scholarly journals Impact of Cytogenetic and Molecular Markers on Disease-Free Survival of Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3217-3217
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Xing-Yu Cao ◽  
Yan-Li Zhao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Leukocyte Count ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Donor Source

Abstract Introduction: Cytogenetics is an independent prognostic factor in acute myeloid leukemia (AML). Molecular genetics including leukemia fusion gene, gene mutation and gene over expression are recognized to have significant impact on survival in patients with AML as well. In present study, the impact of cytogenetic and molecular markers on disease-free survival (DFS) of allogeneic hematopoietic stem cell transplantation (HSCT) for AML was investigated. Methods: Between April 2012 and December 2014, consecutive 345 patients with AML who underwent allogeneic HSCT in our center were analyzed retrospectively. All patients were either in poor-risk or in good-risk/intermediate-risk but with persistent minimal residual disease. The median age was 19 (1.8 to 64) years old. Children (≤14 years) were 96 (27.8%) cases and adults (>14 years) were 249 (72.2%) cases. Male to female was 200:145. The median disease course was 6 (1-64) months. Leukocyte count at diagnosis was < 30 x 109/L in 230 (66.7%) patients (low leukocyte) and ≥30 x 109/L in 115 (33.3%) cases (high leukocyte). Transplants at CR1, ≥CR2, and advanced disease were 168 (48.7%), 53 (15.4%) and 124 (35.9%), respectively. Donor sources were identical sibling (IS) in 45 (13.0%) cases, unrelated (UR) in 71 (20.6%) cases and haploidentical (HI) in 229 (66.4%) cases. Myeloablative conditioning regimens were administered with either Busulfan (Bu) plus Cyclophosphamide (Cy)/Fludarabine (Flu)-based in 285 (82.6%) patients or total body irradiation (TBI) plus Cy/Flu-based in 60 (17.4%) patients. Antithymocyte globulin was used in unrelated and haploidentical HSCT. Unmanipulated bone marrow and peripheral blood stem cells (PBSC) for IS and HI HSCT and PBSC for UR transplant were applied as the grafts. Cyclosporine, short-term Methotrexate, and Mycophenolate mofetil were employed for GVHD prophylaxis. Results: Univariate analysis showed that DFS after allogeneic HSCT in AML was not associated with patient age (children vs. adults, 70.3% vs. 69.4%, p=0.6), leukocyte count at diagnosis (low leukocyte vs. high leukocyte, 68.8% vs. 71.3%, p=0.8), donor source (IS vs. UD vs. HI, 77.3% vs. 76.8% vs. 65.8%, p=0.21), and conditioning regimen (Bu-based vs. TBI-based, 70.1% vs. 67.3%, p=0.45). Multivariate analysis indicated that disease status before HSCT was the only impact factor on DFS (CR1 vs. ≥CR2 vs. advanced disease, 81.6% vs. 70.0% vs. 53.1%, p<0.0001). Therefore, total 221 of 345 patients with AML in complete remission pre-conditioning were analyzed for impact of cytogenetic and molecular markers on survival after HSCT. DFS rates were 79.1%, 80.4%, 74.1% in good-risk, intermediate-risk, poor-risk cytogenetics groups (p=0.81), respectively. According to gene mutations, the DFS rates were 100% in CEBPA+, 91.6% in IDH1+/NPM1+, 85.7% in Flt3-ITD+, 81.5% in c-KIT+, 75.0% in no mutation, 70.2% in MLL-PTD+/ASXL1+/TET2+, 54.3% in Flt3-ITD+ with other mutations (p=0.42). According to gene expression, the DFS rates were 100% in DEK-CAN+, 100% in HOX11+/EVI1+, 84.8% in no abnormal gene expression, 83.3% in CBFb-MYH11+, 78.5% in WT1+, 76.5% in MLL+, 74.9% in AML1-ETO+, 0% in TLS-ERG+ (p=0.004). Conclusions: Under our HSCT protocol, disease status before transplant for the patients with AML has significant impact on DFS but not patient age, leukocyte count at diagnosis, donor source and conditioning regimen. Allogeneic HSCT has attenuated the influence of cytogenetics on DFS in patients with AML. Our preliminary data have shown that patients with CEBPA+, IDH1+/NPM1+, DEK-CAN+, HOX11+/NPM1+ have favorable survival, but patients with both Flt3-ITD+ and other gene mutations or with TLS-ERG+ have poor survival after allogeneic HSCT in AML. Disclosures No relevant conflicts of interest to declare.

Impact of Molecular Markers and Cytogenetic Abnormalities on Long-Term Overall Survival and Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Acute Myeloid Leukemia (AML) patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4476-4476
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Xavier Thomas ◽  
Carole Charlot ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Allogeneic Hsct ◽  
Disease Free

Abstract We performed a retrospective analysis from our transplant registry on first allogeneic hematopoietic stem cell transplantations (HSCT) for acute myeloid leukemia (AML) patients (pts) between 1996 and 2007. Our principal objective was to analyze the impact of molecular markers on the long-term overall and disease-free survival (OS and DFS) after first allogeneic HSCT. We found 364 pts, only 63 pts had retrospectively available conserved cells at diagnosis. The expression levels of WT1, Evi1, Flt3 and Hoxa9 were performed by quantitative RT-RQPCR. The mutational status of MLL duplication, FLT3 (internal tandem duplication or nucleotide substitutions) (ITD), NPM1 and CEBPα were determined by PCR, RFLP and/or sequencing analysis. All pts except 1 had a karyotype analysis at diagnosis. Among these 63 pts, there were 27 (43%) males and 36 (57%) females, with a median age of 41 years (18-64). The FAB classification was M0: 6, M1: 10, M2: 13, M4: 6, M5: 21, M6: 3, M7: 1 and 3 unclassified. Concerning the karyotype analysis, 25 (40%) pts had a normal karyotype, 37 (60%) pts presented cytogenetic abnormalities classified as favourable prognosis in 5 cases (8%), intermediate in 13 cases (21%) and poor in 19 cases (31%). Regarding the molecular markers evaluated in all pts: 4(6%) pts had Flt3over-expressed (ov-ex), 19 (30%) FLT3 ITD+, 3 (5%) MLLdup, 10 (16%) Hoxa9 ov-ex, 7 (11%) Evi1 ov-ex, 15 (24%) NPM1mut+, 25 (40%) WT1 ov-ex and 1 CEBPαmut+ (this marker was evaluated only in 12 pts). Associations between these markers and the karyotype prognosis groups are shown in Figure1. Twenty three (36%) pts had no abnormal molecular markers and 40 (54%) pts had at least one abnormal marker: 10 (16%) 1 marker, 10 (16%) 2 markers, 12 (19%) 3 markers, 4 (6%) 4 markers and 4 (6%) 5 markers. Concerning the karyotype, among the 23 negative molecular pts, 22 have been evaluated and there were 9 (41%) normal, 11 (50%) poor and 2 (9%) favourable; and among the 40 positive pts, 16 (40%) were normal, 8 (20%) poor, 13 (32.5%) intermediate and 3 (7.5%) favourable. Concerning transplantation, 50% of HSCT were done after 2004 and the median interval between diagnosis and transplantation was 6 months (2.6–68.5). Before conditioning, 41 pts were in CR (26 CR1, 14 CR2 and 1 CR3), 8 in PR and 14 in relapse. Twenty five (40%) pts received a non-myelo-ablative conditioning and 38 (60%) a myelo-ablative one. There were 34 sex-mismatched (21 M→F and 13 F→M), 21 ABO incompatibility (6 minor and 15 major), 55 were HLA matched and 8 mismatched. Twenty three (36.5%) pts received PBSC, 37 (59%) bone marrow and 4 (6.5%) cord blood cells from 47 (75%) HLA siblings and 16 (25%) unrelated donors. After transplantation, 59 (94%) pts engrafted, 42 developed AGVHD (21gr1, 13 gr2 and 8 gr4), and among 51 evaluable pts, 13 developed cGVHD (7 limited and 6 extensive). At the last follow-up, 20 pts have relapsed, 29 pts are alive (28 CR and 1PR) and 34 died [18 (53%) from TRM and 16 (47%) from relapse]. At the median follow-up of 48 months, the OS and DFS for the whole population were 40% (33–47) and 40% (34–46) respectively with a maximum follow-up of 130 months and for the different subgroups according to karyotype and molecular markers the results are shown in Table 1. The univariate analysis showed a significant impact of FLT3 ITD and over-expression of FLT3RQ on long-term DFS, (p=0.03 and p=0.02 respectively), and a trend on long-term OS (p=0.08). Concerning the karyotype and some other markers (MLL, EVI1, NPM1 and Hoxa9), we did not observe any significant difference because of small number of pts in some subgroups. The known benefic impact of NPM1mut+, was erased because the majority of this group presented an associated FLT3 ITD+. In addition, we are performing a multivariate analysis that will be presented. In conclusion, allogeneic HSCT in this high risk population of AML pts, allowed a good probability of long-term OS and DFS, despite the presence of high number of bad molecular markers and cytogenetic abnormalities. Finally, AML pts with FLT3 ITD+ seem not benefit from allogeneic HSCT as well as patients with NPM1mut+ associated with FLT3ITD+. Figure 1. Frequencies and distribution of different molecular markers and karyotype subgroups Figure 1. Frequencies and distribution of different molecular markers and karyotype subgroups Table 1. OS and DFS according to different molecular markers and karyotype subgroups

Clinical Outcome of a Second Autologous Hematopoietic Stem Cell Transplant (HCT) for Non-Hodgkin (NHL) and Hodgkin Lymphoma (HL) Relapsing after a First Autotransplant.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3048-3048
Author(s):  
Sonali M. Smith ◽  
Koen van Besien ◽  
Jeanette Carreras ◽  
Julie M. Vose ◽  
Hillard M. Lazarus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Disease Status ◽  
Large Cell ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Free Survival

Abstract Autologous HCT (autoHCT) salvages many patients (pts) with relapsed lymphomas but few relapsing after an autoHCT are cured. We determined feasibility of stem cell collection, engraftment kinetics, treatment-related mortality (TRM), progression free survival (PFS), and overall survival (OS) for a second autoHCT (HCT2) for lymphoma relapsing after prior HCT (HCT1). We studied 35 pts, 20 with HL and 15 with diffuse or follicular large cell and immunoblastic NHL, receiving a HCT2 for relapse between 1986 and 2003 and reported to the CIBMTR. Median (range) age at HCT2 was 36 yrs (16–61); 61% had a performance score less than 90. HCT2 was performed >1 year after HCT1 in 80%. Median (range) time from diagnosis to HCT1 was 20 mo (4–162 mo), from HCT1 to relapse, 17 mo (3–68 mo), and from relapse to HCT2, 5 mo (1–40 mo). 83% underwent a 2nd stem cell / marrow harvest prior to HCT2. Median time to ANC >0.5 x 109/L was 11d. CBV or BEAM were the conditioning regimens for HCT1 in 80% and for HCT2 in 60%. The best response to HCT2 was complete remission in 22 pts and partial remission in 5; 8 pts had either no response or progressive disease. At a median follow up of 92 mo (32–124 mo) after HCT2, 26 pts (74%) have died with 17 (65%) dying of relapsed lymphoma. Two (6%) patients developed therapy-related MDS. The probability of TRM at day 100 was 12% (95% CI, 3–25%). The 1, 3 and 5 yr probability of PFS were 45% (95% CI, 29–62%), 33% (95% CI, 18–50%) and 30% (95% CI, 15–46%), respectively. The 1, 3 and 5 yr probability of OS were 63% (95% CI, 46–78%), 34% (95% CI, 19–50%) and 31% (95% CI, 17–47%), respectively. There were no differences in outcomes between HL or NHL. Pts relapsing >6mo after HCT1 appeared to have better OS (fig 1 and 2). In summary, HCT2 is feasible in pts with lymphoma after relapsing an HCT1. Stem cells harvested prior to HCT2 resulted in rapid engraftment with a day 100 TRM (12%) lower than that reported for alloHCT in this setting. Relapse is the primary reason for failure, but approximately one-third of pts enjoy long-term disease free survival. HCT2 should be considered for young pts with relapsed HL or NHL post-HCT1 without alternative transplant options. HCT1 (%) HCT2 (%) Sensitive disease status pre-HCT 26 (79) 24 (75) Stem cell source BM 15 (43) 10 (29) PBSC 13 (37) 21 (60) Both 7 (20) 4 (11) Median days to platelet recovery ≥ 20 x 109 /L 17 (7–376) 20 (1–101) Stem cell harvest between HCT1 and HCT2 29 (83) Different conditioning regimen for HCT2 25 (74) Outcomes TRM @ 1 yr 21 (9–37) PFS @ 5yrs 30 (15–46) OS @ 5 yrs 31 (17–47) Figure 1 Figure 1. Figure 2 Figure 2.

Disease-Free Survival Of Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation Is Not Associated With Disease Status and Donor Sources

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2158-2158
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Xing-Yu Cao ◽  
Yan-Li Zhao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Free Survival ◽  
Disease Status ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Free ◽  
Related Mortality

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an only curative modality currently for myelodysplastic syndrome (MDS). High-risk MDS usually has lower complete remission (CR) rate and higher chemotherapy-related mortality compared with de novo acute myeloid leukemia (AML). To examine whether CR before HSCT has survival benefit for MDS treated by HSCT, we retrospectively analyzed the data during 11 years from our center. The clinical outcomes of MDS after HSCT from different donor sources have also been evaluated. Objective In present clinical study, the effects of disease status and donor sources on disease-free survival (DFS) of MDS after HSCT were studied. Methods From August 2001 to December 2012, total 122 patients with MDS that underwent HSCT in our center were enrolled. Male to Female was 76: 46. The median age was 35 (8 to 57) years old. The median blasts in bone marrow (BM) before conditioning were 9% (1% to 65%). According to 2008 WHO classification, the patients were diagnosed as refractory cytopenias with unilineage dysplasia (RCUD) in 12, refractory anemia with ring sideroblasts (RARS) in 2, 5q- in 1, refractory cytopenias with multilineage dysplasia (RCMD) in 15, refractory anemia with excess blasts (RAEB) -1/RAEB-2 in 36 and transformed AML in 56. For International Prognostic Scoring System (IPSS), 12 patients were in low-risk, 27 in intermediate-1, 24 in intermediate-2, and 59 in high-risk. Based on BM blast percentage pre-conditioning, 47 cases were less than 5%, 43 patients were between 5% to 20%, and 32 cases were more than 20%. The stem cells were from identical siblings (45) or unrelated donor (24) or haploidentical family members (53). Conditioning regimens were BUCY/BUFLU for identical sibling HSCT, and BUCY/BUFLU plus ATG (Thymoglobuline, 8-10mg/kg) for unrelated or haploidentical transplants. Graft-versus-host disease prophylaxis was employed by Cyclosporin A, Methotrexate and Mycophenolate mofetil as reported previously (DP Lu et al., Blood 2006; 107:3065). Results: With median follow-up 31 (1-144) months, DFS was 73.8%. Fourteen patients (11.4%) relapsed. Transplant-related mortality was 14.8%. No significant differences on DFS were found among RCUD/RARS/5q- (68.8%), RCMD (85.7%), RAEB-1/RAEB-2 (72.2%) and transformed AML (73.2%) (p=0.761). A similar DFS was seen in different risk categories (73.3% in low-risk, 79.2% in intermediate-1, 75.0% in intermediate-2 and 71.2% in high-risk; p=0.861). Moreover, CR or not before HSCT has no remarkable effect on DFS (blasts <5%, 78.7%; blasts 5% to 20%, 67.4%; blasts > 20%, 75.0%; p=0.342). Donor sources have also no significant effects on DFS (identical sibling 75.6%, unrelated donor 79.2%, haploidentical family member 69.8%; p=0.651). Conclusions Our clinical results have shown that under current protocol, DFS of MDS after allogeneic HSCT is quite encouraging no matter the disease status and stem cell donor sources. Therefore, it is not necessary that complete remission is achieved by chemotherapy before transplant. Haploidentical family member is an important alternative donor for patients with MDS when matched either identical sibling or unrelated donor is not available. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of NCCN Risk Stratification and Minimal Residual Disease on Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2296-2296
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Yan-Li Zhao ◽  
Xing-Yu Cao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Donor Type ◽  
Minimal Residual

Abstract Introduction: Cytogenetic abnormality is considered to be an independent prognostic factor in newly diagnosed acute myeloid leukemia (AML). However, recent studies have demonstrated that acquired gene mutations also play an important role in the pathogenesis and prognosis of AML. It has been well known that minimal residual disease (MRD) pre-conditioning has remarkable impact on disease-free survival (DFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia, but the effect of MRD pre-transplant on allo-HSCT in AML is still unclear. Objective: In present study, the effect of NCCN risk stratification which has integrated gene mutations into cytogenetics as well as MRD pre-transplant on DFS after allo-HSCT in AML was studied in order to learn whether risk-directed conditioning and prevention of relapse are needed. Methods: Between April 2012 and March 2015, consecutive 258 patients with AML in complete remission (CR) (186 cases in CR1 and 72 cases in CR2) who underwent allo-HSCT in our hospital were analyzed retrospectively. The median age was 25 (1.8-64) years. Male (M) to female (F) was 147:111. The median disease course was 6 (1-51) months. According to 2015-NCCN risk stratification, 63 (24.4%) cases were in low risk, 112 (43.4%) cases in intermediated risk, and 83 (32.2%) cases in high risk. MRD in bone marrow pre-conditioning was detected by eight-color flow cytometry. Results: With the median follow up 18 (5-41) months, overall 2-year DFS was78.0%. No significant difference in DFS was found among low-risk (78.6%), intermediated-risk (76.0%) and high-risk (80.3%) patients (P=0.886). 205 (79.5%) cases were MRD- and 53 (20.5%) cases were MRD+ before conditioning. DFS after transplant in MRD+ patients was significant lower than that in MRD- patients(65.0% vs. 81.4%, P=0.003). Univariate analysis showed that DFS was not associated with patient age (≤14years vs.>14years, P=0.292), disease course before HSCT (≤6 months vs.>6months, P=0.532), WBC counts at diagnosis (≤50×109/L vs.>50×109/L, P=0.120), CBC recovery pre-HSCT (yes vs. no, P=0.664), disease status (CR1 vs. CR2, P=0.201), extramedullary leukemia before transplant (yes vs. no, P=0.532), conditioning regimen (BUCy/Flu-based vs. TBICy/Flu-based, P=0.753), donor type (identical sibling vs. unrelated vs. haploidentical, P=0.743), donor-recipient gender (M-M vs. M-F vs. F-M vs. F-F, P=0.245), donor-recipient blood type (compatibility vs. major incompatibility vs. minor incompatibility vs. major and minor incompatibility, P=0.402), mononuclear cells infused (≤8×108/kg vs.>8×108/kg, P=0.583), CD34+ cells infused (≤4×106/kg vs.>4×106/kg, P=0.946), and CD3+ cells infused (≤1.6×108/kg vs.>1.6×108/kg, P=0.143). DFS was significant lower in the patients with secondary AML (79.4% in primary AML vs. 53.5% in secondary AML, P=0.006) and MRD+ cases before transplant (81.4% in MRD- vs. 65.0% in MRD+, P=0.003). Accumulative non-relapse mortality (NRM) was significant higher in secondary AML (11.7% in primary AML vs. 33.3% in secondary AML, P=0.004) and MRD+ patients (10.5% in MRD- vs. 21.9% in MRD+, P=0.010). Accumulative relapse rate was significant higher in CR2 cases (8.0% in CR1 vs. 17.5% in CR2, P=0.046). Multivariate analysis showed that MRD pre-HSCT was the only impact factor on DFS and NRM with higher DFS (P=0.020) and lower NRM (P=0.045) in MRD- cases. Conclusions: Allo-HSCT has attenuated the influence of cytogenetics and gene mutations on DFS in AML. Secondary AML has lower DFS and higher NRM. Although disease status (CR1 vs. CR2) has no significant influence on DFS, relapse rate in CR2 is higher than that in CR1. MRD pre-conditioning was a key impact factor on DFS after allo-HSCT in AML but not conditioning regimen and donor type. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rabbit ATG Plus Cyclophosphamide with or without Fludarabine Is Superior Conditioning Regimen for Patients with Severe Aplastic Anemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2212-2212
Author(s):  
Parvez Ahmed ◽  
Tariq Mahmood Satti ◽  
Qamar Un Nisa Chaudhry ◽  
Kamran Mehmood ◽  
Nighat Shahbaz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Aplastic Anemia ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Severe Aplastic Anemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Group A ◽  
Group 2 ◽  
Group B

Abstract Objective: To compare rabbit antithymocyte globulin (ATG) containing conditioning regimen (group A) with horse antilymphocyte globulin (ALG)-based regimen (group B) for sibling allogeneic hematopoietic stem cell transplant (HSCT) outcome, disease free survival, rejection and complications in severe aplastic anemia patients. Methods: We analysed 205 aplastic anemia patients undergoing allogeneic HSCT from HLA matched sibling donors from July 2001 to April 2016. Group A (n=169) received conditioning with ATG plus Cyclophosphamide (CY) 200 mg/Kg with Fludarabine (Flu) 120mg/m2 (n=100) or without Flu (n=69), whereas group B comprised of CY plus ALG (n=36). The stem cell source was bone marrow (43.9%); PBSC (8.3%) and bone marrow plus PBSC (47.8%). Cyclosporin (CsA) was given as GVHD prophylaxis in 129 patients, while methotrexate (MTX) was added to CsA in 76 cases. Chi-square test was used to compare categorical variables. Kaplan Meier survival curves with log rank test was applied to compare the groups for survival analysis. Results: Overall survival was 78.7% in Group A compared to 69.4% in group B (p=0.23). Patients in group A had significantly better disease free survival (DFS) (75.1%) than group B (55.6%) (p=0.018). The incidence of acute GVHD was 18.3% in Group A compared to 22.2% in Group 2 (p=0.64), while chronic GVHD was significantly higher in Group 2 (22.2%) as compared to Group A (9.5%) (p= 0.04). Likewise frequency of Mucositis was high in Group B (30.5%) compared to Group A (10.7%) (p = 0.006). Moreover, patients receiving ALG-based conditioning had more frequent infections (86%) compared to ATG-based group (67.4%) (p=0.03). There was no significant difference within group A with respect to use of fludarabine as part of conditioning. Conclusion: Rabbit ATG containing conditioning regimen is associated with less complications and better survival in patients with severe aplastic anemia undergoing allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Patients Aged 65 Years or Older with AML and MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2301-2301 ◽  
Author(s):  
Marcos de Lima ◽  
Munir Shahjahan ◽  
Jorge Alamo ◽  
Patricia Williams ◽  
Brigitte von Wolff ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Stem Cell Source ◽  
One Year ◽  
Active Disease

Abstract Allogeneic HSCT is a potentially curative treatment for AML/MDS, but aging is generally associated with poorer outcomes. The incidence of AML/MDS, however, increases after the 7th decade of life, and there is limited data with transplantation in this age group. Here we review our experience treating such patients. Methods: Retrospective analysis of outcomes of patients aged 65 or older treated from 1996 to 2004 with allogeneic HSCT (n=40; median age 67 years, range 65–75 years). Diagnosis was MDS in 5 cases and AML in 35 patients. Cytogenetics were high-risk in 50% and intermediate risk in 50%; 80% of the patients had active disease at HSCT (n=32). All preparative regimens contained fludarabine 100–150 mg/m2, combined with cytarabine 4 gm/m2, and idarubicin 36 mg/m2 (n=12); or with busulfan (n=8); with melphalan 140 or 180 mg/m2 (n=12); and with melphalan 140 mg/m2 and Mylotarg 2 or 4 mg/m2 (n=8). ATG was added in unrelated donor (MUD) HSCT. All but 2 patients received tacrolimus and methotrexate for graft-versus host disease (GVHD) prophylaxis. Stem cell source was bone marrow in 11 cases and peripheral blood in the others. Donors were related in 27 cases and unrelated in 13 cases (33%). Results: 35 patients engrafted (88%); complete remission (CR) rate was 72%, 6 patients died early and 3 did not respond. Eleven patients are alive at a median of 12.5 mo (range, 2.6–59 mo), 10 of them in CR. One-year overall survival was 30% for the whole group, 26% for recipients of MUD and 32% for recipients of related donor HSCT (MUD x sibling, P=NS). One-year event-free survival was 28%. Median survival and disease-free survival was 4.5 and 2.5 mo, respectively; 42% of the patients in CR post HSCT have relapsed (n=13). Acute and chronic GVHD rates were 45% and 48%, respectively. Non-relapse mortality (NRM) was 40%. Figure shows survival of patients with and without circulating blasts at the time of transplant. Figure shows survival of patients with and without circulating blasts at the time of transplant. Conclusions: Here we expanded our previous observations indicating that allogeneic HSCT is a treatment option for selected patients in this age range. In this cohort with advanced stage disease (80% with active disease at transplant), NRM was high, but survival after sibling and unrelated donor transplants was similar.

Natural History of AML / MDS Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Using Reduced Intensity (RIC) Preparative Regimens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2019-2019
Author(s):  
Betul Oran ◽  
Sergio Giralt ◽  
Munir Shahjahan ◽  
Athanasios Anagnostopoulos ◽  
Daniel Couriel ◽  
...  
Keyword(s):  
Palliative Care ◽  
Natural History ◽  
Salvage Therapy ◽  
Disease Status ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
History Of ◽  
One Year

Abstract Patients relapsing after HSCT preceded by myeloablative preparative regimens have in general a poor prognosis. Less is known of the natural history of relapses after RIC for AML/MDS. Here we analyzed the outcomes of patients relapsing after RIC. Patients and Methods: 208 patients with a diagnosis of AML/MDS treated from August 1996 to December 2003 with fludarabine 100–150mg/m2 combined to IV busulfan 6.4–11.2mg/Kg (FluBu; n=53), to melphalan 100–180mg/m2 (FM; n=122), or to AraC 4 g/m2 and idarubicin 36 mg/m2 (Flagida; n=34) and unmanipulated HSCT. Donors were HLA matched related (MRD; n=111), unrelated (MUD; n=78) or mismatched related (MMRD; n=19). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus based in all but 8 pts that received cyclosporin-based regimens. Anti-thymocyte globulin was used in 61 MUD or MMRD HSCT. Results: 64 of 176 patients in complete remission (CR) 30 days post HSCT relapsed (FM, n=29; FluBu, n=17; Flagida, n=18) with one-year relapse-free survival (RFS) of 65%. Among the 64 relapsed patients, disease status at first HSCT was CR (n=13), relapsed/refractory (n=31), primary induction failure (PIF) (n=18) or untreated (n=2). Median time to relapse was 110 days (95% CI 89–131 days). Initial treatment was immunossupression withdrawal in 51 pts who had no ongoing GVHD; two achieved a transient CR for 1.3 and 8 months. 39 patients received further salvage therapy, 18 patients preferred palliative care, and in 7 cases no data was available. Median overall survival (OS) after relapse was 34 days (range, 12–246) on palliative care. Among pts that received salvage therapy, those achieving a CR had an OS of 27 months (range 2.6–68.2). OS was 94 days (range, 22–290) after failing any type of salvage therapy. Although one patient survived more than one year in CR after DLI +/− chemo salvage, all other long-term survivors received a second HSCT (Table). Conclusion: The likelihood of achieving a CR after failure of the first HSCT was greater among patients treated in CR at the time of the first HSCT. In this high-risk population, only a second HSCT provided prolonged relapse-free survival. Overall and relapse-free survival (RFS) after salvage therapy Disease status at first HSCT (number of responders/number treated) CR rate 1 yr OS 1 yr RFS for responders Salvage therapy CR Relapsed PIF Untreated NA* : Not applicable; 1 patient alive in CR; NA**: Not applicable, n =1 Chemotherapy alone (n=12) 0 / 1 2 / 8 0 / 3 16% 0% 0% Allogeneic HSCT alone (n=7) 2 / 2 1 / 3 0 / 2 43% 28% 67% Allogeneic HSCT+/− chemotherapy/DLI (n=11) 5 / 6 3 / 3 1 / 1 0 / 1 82% 73% 67% DLI+/− chemotherapy (n=9) 0 / 1 1 / 5 0 / 3 11% 13% NA* CR rate 70% 37% 11% 0% 1 yr OS 60% 23% 11% NA** 1 yr RFS for responders 58% 58% NA*

Allogeneic and Matched Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Using a Modified Reduced Intensity Conditioning Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5324-5324
Author(s):  
Marion Raflores ◽  
James Rossetti ◽  
John Lister ◽  
Richard Shadduck ◽  
John Lech ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Reduced Intensity Conditioning Regimen ◽  
Disease Free ◽  
Related Mortality

Abstract INTRODUCTION:Use of a reduced intensity conditioning regimen (RICR) in hematopoietic stem cell transplant may result in lower treatment related mortality (TRM), less acute graft versus host disease (aGVHD) and better survivability, utilizing the graft versus tumor effect from HSCT. METHODS: Our institution’s original RICR protocol conditioning regimen (Trial A) consists of fludarabine 30 mg/m2 (Day-5 to D-2), melphalan 140–180 mg/m2 (Day -3) and ethyol 910 mg/m2 (Day-3) in addition to mycophenolate mofetil 1 g q12H and tacrolimus(serum level 5–15 ng/ml) beginning Day -3 as immunosuppressive therapy. Transplantation was done using peripheral blood stem cells from the best HLA-antigen match sibling (allo) or matched unrelated donor (MUD). We retrospectively compared transplant data from this original protocol to a modified RICR protocol (Trial B) using a lower dose of melphalan 100mg/m2 and addition of thymoglobulin 2mg/kg/d (D-2 to D0). RESULTS: 46 patients were transplanted in Trial A with median age of 46 years. 25 patients had allogeneic and 21 had MUD transplant. 30 patients were transplanted in Trial B with median age of 44 years. 22 patients had an allogeneic and 8 had a MUD transplant. All patients were heavily pretreated with 13 patients in Trial A and 9 patients in Trial B have undergone at least one previous stem cell transplant. At D30, all patients in Trial B were alive while 11% of patients in Trial A died of treatment related cause. At D100, 51% of patients in Trial A and 70% of patients in Trial B were alive. D100 TRM was 40% in Trial A and 20% in Trial B. Table 1. Treatment Outcome OS(%) TRM (%) RM (%) Trial A Trial B Trial A Trial B Trial A Trial B OS:overall survival TRM:treatment related mortality RM: relapse mortality 30 Days MUD 81 100 19 0 0 0 Allo 96 100 4 0 0 0 Total 89 100 11 0 0 0 100 days MUD 40 63 60 38 0 0 Allo 60 73 24 14 16 14 Total 51 70 40 20 9 10 1 year overall survival was 30% in trial A and 20% in Trial B. 1 year disease free survival (DFS) was 18% in trial A and 13% in Trial B. Table 2. 1 year treatment outcome* Overall Survival(%) Disease Free Survival (DFS) % Trial A Trial B Trial A Trial B *for Trial B, 5 living patients have not yet reached 1 year follow-up MUD 21 13 14 0 Allo 37 23 21 18 Total 30 20 18 13 Incidence of aGVHD≥2 in patients not receiving DLI and alive for more than 30 days post transplant was 56% in Trial A (MUD 67%, Allo50%) and 25% in Trial B (MUD63%, Allo 6%). At D100, aGVHD was the most common cause of death in Trial A while overwhelming sepsis was leading cause of death in Trial B. WBC engraftment with ANC&gt;500 was achieved in 98% of patients in Trial A and 93% of patients in Trial B. Average day of engraftment was 13 days in Trial A and 15 days in Trial B. Platelet engraftment with platelet count at least 20,000 was achieved in 80% of patients in both protocols with average day of engraftment at 18 days in Trial A and 21 days in Trial B. 95% of patients in Trial A had achieved at least 80% donor marrow cells at D100 while only 81% achieved this level of chimerism in Trial B. CONCLUSION: The modified RICR protocol for HSCT is a tolerable regimen which results in a lower incidence of D100 TRM and aGVHD but overall and disease free survival are not improved. Marrow engraftment is achieved although slightly delayed compared to the original protocol.

Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) Not in First Remission

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4388-4388 ◽  
Author(s):  
Kendra L Sweet ◽  
Jeffrey E Lancet ◽  
Ryan Hillgruber ◽  
Megan Melody ◽  
Amina Llishi ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Mutational Status ◽  
The Impact

Abstract Background: Approximately 60 - 80% of AML patients achieve a complete remission [CR] with one or two cycles of induction chemotherapy, leaving many patients with refractory AML [PIF]. Unfortunately, the majority of patients in CR1 ultimately relapse. With salvage therapy, only 30-50% achieve CR2. Those with PIF or relapsed AML have shortened survival and few therapeutic options. Risk stratification is primarily based on karyotype, however other factors including age, initial white blood cell count, secondary AML and mutational status are also utilized to determine prognosis. HCT is an effective option for treatment of AML with intermediate/high risk features in CR1. It has also been utilized in refractory or relapsed disease. Advances in HCT over the last decade have improved overall survival (OS) and extended this option to older patients. Our aim is to characterize outcomes after HCT for AML patients who are not in CR1. Methods: We analyzed 136 AML patients who were not in CR1 at the time of HCT from 2004 - 2013. The conditioning regimen was fludarabine and myeloablative doses of PK targeted busulfan. IWG AML response criteria were used to define disease status at the time of transplant. Cytogenetic risk was based on the NCCN AML guidelines. OS is defined as the time from HCT until the time of death from any cause. Disease free survival (DFS) is defined as the time from HCT to the time of relapse or death from any cause. Results: Disease status consisted of 74 (54.4%) in CR2, 6 (4.4%) in CR3 or beyond, 27 (18.9%) were PIF, 21 (15.4%) with relapsed AML (REL) that was treated but still present at time of transplant, and 8 (5.7%) who received either no treatment or a hypomethylating agent (HMA). Median age was 52.0 (21.8 - 72.5) years, and 80 (59%) were male. Time from most recent treatment to HCT was < 1 month in 8 (5.8%), 1-3 months in 75 (55.8%), >3 months in 50 (36.8%) and not applicable in 3. Ninety-six (70.6%) had de novo AML, while 40 (29.4%) had secondary AML. Cytogenetic risk was favorable in 32 (23.5%), intermediate in 57 (42%), poor in 40 (29.4%) and unknown in 7 (5.1%). Graft-versus-host disease prophylaxis was tacrolimus with methotrexate or sirolimus, or mycophenolate mofetil. Donors included 41 (30.2%) matched related, 2 (1.4%) mismatched related, 65 (47.8%) matched unrelated and 28 (20.6%) mismatched unrelated donors. Peripheral blood stem cells were used in 97.2% of cases. Two year OS, DFS, cumulative incidence (CI) of relapse and CI-NRM for all patients was 45.3%, 35.2%, 47.1% and 18.2%, respectively. Two-year DFS stratified by disease status at time of HCT was 41.9%, 33.3%, 25.9%, 33.3% and 12.5% in CR2, CR3 or beyond, PIF, REL and HMA, respectively(p=0.011 for CR2 vs HMA) (Figure 1). Two-year DFS stratified by cytogenetic risk was 43.8%, 31.6%, 37.1% and 14.3% in favorable, intermediate, poor and unknown, respectively (p>0.05) (Figure2). CI-Rel stratified by disease status was 43.2%, 16.7%, 66.7%, 42.9% and 50% in CR2, CR3 or greater, PIF, REL and HMA, respectively (Figure 3). Conclusions: We analyzed 136 AML patients after undergoing HST outside of CR1 and the cumulative incidence of relapse at two years was 47%. Relapse was highest in those with primary induction failure or residual disease after either no or low intensity therapy. These data suggest that patients with active disease at the time of transplant fare worse than those who are transplanted in remission, highlighting the importance of effective upfront therapies in order to obtain the maximum potential benefit from HCT. Cytogenetic risk stratification did not significantly impact outcomes, although those with favorable risk cytogenetics trend towards higher 2-year DFS vs those with intermediate or poor-risk disease. Trials looking at the impact of maintenance therapy post-transplant may be valuable in this patient population. Table 1. Disease Status @ HSCT CR2 CR3 or beyond PIF RES HMA/untreated 2 years 41.9% (30.6 - 52.8) 33.3% (4.6 - 67.6) 25.9% (11.5 - 43.1) 33.3% (14.9 - 53.1) 12.5% (0.7 - 42.3) Table 2. Cytogenetic Risk Group Favorable Intermediate Unfavorable Unknown 2 years 43.8% (26.5 - 59.8) 31.6% (20.1 - 43.7) 37.1% (22.5 - 51.8) 14.3% (0.7 - 46.5) Table 3. Cumulative Incidence of Relapse CR2 (1) CR3 or beyond (2) PIF (3) REL (4) HMA/untreated (5) 2 years 43.2% (32.2 - 54.6) 16.7% (0.0 - 53.5) 66.7% (48.1 - 82.9) 42.9% (23.0 - 64.0) 50.0% (18.1 - 81.9) Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sweet: Novartis Pharmaceuticals: Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Karyopharm Therapeutics Inc: Research Funding; Incyte: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy; Boehringer-Ingelheim: Consultancy; Pfizer: Research Funding; Kalo-Bios: Consultancy; Amgen: Consultancy. Perkins:PDL Biopharma: Research Funding. Field:PDL Biopharma: Research Funding.

scholarly journals Antithymocyte globulin administration in patients with profound lymphopenia receiving a PBSC purine analog/busulfan-based conditioning regimen allograft

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maxime Jullien ◽  
Thierry Guillaume ◽  
Pierre Peterlin ◽  
Alice Garnier ◽  
Amandine Le Bourgeois ◽  
...  
Keyword(s):  
Antithymocyte Globulin ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Absolute Lymphocyte Count ◽  
Standards Of Care ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Purine Analog ◽  
The Impact

Abstract Graft-versus host disease (GVHD) remains one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (ASCT). Prophylactic T cell depletion via antithymocyte globulin (ATG) during ASCT conditioning is one of the standards of care for GVHD prophylaxis, although the optimal dosing strategy is still unclear. Recent studies have reported that absolute lymphocyte count at the time of ATG administration could predict survivals in ASCT from unrelated donors. Here this issue was examined in 116 patients receiving peripheral blood stem cells (PBSC) ASCT with purine analog/busulfan-based conditioning regimens between 2009 and 2019 in our department. The impact of lymphopenia at the time of ATG administration was evaluated in terms of overall survival, disease-free survival and GVHD-free/relapse-free survival. After a median follow-up of 4 years, no adverse effect of a profound lymphopenia was observed on patients’ outcome. Notably, a reduced dose of ATG in patients with profound lymphopenia did not translate into better survivals. This study indicates that ATG can be administered whatever the recipient’s lymphocyte counts in patients receiving a PBSC purine analog/busulfan-based conditioning regimen ASCT.

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