n=20), PBSC (n=4) and G-CSF-primed BM (n=14). All patients received cyclosporine and methotrexate as GVHD prophylaxis. Results: The median dose of CD34+ cells infused was 3.7x106/kg (1.2~11.9). All patients achieved successful primary engraftment, and the median time for ANC and platelet to reach 0.5x109/L and 20x109/L was 12 (10~19) and 17 (10~25) days, respectively. Three patients (6%) developed delayed graft failure whereas 14% (16 out of 113) developed both primary and secondary graft failure in our previous study. But all achieved successful engraftment after booster infusion (n=1) and second SCT (n=2). The incidence of acute GVHD (more than grade II) and chronic GVHD was 8% (n=4) and 4% (n=2; extensive type), respectively. The incidence of acute and chronic GVHD seems to be lower than those of previous conditioning regimen (11% and 12%, respectively) (BMT31:79, 2003). The incidence of CMV infection requiring preemptive treatment was 54 % (n=27). Three patients died of reactivation of chronic hepatitis C with hepatic GVHD (n=1), CMV pneumonia (n=1), and invasive fungal infection (n=1). PNH clone monitored by flow cytometry disappeared posttransplant in all 6 PNH patients. With median follow up of 32 months (1~74), the estimated probability of survival at 3 years was 94 % compared with those of 89% in our previous report. Conclusions: These data demonstrate that the conditioning regimen used in this study is feasible for patients with SAA who received matched sibling SCT. Of note, the observation of successful engraftment as well as lesser acute and chronic GVHD compared with previous study suggest that increasing dose of ATG and the addition of Fludarabine has potent in vivo T cell depletion and immunomodulatory activity.

Outcome of Allogeneic Stem Cell Transplantation for Patients with Severe Aplastic Anemia after Conditioning with Procarbazine, ATG and Cyclophosphamide: A Single Center Experience.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2027-2027
Author(s):  
Ki Seong ◽  
Jong Wook Lee ◽  
Yoo Jin Kim ◽  
Hee Je Kim ◽  
Chang Ki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Severe Aplastic Anemia ◽  
Platelet Recovery ◽  
Matched Sibling

Abstract Background: Cyclophosphamide (CY, 200 mg/kg) plus ATG seems to be accepted as a standard conditioning regimen in HLA-matched sibling stem cell transplantation (SCT) for severe aplastic anemia (SAA). We report herein the outcome of allogeneic SCT for the patients with SAA conditioned with procarbazine (PCB), ATG and CY. Methods: Between January 1995 and March 2004, consecutive one hundred and sixty two patients with SAA received matched sibling SCT after conditioning with PCB, ATG and CY. The median age of patients was 28.5 (16~50) and median interval between diagnosis and SCT was 10.5 months (1~216). Fifty-five patients (34%) had a history of immunosuppressive therapy before SCT. The conditioning regimen consisted of PCB (6.25 mg/kg/day, 6 days), CY (50 mg/kg/day, 4 days) and ATG (1.25 mg/kg/day, 3 days). No graft manipulation was performed in 92 patients (52%), and donor marrow expansion and megadose transplantation (bone marrow plus CD34+ isolated PB as a stem cell source) were done in 35 patients (21.6%). All patients received of cyclosporine and methotrexate as GVHD prophylaxis. Results: The median dose of CD34+ and CD3+ cells infused were 4.8 x 106/kg (0.8~49.6) and 5.1 x 107/kg (0 ~ 38), respectively. Median time to neutrophil recovery more than 500/μL and platelet recovery more than 20,000/μL were 13 days (0~49) and 19 days (0~150), respectively. All patients achieved successful primary engraftment, but delayed engraftment failure developed in 18 patients (11%). Ten among 18 patients who developed graft failure received second SCT, resulting survival of 9 patients. The incidence of acute (more than grade II) and chronic GVHD were 9.3% (n=15) and 13.0 % (n=21), respectively. DFS and overall survival (OS) at 6 years was also 90%. Factors influencing on DFS on univariate analysis were patient and donor’s age, development of acute and chronic GVHD, and times of pregnancy (over 2 times). Development of acute and chronic GVHD, and occurrence of rejection were factors that influence DFS on multivariate analysis. Causes of death (n=15) were pneumonia (n=4), rejection (n=4), GVHD±infection (n=2), chronic GVHD (n=1), MOF (n=1), CVA (n=1), autoimmune hemolytic anemia (n=1), and unknown (n=1). Conclusions: These data suggest that the conditioning regimen used in this study is feasible for patients with SAA who received matched sibling SCT. GVHD and rejection were the most important factors that influence DFS.

More Intensity Immuno-Suppression In Conditioning Regimen  may Favor Donor Stem Cell Sustained Engraftment In Allogeneic Stem Cell Transplantation For Acquired Severe Aplastic Anemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5452-5452
Author(s):  
Sun Can ◽  
Lin Xia ◽  
Huang Yuxian ◽  
Chen Tuzhen ◽  
Bingyi Wu
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Severe Aplastic Anemia ◽  
Hematopoietic Stem ◽  
Acquired Severe Aplastic Anemia

Abstract Background Hematopoietic stem cell transplantation (HSCT) is the first-line therapy for patients younger less than 40 years old with severe aplastic anemia (SAA). And the long-term survival for patients with SAA who received HSCT reaches to 70%-90%. Cyclophosphamide-based conditioning regimen with or without antithymocyte globulin (ATG) has been adopted in majority of HSCT for SAA patients with HLA matched related donor. However the graft rejection and graft failure in HSCT for SAA with cyclophosphamide-based conditioning regimen is still as high as 5%-16%. The aim of this study is to explore whether more immue suppression in conditioning regimen could favor the donor stem cells sustained engraftment for severe aplastic anemia patients receiving allogeneic hematopoietic stem cell transplantation. Fludarabine and busulfan were added in cyclophosphamide-based conditioning regimen to intensity immune suppression in conditioning. Methods To analyze the outcomes and chimeras of 40 patients with SAA who received HLA matched allo-HSCT from 2000 to 2012 with either fludarabine-based conditioning regimen or cyclophosphamide-based conditioning regimen retrospectively and to explore the relationship between the chimeras and conditioning regimen. Results Forty patients with SAA who received HLA matched allo-HSCT From May, 2000 to Dec. 2012. Twelve patients ( median age 25 year old  range 13-52, male 7, femal 5) received  fludarabine-based conditioning regimen which composed of fludarabine (30 mg/m2/d ×5d), busulfan ( 3 mg/kg ×2d ), cyclophosphamide ( 60mg/kg/d×2d) and ATG (2.5mg/kg/d ×5d). Twenty patients( median age 23 year old  range 12-42, male 19, femal 9)  received  cyclophosphamide-based conditioning regimen which composed of cyclophosphamide (50mg/kg/d ×4d )and ATG (2.5mg/kg/d ×2d ). The  median dose of MNC were 4.5×108/kg (range 3.8-7.0×108/kg )and 3.58×108/kg (range 3.2-6.8×108/kg ) and CD34+ cells were  4.5×108/kg and 3.58×108/kg respectively. GVHD prophylaxis were cyclosporine and short-term course methotrexate. Donor chimera was detected on day+30, +90, +180, and 360 after HSCT by short tandem repeat polymerase chain reaction, or fluorescein in situ hybridization for X and Y chromosomes in cases when patients and donors were sex mismatched. Results All patients with fludarabine-based conditioning regimen were successful Hematopoietic reconstitution and no graft failure occurred in this group patients. But two patients could not get recovery in cyclophosphamid-based conditioning regimen group. And complete donor chimeras always present when chimeras were detected by STR-PCR or FISH at day 30,day 60, day 90 and d 180 post transplantation in fludarabine-based conditioning regimen group, while seven patients with cyclophosphamide-based conditioning regimen were mixed chimeras at day 30 post transplant.  The graft was rejected in six of the seven patients at day 90 post transplant in cyclophosphamide-based conditioning regimen group. The complete donor chimera in fludarabine-based conditioning regimen group was obvious higher than that in cyclophosphamide-based conditioning regimen group ( p=0.037). The incidence of aGVHD in the fludarabine group was 16.7% and 10.7% in the cyclophosphamide-based group. There is no significant difference of aGVHD between two group (P = 0.627). The incidence of cGVHD was 8.3% and 10.7% respectively. The bacterial infections developed in 16.7% and 28.6% of patients respectively (P=0.693), The overall survival were 83.33% and 82.14% in fludarabine-based conditioning regimen group and cyclophosphamide-based group respectively (p=0.870). Conclusions More intensity immuno-suppression in conditioning regimen may favor donor stem cell sustained engraftment in allogeneic stem cell transplantation for acquired severe aplastic anemia patients. Disclosures: No relevant conflicts of interest to declare.

High Engraftment Rate after Second Stem Cell Transplantation for Thalassemia: A Prospective Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1107-1107
Author(s):  
Javid Gaziev ◽  
Guido Lucarelli ◽  
Pietro Sodani ◽  
Paola Polchi ◽  
Katia Paciaroni ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Second Transplantation ◽  
Increased Risk ◽  
Preparative Regimen

Abstract Unlike hematological malignancies patients with thalassemia have an increased risk of graft failure or rejection occurring in up to 15% of patients after myeloablative stem cell transplantation from HLA identical related donors. Patients who reject their grafts and have a return of thalassemic hematopoiesis could benefit from second transplantation with the prospect of cure. Our previous experiences of second SCT using BUCY conditioning regimen alone or in combination with antilymphocyte globulin or total lymphoid irradiation showed a higher graft failure rates (43% to 69%). In 2003 we devised a new preparative regimen in an attempt to improve engraftment rate after second transplantation for thalassemia. The treatment protocol (Protocol 26.1) consisted of pre-conditioning immunosuppression-cytoreduction with hydroxiurea 30 mg/kg/day, azathioprine 3 mg/kg/day (day -45 to -12) and fludarabine 30 mg/m2/day (day -17 to -13) and conditioning regimen with BU 14/16 TT10 CY200 ATG (Thymoglobulin)12,5/10. Thirteen patients with median age of 9 years (range, 4–20 years) were given a second SCT according to this protocol. The median time between the first and second transplant was 29 months (range, 8–204 months). As a stem cell source 4 patients received bone marrow and 9 patients unmanipulated peripheral blood stem cells (PBSC). All but two patients received stem cells from the same donor. Twelve out of 13 patients (92%) had sustained full donor engraftment. One patient had early graft failure and died from cerebral bleeding due to refractory thrombocytopenia despite an autologous back-up. Other two patients died from acute or chronic GvHD -related complications. The probability of survival, thalassemia-free survival, transplant related mortality and rejection were 76%, 76%, 18% and 8% respectively with a median follow-up of 26 months (range, 8–47 months). Four patients developed grade II–III and 1 patient grade IV acute GvHD responsive to steroids and 3 patients had extensive chronic GvHD. Both acute and chronic GvHD occurred in patients who received PBSC. The incidence of CMV and EBV reactivation was 62% and 38% respectively. None of these patients developed EBV related lymphoproliferative disorders. Six patients had BK virus- related hemorragic cystitis (2 moderate, 2 severe and 2 mild cystitis). In conclusion, the high engraftment rate observed in this study suggests that this new preparative regimen is effective curative treatment for second transplant in patients with thalassemia. Disclosure: No relevant conflicts of interest to declare.

Short Term Outcome after Allogeneic Stem Cell Transplantation in 70 Cases of Severe Aplastic Anaemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5046-5046
Author(s):  
Parvez Ahmed ◽  
Khalil Ullah ◽  
Tariq M. Satti ◽  
Shahid Raza ◽  
Qamar-Un-Nisa Chaudhry ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anaemia ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Severe Aplastic Anaemia ◽  
Post Transplant ◽  
Matched Sibling

Abstract Allogeneic stem cell transplantation (SCT) from HLA matched sibling donor is the standard treatment option in younger patients with severe aplastic anaemia (SAA). In the current study outcome of 70 patients with SAA undergoing allogeneic SCT at our institution from July 2001 to June 2007 is presented. Median follow up time was 727 days (range 100–2187). Three patients received 2nd SCT due to graft failure or rejection so actual number of SCT in the patients was 73. Median age of the patients was 16 years (range 5–38), 55 males, and 15 females. Seventeen had major ABO mismatch while sex mismatch in the form of female donor to male patient was present in 23 cases, 7 had both major ABO and sex mismatch. Sixty four patients were CMV positive while 6 had CMV negative status. Conditioning regimens included; cyclophosphamide (Cy) 200 mg/kg with either antilymphocyte globulin (ALG) 45 mg/kg (n=33) or antithymocyte globulin (rabbit ATG) 11.25 mg/kg (n=26); Cy plus Campath 100 mg (n=6), fludarabine 150 mg/m2 plus Cy 300 mg/m2 and ATG (n=8). All patient undergoing 2nd transplant received conditioning with Cy, fludarabine and ATG. GVHD prophylaxis was given with cyclosporin (CSA) plus prednisolone (41) with or without short course of methotrexate (29). Patients received PBSC (10) or bone marrow (12) alone or both (48). Mean mononuclear and CD34+ cell doses were 5.59 x 108/Kg and 4.8 x 106/Kg respectively. Median time to neutrophil recovery was 11 days (range 7–24). Neutropenic fever was seen in 60% cases, with mean duration of fever being 8 days. In majority (66%) no focus of infection could be found. Various isolates included gram negative rods (n=6), staphylococcus (n=2) and fungi (n=5). Other post-transplant infections were tuberculosis (n=2), herpes zoster (n=2) and transfusion associated falciparum malaria (n=2). Post-BMT non-infectious complications included acute GVHD (24%), chronic GVHD (08%), hemorrhagic cystitis (14%), seizures (5%), and VOD (3%). Graft rejection and primary graft failure was seen in 3 and 2 cases respectively. Three of them received 2nd transplant and had successful recovery while the other 2 died of septicemia. Six patients died during peri-transplant period, 3 at day 100, and 8 beyond day 100. One patient died of unrelated cause at 2 years post-transplant. Main causes of death were septicemia (n=4), conditioning regimen toxicity (n=3), VOD (n=2), GVHD (n=2) and disseminated aspergillosis (n=2). The overall and disease free survival was 76%. In univariate analysis using Logrank and Wilcoxon test factors correlated with better survival were patient’s age <15 years, disease duration <6 months, previous transfusions <20 events, conditioning with fludarabine/Cy/ATG, and absence of chronic GVHD. SCT from HLA matched sibling donor is effective treatment modality in majority of the young patients with SAA.

Alemtuzumab Used with Fludarabine and Cyclophosphamide (FCC) for Stem Cell Transplantation in Acquired Aplastic Anemia Is Associated with a Low Risk of Graft Versus Host Disease and Viral Infections and with Sustained Engraftment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1084-1084
Author(s):  
Judith C W Marsh ◽  
Vikas Gupta ◽  
ZiYi Lim ◽  
David Marks ◽  
Edward C. Gordon-Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Graft Rejection ◽  
Graft Failure ◽  
Viral Infections ◽  
Chronic Gvhd ◽  
Stem Cell Source ◽  
Low Incidence

Abstract Abstract 1084 Poster Board I-106 Graft rejection and chronic GVHD remain major obstacles to successful outcome after stem cell transplantation (SCT) for aplastic anemia (AA). Using cyclophosphamide (CY) 200mg/kg with ATG, rejection occurs in 5-10% and chronic GVHD in 30-40% of patients transplanted from HLA matched sibling donors (MSD). For unrelated donor (UD) SCT using Fludarabine with CY and ATG, rejection occurs in 18% (30% for patients > 14 years of age) and chronic GVHD in 27%. We have pioneered the use of Alemtuzumab with CY in AA SCT and shown a reduction in GVHD although graft rejection was high at 24%. More recently, Fludarabine has been added to the conditioning to reduce graft rejection. In this retrospective, multi-center study, we report outcomes after SCT for acquired AA in 37 patients using Alemtuzumab, Fludarabine and CY (FCC) conditioning regimen. Alemtuzumab dose was 0.2mg/kg x5 days (n=20), 60mgx1 (n=12), 25mgx4 (n=4) and 40mgx1+30mgx2 (n=1). All patients received Fludarabine 30mg/m2x4 and CY 300mg/m2 x4 (FCC). Patients were transplanted from 1999 to 2009. Median follow up of survivors was 641days (range 72-3547). Disease severity was ‘very severe’ in10, ‘severe’ in 20 and ‘non-severe’ in 7 patients. SCT was performed using MSD in 15 patients (40%) and UD in 22 (60%), of whom all but one were matched for 8/8 or 10/10 alleles. Median age was 35 years (range 8-55). Stem cell source was bone marrow (BM) in 21 (57%), peripheral blood stem cells (PBSC) in 7 (19%), BM+PBSC in 5 (13%) and G-mobilised BM in 4 (11%). Time from diagnosis to SCT was < 12 months in 57% of patients and > 12 months in 41%. 8/15 (53%) of sibling transplants and 18/22 (82%) of UD transplants received immunosuppressive therapy prior to SCT. There were 5 cases of graft failure, early rejection in 2 UD SCT and late graft rejection in 3 (one UD and two MSD). Of the 5 patients with graft rejection, BM was used as the stem cell source in 3, G-mobilised BM in one and PBSC in one. Cumulative incidence of graft failure at 1 year was 15% ± 4% (14% for MSD and 15% for UD SCT). For patients transplanted > 12 months from diagnosis, graft failure was 25% compared with 10% for patients transplanted within 12 months (p= 0.191). Acute GVHD occurred in 13.5% patients, grade I-II in all cases. Chronic GVHD occurred in only one patient (2.7%, extensive). Data for CMV and adenovirus infections was available in 21 patients, and in 20 patients for EBV. CMV reactivation occurred in 2/21 (9.5%) patients, with one case of CMV disease. EBV infection occurred in 2/20 patients (10%): one responded to Rituximab and one patient died from progressive EBV PTLD. There were no cases of adenovirus infection. Overall survival (OS) at 3 years was 89% (93% for MSD and 85% for UD SCT, p= 0.658). For all patients, OS was 95% when time from diagnosis to SCT was < 12 months and 80% for > 12 months (p= 0.273). For patients > 40 years of age, there was no significant difference in OS compared with patients < 40 years old (93% vs 82%). There were 3 deaths, one from chronic GVHD and CMV at day + 427, one from graft failure at day +134 and one due to EBV PTLD at day +180. We conclude that the use of Alemtuzumab with Fludarabine and CY (FCC) for MSD and UD SCT for acquired AA is associated with excellent survival, a low incidence of acute and chronic GVHD and a low incidence of viral infections. Disclosures Marsh: Genzyme: Consultancy, Honoraria. Off Label Use: Alemtuzumab used for conditioning for stem cell transplantation for aplastic anemia. Gupta:Genzyme: Honoraria, Research Funding.

Pharmacokinetics of Fludarabine in Patients with Aplastic Anemia Undergoing Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3884-3884
Author(s):  
Ezhil Pavai Mohanan ◽  
John C Panetta ◽  
Kavitha M Lakshmi ◽  
Fouzia NA ◽  
Abhijeet Ganapule ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Population Pk

Abstract Hematopoietic stem cell transplantation (HSCT) is the best treatment option for young patients with aplastic anemia. Conditioning with fludarabine (Flu) and cyclophosphamide (Cy) has been associated with improved long-term survival in patients undergoing HSCT (George et al, 2013). Graft versus host disease (GvHD), graft failure and infection associated mortality are still some of the major hurdles towards a successful outcome. Limited data available on the association between plasma Flu levels and HSCT outcome showed higher plasma Flu AUC levels to be a risk factor for non-relapse mortality. Fludarabine given intravenously as fludarabine mono-phosphate is readily converted to Flu by the enzyme ecto-5'-nucleotidase or NT5E and then is taken up into the cells by nucleoside transporters. NT5E mRNA expression and gene polymorphism in the lymphoblastoid cell lines have been shown associated with cytotoxicity to thiopurine drugs but its role on Flu pharmacokinetics (PK) is not known. We proposed to evaluate the population PK of Flu in patients with aplastic anemia undergoing HSCT and to test their influence on transplant outcome. Thirty patients diagnosed with aplastic anemia and consented to undergo HLA identical sibling HSCT using a Flu/Cy based conditioning regimen between January 2012 and February 2014 at the Department of Hematology, Christian Medical College, Vellore were included in the study (Table: Patient demographics). Pre-HSCT DNA was used to screen polymorphisms in the NT5E gene. Plasma was separated from the peripheral blood collected before (0hr) and 1,2,3,5,7 and 24 hrs after the infusion of fludarabine (30mg/m2/day x 6 days over 1 hr infusion) on days 1 and 4 and stored at -80oC until further analysis. Plasma fludarabine was analyzed using a LC-MS/MS based method and the concentration was expressed as ng/ml. Flu PK was estimated using a 2-compartment model with linear elimination. Inter-occasion variability (between dose 1, 4, 5, and 6 PK studies) on the volume (V) and elimination rate (k) was accounted for in the model. The covariates tested were: age, sex, body weight, BSA, disease type, and a polymorphism in NT5E gene. The population PK was analyzed using Monolix 4.3.2. The PK parameters AUC, CL, V and k were calculated for day 1 and day 4 of sampling. A limited sampling model (LSM) was developed with this data in order to reduce sample collection time points for future studies. The PK and PG parameters estimated are listed in Table. The influence of flu PK on clinical outcome parameters including overall survival, GvHD and rejection were estimated using Cox regression analysis. Flu PK showed wide inter-individual variation in patients with aplastic anemia receiving fludarabine based conditioning regimen (Table), which could be explained by the polymorphism in the gene converting the prodrug to active form of fludarabine. The NT5E 5’UTR variant rs2295890 was in complete linkage disequilibrium with 4 other SNPs namely: rs9450278, rs9450279, rs4599602, rs4458647 as seen both in patients and in normal healthy volunteers. Patients with variant genotype for rs2295890 showed significantly lower plasma Flu clearance compared to those with wild type genotype (p=0.0244) (Figure). Comparison of Flu PK parameters with previous studies is not possible due to heterogeneous population of patients, Flu dose and donor type included (Long Boyle et al, 2011; McCune et al, 2012). The LSM developed based on the current PK and using a D-optimality approach (via ADAPT 5) suggested a 4 time point sampling including 1 hr (end of infusion), 3, 7, and 24 hrs as a reasonable approach. This LSM will be validated by analyzing future samples. Of the 30 patients, 26 (86.6%) engrafted at a median of 14 days post BMT (range: 11-18) while 2 (6.6%) had primary graft failure and 2 died within the first 2 weeks of transplant. Grade 2-4 acute GVHD was seen in 6 (25%) with chronic GVHD in 28.5%. One patient had secondary graft failure. The Day 100 mortality was 26.6% and at present 19 (63.3%) are alive. None of the Flu PK parameters showed any significant association with engraftment, GVHD, rejection and mortality. This first study on Flu PK in a uniform cohort of patients with aplastic anemia undergoing HSCT shows that the PK of Flu is highly variable and there is genetic basis for this variation. The clinical significance of the variation in the Flu PK needs to be studied in a larger cohort of patients. Figure 1 Figure 1. Disclosures Srivastava: Octapharma: Consultancy, Other.

Allogeneic Stem Cell Transplantation from Unrelated Donors within the Seventh Decade of Life.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2062-2062
Author(s):  
Joachim Dahlke ◽  
Tatjana Zabelina ◽  
Francis Ayuk ◽  
Jens Panse ◽  
Heike Schieder ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Disease Free

Abstract We analyzed the outcome of 28 patients who were treated within prospective treatment protocols to investigate the feasibility of unrelated stem cell transplantation for patients with haematological malignancies within the seventh decade of life. Twenty-eight patients with a median age of 62 years (range 60–70) were enrolled. Twenty-six received a dose-reduced conditioning regimen while two patients were transplanted after standard conditioning regimen, and eight of the patients had received at least one prior high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation. Diagnoses were leukaemia (AML: n=10; ALL: n=1; CML: n=2), MDS (n=5), myelofibrosis (n=3), multiple myeloma (n=6) or non-Hodgkin’s lymphoma (n=1). No primary graft-failure was observed, and the median number of days to leucocyte and platelet engraftment was 18 days and 23 days, respectively. Acute GvHD grade II–IV was seen in 35% of the patients, chronic GvHD was seen in 56% of the patients. The one-year cumulative incidence of treatment-related mortality was 25%. The four-year estimated overall- and disease-free survival was 49% and 40%, respectively. Unrelated stem cell transplantation in patients within the seventh decade of life is a feasible treatment option and may induce long-term disease-free survival.

Stem Cell Transplantation from HLA-Identical Siblings Versus Alternative Donors in β-Thalassemia Diseases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3157-3157
Author(s):  
Preeda Vanichsetakul ◽  
Panya Seksarn ◽  
Issarang Nuchprayoon
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Thalassemia Major ◽  
Hematopoietic Stem ◽  
Unrelated Donors ◽  
Matched Sibling

Abstract Background: Allogeneic hematopoietic stem cell transplantation (SCT) has been established as a curative therapy for β-thalassemia major which is prevalent among Thais. Donors are usually patients’ siblings but the chance to find an optimal HLA-identical is just about 30%. Thus clinical trial using alternative donors such as partially-mismatched related donors or matched unrelated donors could be a good choice. Methods: To study the efficacy and results, we retrospectively review our experience with β-thalassemia pediatric patients undergoing transplantation from July 1999 to July 2006. Results: There were 43 patients categorized into HLA-identical siblings group (n=26, 13 male and 13 female) and alternative donors group (n=17, 14 male and 3 female). Median age and weight were 7.2 years (1.2–14.8 years), 19.8 kg (9.8–34 kg) and 7.7 years (1.4–14.8 years), 21.5 kg (11–33 kg), respectively. Amongst 26 matched siblings there were 17 bone marrow (BM), 4 peripheral blood stem cell (PBSC), and 5 cord blood (CB) donors. Of the alternative group stem cells derived from 12 matched unrelated, 2 two-antigen mismatched sibling CB, 2 one-antigen mismatched unrelated CB, and 1 one-allele mismatched unrelated BM donors. Myeloablative conditioning regimen consisted of busulfan (oral or intravenous) and cyclophosphamide for matched siblings SCT. Anti-thymocyte globulin was added for alternative donors SCT. Fludarabine was also used in addition for unrelated donors SCT. Graft-vs-host disease (GvHD) prophylaxis consisted of cyclosporine plus methotrexate except for unrelated SCT that tacrolimus plus methotrexate were used instead. Median numbers of infused CD34+ cells of the matched siblings group were 11.1x106/kg (3.7–35.4) in BMT (n=17), 9.3x106/kg (7.1–12.8) in PBSCT (n=4), and 0.94x105/kg (0.2–5.3) in CBT (n=5), compared to 5.5x106/kg (1.5–18.1) in BMT (n=10), 11.1x106/kg (11–17.2) in PBSCT (n=3), and 2.1x105/kg (1.5–3) in CBT (n=4) of the alternative group. Median times to neutrophil and platelet engraftments in each groups were 15 and 33 days, compared to 17 and 41 days, respectively. 39 successful donor engraftments were achieved from 38 HLA-matched (25 related and 13 unrelated) donors and from 1 mismatched unrelated CB unit. The remaining 1 of the matched related group and 3 of the alternative group did not engrafted, all but one case subsequently resumed autologous recovery. Acute GvHD occurred in 4 matched-sibling and 5 unrelated SCT recipients. After immunosuppressive therapy the lesions were completely resolved in all but two patients, one who suffered from severe grade IV intestinal GvHD and another who later developed extensive chronic GvHD which required treatment longer than 4 years. There were 4 mortalities only in the alternative group: 3 patients died post-engraftment due to severe fatal GvHD (n=1), cerebral aspergillosis (n=1), severe veno-occlusive disease with liver failure (n=1; Pesaro class 3); and one died from neutropenic sepsis 3-week after 4/6 matched related CBT. Median follow-up time for surviving patients was 53.5 months (2–84 months). Overall and disease-free survival in HLA-matched SCT (n=38) recipients were 94.7% (n=36) and 92.1% (n=35), compared to in HLA-mismatched (n=5) 60% (n=3) and 20% (n=1), respectively. Conclusions: SCT for β-thalassemia major using HLA-matched donors, either related or unrelated, had superior results than HLA-mismatched. In situation of unavailable matched sibling donors, the search for an appropriate complete HLA-matched unrelated volunteer donor using high resolution DNA typing is essential for favorable outcomes.

Allogeneic Hematopoietic Stem Cell Transplantation for Children with Myelodysplastic Syndrome: A Report of a Korean Single Center Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4500-4500
Author(s):  
Jeong A. Park ◽  
Ho Joon Im ◽  
Jong Jin Seo
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Refractory Anemia ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Matched Sibling

Abstract Abstract 4500 Purpose: Accounting for 4% of childhood hematological malignancy, myelodysplastic syndrome (MDS) is very rare in children than in adults. Therapy of these disorders has been associated with intensive treatment related toxicities and a high risk of relapse. Children with refractory anemia (RA)/refractory anemia with excess blast (RAEB) usually do not respond to acute myeloid leukemia (AML)- type chemotherapy, and chemotherapy without hematopoietic stem cell transplantation (HSCT) resulted in survival rates below 30%. Since failure rates after HSCT are lower in this group when treated at diagnosis, HSCT should be strongly considered, especially when a fully matched sibling donor (MSD) is available. The optimal treatment for children with RA/RAEB without matched sibling donor is presently undetermined. Some of them have stable disease course and require no therapy for years. However, aggressive treatment with HSCT using alternative donors should be considered for severe cytopenia. We analyzed the results of allogeneic HSCT in 16 children who were diagnosed with de novo MDS in a single Korean center. It is the first report about the outcome of HSCT for Pediatric MDS in Korea. Patients and Methods: Between November 1997 and June 2011, 16 children with MDS underwent allogeneic HSCT at Asan Medical Center. These patients had RA (n=7), and RAEB (n=9). Peripheral blood smears, bone marrow aspirates and biopsies of all patients were assessed by central morphology review according to the WHO classification. HSCT was recommended if the patients developed neutropenia (ANC<500/μ L) or transfusion dependency. Median age at transplant of 9 males and 7 females was 8.9 years (range 1.6–20.3). Cytogenetic analysis at diagnosis was available in 15 patients. Nine of them had a normal karyotype and 6 patients had miscellaneous chromosomal changes, but nobody had monosomy 7. Six patients (33%) were grafted from an MSD, whereas the remaining were transplanted from an unrelated donor (UD) (n=6), umbilical cord blood (n=3) or a haplo-identical family donor (n=1). All patients received myeloablative conditioning including busulfan (n=13) or total body irradiation (n=3). The median number of transfused CD34 cells was 8.2×106/kg for bone marrow or peripheral blood stem cell transplantation, and 1.3×105/kg for umbilical cord blood transplantation (UCBT). Graft-versus-host disease (GVHD) prophylaxis with cyclosporine and methotrexate was used for 14 patients, and cyclosporine and MMF were used for UCBT. Results: Sustained neutrophil engraftment was achieved in 11 patients, and five patients experienced graft failure. One patient died of subarachnoid hemorrhage on day 1 before engraftment, and 4 patients experienced primary graft failure; all patients were regrafted from haplo-identical related donors. Three patients are alive without disease, but one patient died 103 days after third HSCT from CMV pneumonia. The cumulative incidence of grade II-IV acute GVHD in the 15 evaluable patients was 0.27, and they were all manageable. Two patients developed extensive chronic GVHD; one patient died from disease progression to AML 579 days after HSCT, the other died from fungal pneumonia and intracranial hemorrhage 113 days after HSCT. With a median follow-up of 6.0 years (range 0.1–14), the cumulative incidence of treatment related mortality (TRM) and relapse was 0.19 and 0.20, respectively. The Kaplan-Meier estimates of overall survival (OS) and event free survival (EFS) at 5 years were 0.64 and 0.41. The diagnosis of RAEB was positively associated with relapse (P=0.02) and significantly decreased OS (P=0.024). Donor type was not significantly associated with TRM, graft failure, relapse and outcome. While acute GVHD did not affect the outcome, chronic GVHD significantly affected OS (P=0.0013). Conclusions: Though our results showed considerable early engraftment failure rates (31.3%), most of all were successfully regrafted form haplo-identical related donors, and showed comparable treatment outcome. Allogeneic HSCT following a myeloablative conditioning can offer a high probability of cure for children with MDS, however, efforts to further reduce the rejection, relapse and TRM in patients undergoing allogeneic HSCT are needed. Disclosures: No relevant conflicts of interest to declare.

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