Updated Analysis of Hematopoietic Stem Cell Transplantations after Reduced Intensity Conditioning Regimen (RIC HSCT) for Hematological Malignancies from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire (SFGM-TC) Registry.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 45-45 ◽  
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Thomas Prebet ◽  
Mohamad Mohty ◽  
Jean Michel Boiron ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
The Impact ◽  
Global Population

Abstract This report updates a retrospective study from SFGM-TC registry concerning 738 patients who underwent RIC HSCT for hematological malignancies [280 F, 458 M, median age: 51 years (1–72)] between 1997 and 2004. The diagnosis were 173 AML, 40 ALL, 68 MDS, 152 NHL, 36 HD, 45 CLL, 70 CML, 154 MM; 332 patients have been previously transplanted. At time of conditioning, 261 patients were in CR, 224 in PR and 253 in progressive disease (PD). Peripheral blood stem cells (PBSC) were used in 574 patients and bone marrow in 164 patients from 655 HLA related donors and 83 unrelated donors. As conditioning, 152 patients received fludarabine and TBI (2 grays), 300 patients fludarabine, busulfan and anti-thymocyte globulins (FBS) (ATG 1d: 57, 2 d: 84, 3 d: 58, 4 d: 18, 5 d: 83) and 286 patients an other regimen. As GVHD prophylaxis, 722 patients received a cyclosporine A (CsA) based regimen. After transplant, 252 patients (35%) in the global population developed an acute GVHD ≥ grade II (grades III and IV: 116) and 208 patients (37%) in the PBSCT population (grades III and IV: 100). A chronic GVHD was present in 258 patients (38%) in the global population (115 limited and 143 extensive) and 221 patients (42%) in the PBSCT population (95 limited and 126 extensive). With a median follow-up of 27 months, the 3-year probability of overall survival (OS) and event-free survival (EFS) for the global population was 38% (33–44) and 28%(24–34) and for PBSC SCT patients 39%(33–46) and 32%(27–39) respectively. The 3-year probability of OS varied according to diagnosis (CLL: 62%, NHL:50%, CML:44%, MM:41%, MDS:37%, AML:26%, ALL:20%) and cGVHD (no:28%, yes:61%). The cumulative TRM incidence was 12% at 1 year and 13% at 3 years. A multivariate analysis was performed studying pre and post transplant factors for OS, EFS and GVHD:. Table 1 summarizes all variables showing a significant impact on OS and EFS. Furthermore, analyses showed the impact of one variable on AGVHD and cGVHD for PBSCT population: FBS with ATG 1day vs 2 days [HR:1.56(1.19–2.04) p=0.001, HR:1.50(1.14–1.97) p=0.003]. In conclusion, besides the influence of known factors on OS and EFS after RIC HSCT, this study pointed out, on a large series with a long-term follow-up, the major impact of disease status, acute and chronic GVHD and demonstrated the important role of ATG duration on GVHD incidence. Table 1: Multivariate analyses OS/EFS Variables OS (HR) p EFS (HR) p Conditionning :FBS ATG 1d vs 2 d Global 1.47 (1–2.2) 0,05 NS PBSC 1.6 (1.03–2.49) 0,04 NS FBS ATG 5d vs 2 d PBSC NS 1.13(1.04–1,24) < 0.01 PD vs CR Global 1.22 (1.1–1.32) < 0.01 1.15 (1.07–1.25) < 0.01 PBSC 1.2 (1.1–1,3) < 0.01 1.14 (1.05–1.24) < 0.01 Previous HSCT: yes vs no Global 1.27 (1.02–1,59) 0,04 1.25 (1.01–1.55) 0.04 AGVHD : Grade II vs 0-I PBSC 1.21 (1–1.47) 0,05 NS AGVHD : Grade III-IV vs 0-I Global 1,28 (1,14–1,43) < 0.01 1.12 (1–1.25) 0.04 PBSC 1.3 (1.14–1.47) < 0.01 1.13 (1–1.28) 0.05 cGVHD : yes vs no Global 0.2 (0.14–0.28) < 0.01 0.25 (0.19–0.35) < 0.01 PBSC 0.19 (0.13–0.28) < 0.01 0.25 (0.18–0.34) < 0.01

Updated Analysis of Allogeneic HSCT after RIC for Hematological Malignancies from the Société Française de Greffe de Moelle Osseuse et de Thérapie Cellulaire (SFGM-TC) Registry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1085-1085
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Mohamad Mohty ◽  
Franck E. Nicolini ◽  
Jean-Michel Boiron ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Term Survival ◽  
Allogeneic Hsct ◽  
Unrelated Donors ◽  
Grade Ii ◽  
Long Term Survivors

Abstract This report updates a retrospective study from SFGM-TC registry concerning 1108 patients who underwent allogeneic hematopoeitic stem cell transplantation (HSCT) after reduced intensity conditioning (RIC) from HLA identical siblings (84%) and unrelated donors (16%) for hematological malignancies. At time of conditioning, 442 patients were in CR, 337 in PR, 107 in stable disease (SD) and 222 in progressive disease (PD). As conditioning, 255 patients received fludarabine and TBI (2 grays), 465 patients fludarabine, busulfan and ATG and 388 patients an other regimen. After transplant, 336 patients (30%) developed an acute GVHD ≥ grade II (grade II: 178, III: 80 and IV: 78). A chronic GVHD was present in 388 patients (35%) (185 limited and 203 extensive). With a median follow-up of 30 months, the 3 and 5-year probability of overall survival (OS) were 43.5% (40–47) and 32%(29–35) respectively and the 3 and 5-year probability of event-free survival (EFS) were 35%(31–39) and 28% (24.5–31) respectively. The TRM at 1 year, 2 years and 3 years was 15% (13–17), 18% (15.5–21) and 20% (17–23). A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The probability to be a long-survivor was 24% (17.5–32.5) (Fig.1) and to be a long event-free survivor was 23% (19–28) (Fig. 2). The multivariate analysis has tested recipient and donor age, disease status pre-transplant, number of transplants before RICT, HSC source, sex matching, HLA matching, CMV status and ABO compatibility. The only factor which had a significant impact on long-term survival after RICT was the disease status just prior conditioning: PR versus CR: HR: 3.63 [1.14–9.18] p<0.001 and PD versus CR: HR: 4.35 [2.22–8.51] p<0.0001. In conclusion, these updated data demonstrate that allogeneic HSCT after RIC was able to possibly cure 23% of patients with haematological malignancies and the most important factor to take into account remains to be in CR pre-transplant. Figure 1 Figure 1. Figure 2 Figure 2.

Optimizing the Outcomes of Allogeneic Hematopoietic Stem Cell (HSC) Transplantation for Hematological Malignancies: The Perfect Combination of Conditioning Regimen, Disease Stage and Type of HSC Donor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4324-4324
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Hélène Labussière-wallet ◽  
Marie Balsat ◽  
Caroline Lejeune ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Hematological Malignancies ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Disease Stage ◽  
Hla Matching ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative strategy for a majority of patients with high-risk hematological malignancies. Several studies have evaluated the impact of conditioning intensity on the long-term transplantation outcomes, mainly retrospective and derived from large registries or non-randomized trials. These studies showed that more intensive conditioning (MAC) regimens are associated with a reduced risk of relapse, but do not translate into improvement of survival due to increased non-relapse mortality (NRM). Reduced intensity/Non-myeloablative conditioning (RIC/NMA) through graft-versus-leukemia effect has been associated with lower NRM, but higher relapse rates leading to similar overall survival (OS) when compared to MAC. However, in daily clinical practice, these results are difficult to follow because of the combination of important impact of disease stage, the type of HSC donor and its HLA matching with the patient. In addition, the historical nature of the previous studies may lead to the observation of different results today as the experience in drugs toxicities management has changed over time. The objective of this study is to evaluate the impact of the conditioning regimen intensity taking into account the disease stage and the type of HSC donor with its HLA matching on transplantation outcomes in a large population of patients with high-risk hematological malignancies. Material and methods A total of 542 patients who received allo-HSCT between January 2006 and December 2014 in our center were included, 321 (59%) were males, the median age at allo-HSCT was 49 years (range: 18-70). There was 256 (47%) acute leukemia (202 AML, 54 ALL), 61 (11%) MDS, 60 (11%) multiple myeloma, 46 (8%) NHL, 25 (5%) Hodgkin's disease, 23 (4%) myeloproliferative neoplasms, 21 (4%) CML, 12 (2%) CLL and the rest with other hematological diseases. All patients were classified as at high-risk according to either clinical, immunophenotypic, cytogenetic or molecular markers. Conditioning regimen was classified as recently published (Gyurkocza et al. Blood 2014), therefore 282 (52%) received MAC and 260 (48%) received RIC/NMA; at allo-HSCT 320 (59%) patients were in CR and 222 (41%) in less than CR. HSC donor was identical siblings (Sib) for 199 (37%) patients (100 BM, 99 PBSC), 10/10 HLA matched unrelated (MUD) for 159 (29%) (79 BM, 80 PBSC), 6/6 HLA matched double cord blood (CB) units for 12 (2%), 9/10 HLA mismatched unrelated (MMUD) for 114 (21%) (54 BM, 60 PBSC), and the rest of 58 (11%) were 5/6 or 4/6 MM double CB units. For sex mismatching, in 119 (22%), it was female donor to a male patient; 295 (54%) were ABO compatible, 105 (20%) had minor incompatibility and 142 (26%) major incompatibility. Results The median follow-up for surviving patients was 29 months (range: 4-96). We conducted a cox multivariate model for OS including patient age, disease status at allo-HSCT, conditioning regimen, type of donor and HLA matching, in addition to ABO and sex mismatching, with stratification on the type of disease; this model showed a significant impact of disease status in favor of CR (HR=1.5, 95%CI: 1.2-2.0, p=0.001), conditioning regimen in favor of MAC (HR=0.68, 95% CI: 0.53-0.88, p=0.003) and type of donor in favor of Sib (HR=0.68, 95%CI: 0.5-0.9, p=0.01). Interestingly, we were able to find an optimal association between these 3 factors leading to significantly better results in terms of OS and NRM independently of the disease type. When in CR, patients receiving MAC from Sib or from MUD had significant better OS and NRM compared to the rest of patients with 5-years rates of 71% vs 36% (p<0.0001) and 15% vs 37% (p=0.001) respectively. If not in CR, only patients who received HSC from Sib either after RIC or MAC showed significantly better OS and NRM compared to the rest of patients with 5-years rates of 50% vs 26% (p=0.001) and 22% vs 45% (p=0.008) respectively (see Figure). Considering only MMUD, patients receiving CB with RIC had better OS and NRM rates compared to 9/10 MMUD (RIC or MAC) and to MAC CB (p=0.07). Conclusion We provide in this large study, a practical daily clinical practice outcome preview after allo-HSCT, independently of the type of disease, for the combination of significant impacting factors namely disease status at allo-HSCT, conditioning regimen and type of HSC donor with a superiority for MAC when used in CR from Sib or MUD. Figure 1. Figure 1. Disclosures Nicolini: Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Single Center Experience of Allogenic Hematopoietic Stem Cell Transplantation in 100 Patients with Myelodysplasia: The Impact of Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5537-5537
Author(s):  
Colombe Saillard ◽  
Raynier Devillier ◽  
Sabine Furst ◽  
Jérome Rey ◽  
Angela Granata ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Donor Type ◽  
The Impact ◽  
Disease Free

Abstract Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for patients with myelodysplasia (MDS). However, because of age, MDS patients represent a challenging population for such an intensive treatment. Additionally, the low rate of HLA-identical donor has represented a major limitation in this strategy. Recently, reduced-intensity conditioning (RIC) regimens have made feasible Allo-HSCT in the elderly, although relapse rate might be increased. Additionally, the development of HSCT using alternative donors overcomes HLA-compatibility limitations. Graft-versus-host disease (GVHD) is a major post-transplant event, graft-versus-leukemia effect being counterbalanced by toxicity and impaired quality of life. The aim of this retrospective study was to report outcome of patients with MDS who underwent Allo-HSCT and to study the impact of GVHD. Methods Between 2003 and 2014, 100 consecutive patients presenting with MDS, or MDS-secondary AML, underwent Allo-HSCT in our institution. At diagnosis, 58 patients had ≥ 2 cytopenias. IPPS was low/intermediate-1 in 46% and intermediate-2/high in 54%, R-IPSS was very low/low in 25%, intermediate in 20% and high/very high in 55%. Cytogenetics, according to Disease Risk Index (DRI), was intermediate in 79% and adverse in 21%. Secondary MDS represented 27% of our cohort. Before Allo-HSCT, 42% received 5-Azacytidine, 27% intensive chemotherapy and 9% were transplanted upfront. At the time of Allo-HSCT, the median recipient age was 61 (19-71) years. Median time between diagnosis and Allo-HSCT was 12 months (1-131). After excluding patients transplanted upfront, 31 patients still had ≥5% blasts after treatment. Donors were HLA-matched in 70% (41% related, 29% unrelated), 30% were not HLA-matched (10% unrelated, 7% cord blood, 13% T-repleted haplo-HSCT). Stem cell source was peripheral blood stem cells in 90%. Twelve percent of patients received non-myeloablative (NMA) conditioning regimen, 75% RIC and 13% reduced-toxicity conditioning (RTC) regimens. Post-graft immunosuppression consisted in cyclosporine A (CSA) in 58%, CSA-Mycophenolate Mofetil (MMF) in 15%, CSA-Methotrexate in 14% and CSA-MMF-Cyclophosphamide for haplo-HSCT (13%). Results Median follow-up was 37 months (3-197). The incidence of 3-4 acute GVHD at day 100 was 7% (95% CI = 2-12). The incidence of severe chronic GVHD at 3 years was 19% (95% CI = 11-27). One and 3-year non-relapse mortality (NRM) were 23 and 29% respectively. The cumulative incidence of relapse (CIR) at 1 year and 3 years 24% and 33% respectively. One and 3-year progression-free survival (PFS) were 52% (95% CI = 43-63) and 37% (95% CI = 28-49). One and 3-year overall survival (OS) were 60% (95% CI = 51-71) and 48% (95% CI = 39-60). At one year, 51 patients were alive and disease-free, including 61% (n=31) without immunosuppression. At the end of follow-up, 39 patients were alive and disease-free, including 85% (n=33) without immunosuppression and 77% (n=30) GVHD-free. Time-dependent analysis of GVHD impact (Table 1), adjusted on age, donor-type, DRI and conditioning regimen, revealed that acute GVHD strongly impacts on OS (HR 3.8, 95% IC = 2-7, p<0.01), PFS (HR 3.1, 95% CI = 1.7-5.6, p<0.01) and NRM (HR 12, 95% CI = 5.2-28, p<0.01). Chronic GVHD was statistically significant on CIR (HR 0.16, 95% CI = 0.04-0.7, p=0.02) and NRM (HR 2.8, 95% CI = 1-8, p=0.05). Pre-transplant disease characteristics did not have any impact by univariate analysis. Multivariate analysis did not find any impact of age, donor type, DRI and conditioning regimen in terms of OS, PFS, NRM and CIR. Conclusion Our results suggest that GVHD highly influences outcome, regardless of MDS and Allo-HSCT characteristics. It should be quoted that a significant number of patients are alive, long-term survivors, disease-free and GVHD-free suggesting good quality of life. These results invite defining better strategies of GVHD prevention while retaining disease control magnifying the existing graft-versus-leukemia effect. Table 1. Time-dependent analysis of the impact of acute and chronic GVHD, adjusted on age (< or > 60), donor-type (HLA-matched or not matched), DRI and conditioning regimen (NMA, RIC or RTC). HR 95% CI p Acute GVHD OS PFS NRM CIR 3.8 3.1 12 0.4 2-7 1.7-5.6 5.2-28 0.09-1.7 <0.01 <0.01 <0.01 0.2 Chronic GVHD OS PFS NRM CIR 0.7 0.8 2.8 0.2 0.3-1.5 0.4-1.8 1.01-8 0.04-0.8 0.4 0.6 0.050.02 Disclosures Vey: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

Total Body Irradiation (TBI), Fludarabine (F), Melphalan (M) and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Pediatric Hematologic Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1827-1827 ◽  
Author(s):  
Demetrios Petropoulos ◽  
Laura L. Worth ◽  
Craig A. Mullen ◽  
Anita Mahajan ◽  
Mary S. Choroszy ◽  
...  
Keyword(s):  
Cord Blood ◽  
Graft Failure ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Early Death ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem

Abstract The FM reduced-intensity preparative regimen has been used successfully in adults for allogeneic HSCT. Its role in pediatric hematologic malignancies is unclear. We studied the engraftment efficacy and the antineoplastic effect of adding TBI to the FM combination. Between July 1998 and January 2004 a total of 29 pediatric (19 males) patients were treated. Twenty-two had acute lymphoblastic leukemia (ALL), 6 had acute myeloid leukemia (AML), and 1 anaplastic large cell lymphoma. Disease status at the time of SCT was: CR2 (19 patients), CR3 (5), CR1 (2, with Ph+ leukemia), and induction failure/relapse (3). Six patients received this regimen for a second HSCT. The donor was unrelated in 21 cases: 1–2 antigen mismatched cord blood (CB) in 20, and peripheral blood stem cells (PBSC) in one. Of the 8 related-donor HSCT, 2 were not genotypically identical. The conditioning regimen was TBI 9Gy (3 fractions on day -7, -6, and -5), F 30 mg/m2 IV daily (days -4 to -1) and M 140 mg/m2 IV on day -1. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. No anti-thymocyte globulin was used. The regimen was well-tolerated, with grade II-III oral mucositis and diarrhea the most common side effects seen. Twenty-seven patients achieved ANC engraftment after a median time of 16 days (range 11–35), and 23 also had platelet engraftment at a median of 42 days (range 14–200). There was one case of primary graft failure and one early death. Six of 27 evaluable patients developed grade III-IV acute GVHD and three chronic GVHD. There were seven deaths in the first 100 days (3 from interstitial pneumonitis, 1 GVHD, 1 renal failure, 1 VOD, 1 graft failure), all in patients with ALL. Nine patients (7 with ALL) relapsed at a median of 8 months post-transplant (range 2–54). With a median follow-up of 54 months (range 7–79), 7 of 22 ALL, 5 of 6 AML, 1 of 1 lymphoma patients are alive and in remission (12 are over two years post HSCT). In conclusion, the addition of TBI to FM leads to successful engraftment of allogeneic HSC (including 1–2 antigen mismatched unrelated cord blood units) in heavily pretreated pediatric patients with hematologic malignancies, without the inclusion of ATG. The regimen was well tolerated and its activity in AML deserves further evaluation.

Multi-Center Prospective Trial on Conditioning with Treosulfan, Fludarabine and ATG Before Allogeneic HSCT from Unrelated Donors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4949-4949
Author(s):  
Mauricette Michallet ◽  
Quoc-Hung Le ◽  
Anne Thiebaut ◽  
Sophie Ducastelle ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Prospective Trial ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Low Risk ◽  
Unrelated Donor ◽  
Match Analysis ◽  
Hematopoietic Stem ◽  
Unrelated Donors ◽  
Grade Ii

Abstract This prospective multi-center trial (MiniMud) concerns 27 patients (13 females, 14 males - 56 years[18–65]) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors. The diagnosis and disease status pre-transplant were AML (n=12; 5 CR1, 7 CR2), ALL (n=1; 1 CR2), MM (n=5; 3 PR2,1 PR3, 1 PR4), NHL (n=4; 1 CR1, 2 PR3, 1 PR4), MPS (n=3; 2 stable disease (SD), 1 Relapse), acute RAEB (n=1; 1 progressive disease (PD) and CLL (n=1; 1 PR2). In total, 14 patients were in CR, 9 in PR, 2 in SD, 2 in PD. The median interval between diagnosis and transplant was 27 months [5;171], 24 patients received PBSC and 3 received bone marrow from unrelated 10/10 antigen HLA-identical (high-resolution level). All patients received Fludarabine 30 mg/m2/dx5d, Treosulfan 12 g/m2/dx3d and ATG 2,5 mg/kg/dx3d. After transplant, we observed 2 graft failures, 7 patients developed an AGVHD ≥ grade II (30%). Only 23 patients were eligibile to be analysed after 3 months of follow-up post transplant, 7 patients developed cGVHD (30%) (5 limited and 2 extensive), 12 patients died (7 from TRM causes and 5 from relapse) and 12 patients are alive in CR with a median follow-up of 14 months. Among the global population we defined a low risk subgroup: 17 patients [12 AML (5 CR1, 7 CR2), 1 ALL (CR2), 3 MM (3 PR2) and 1 NHL (CR1)], 2 patients presented an AGVHD ≥ grade II (13%). With a median follow-up of 18 months, 2 patients had a follow-up of less than 3 months, 3 patients developed a cGVHD (20%), 6 patients died (40%) and 9 patients are alive in CR. At one year, the probability of overall survival (OS) and event-free survival (EFS) were 50.4% [32;79], 40% [23;70] for the total population and 60% [37;96], 51.5% [29;90] for the low risk subgroup respectively. To try to demonstrate if Treosulfan allowed a better transplant outcome we performed a paired match-analysis [center and 4 out of 5 other parameters (age, gender, HSC, pre-transplant status and diagnosis] comparing our Treosulfan series and RIC transplants receiving Fludarabine, Busulfan and ATG (2.5–12.5mg/kg) from the SFGM-TC registry. This paired match-analysis found only RICT from related donors in the SFGM-TC database and showed no difference in term of OS and EFS between our unrelated donor-Treosulfan and related donor-SFGM-TC series. Figure Figure Figure Figure In conclusion, these results demonstrate that Treosulfan appears to be a very promising drug that could be included in the conditioning regimen before HSCT from either related or unrelated donors.

Platelet-Derived Microparticles Accelerate Engraftment of Peripheral Blood Stem Cells in Human Allogeneic Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3035-3035
Author(s):  
Christiane de Rop ◽  
Jan Priesack ◽  
Andreas Tiede ◽  
Arne Trummer
Keyword(s):  
Stem Cells ◽  
Cell Count ◽  
Peripheral Blood ◽  
Hematological Malignancies ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Positive Control ◽  
Peripheral Blood Stem Cells ◽  
Blood Stem Cells ◽  
The Impact

Abstract While the procoagulant activity of platelet derived microparticles (PMP) has been widely accepted, knowledge regarding their immunological and adhesive qualities is still limited. It has been shown that murine BM cells covered with PMP engrafted lethally irradiated mice significantly faster than those not covered, indicating that PMPs play an important role in the homing of peripheral blood stem cells (PBSC). Here we studied the impact of PMP on engraftment in human allogeneic PBSC transplants for patients with hematological malignancies. PBSC samples were collected in buffered citrate from transplantation bags after infusion of transplants into patients with hematological malignancies (AML = 5, ALL = 1). Conditioning regimens included busulfan/cyclophosphamide (Bu/Cy), anti-CD66b-radioimmunotherapy (RIT)/Bu/Cy, and reduced intensity regimens with fludarabin/busulfan (Flu/Bu) and FLAMSA. Platelet-poor plasma (PPP) was prepared (1500g for 20min), immediately shock-frozen in liquid nitrogen and stored at −80°C. For further analysis PPP’s were carefully thawed at room temperature (RT). 90μl of PPP was stained with 5μl of CD41-PE and CD62P-FITC each for 15min at RT in the dark (IgG1-FITC and -PE served as negative controls, TRAP-6 (10μM) stimulated whole blood processed in same way as samples as positive control). To stop staining 900μl PBS/BSA 2% was added and 500μl of this solution were transferred into BD Trucount tubes by reverse pipetting giving a final concentration of 100 beads/μl. Samples were analyzed immediately using Coulter FC500 flow cytometer with CXP software. As expected the CD34 cell count (mean=5.1x106/kg body weight, SD=2.0x106/kg) showed a significant correlation (p=0.0197, Pearson r=−0.83) with the time to engraftment (mean=15.7days, SD=2.0d). The amount of CD62P positive microparticles (mean=423/μl, SD=119/μl) and the conditioning regimen showed no significant correlation with CD34 cell count or time to engraftment with leucocytes >1000/μl. In contrast, CD41-PMP count (mean=1223/μl, SD=857μl) correlated significantly with the CD34 cell count (p=0.0086, Pearson r=0.92) and the time to engraftment (p=0.0039, Pearson r = −0.95). Therefore, PBSCT contain significant amounts of PMP which are most likely generated during apheresis. Preliminary results show a stronger correlation with time to engraftment than does CD34 cell count. We conclude that PMP may accelerate engraftment of PBSC in humans. However, this function seems unrelated to P-Selectin expression. Therefore, further studies aiming to identify other adhesion molecules involved in PMP-mediated engraftment of PBSCT are warranted.

Durable Remission with Decreased HTLV-I Proviral Load after Reduced-Intensity Stem Cell Transplantation (RIST) in Patients with Adult T-Cell Leukemia/Lymphoma (ATL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3347-3347
Author(s):  
Ryuji Tanosaki ◽  
Kisato Nosaka ◽  
Shin Mineishi ◽  
Shin-ichiro Mori ◽  
Sung-Won Kim ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Disease Status ◽  
Donor Lymphocyte Infusion ◽  
Acute Type ◽  
Adult T Cell Leukemia ◽  
Trial Testing ◽  
Grade Ii ◽  
Related Donor ◽  
Healthy Carriers

Abstract Background. ATL is an HTLV-I-associated hematological malignancy. The majority of ATL patients are not curable using current chemotherapy with median survival time of 13 months. Recently, patients undergoing allo-SCT with conventional conditioning regimen were reported to have a 3-year overall survival (OS) rate of 45%, however, with high transplant-related mortality (TRM) rate as much as 40% (Fukushima T. Leukemia19:829, 2005). Since most ATL patients are over 50 years old with various complications, limited numbers of patients are eligible for conventional transplant. We have already conducted a phase I multi-center trial testing the feasibility of RIST in ATL patients, where 2-year OS was 33% and some differences in the outcome were suggested among participating institutes. Hence, we investigated the efficacy of RIST performed exclusively in our single institute (NCCH, Japan). Patients and Methods. Between Oct 2000 and Jun 2005, 16 ATL patients underwent RIST from a related donor. Since 3 have been enrolled into an on-going multi-center trial, 13 patients were analyzed in this retrospective study, including 3 who were enrolled into the above-mentioned multi-center trial (Okamura J. Blood105;4143, 2005). Median age was 51 years old (range, 44–61), 8 males and 5 females, and 8 were of acute type and 5 of lymphoma. The disease status at transplant was 3 CR, 7 PR and 3 primary refractory. Three donors were HTLV-I healthy carriers. Eleven were HLA 6/6, 2 were 5/6, 12 were PBSCT and 1 was BMT. Conditioning regimen was fludarabine 30 mg/m2 x6, busulfan 4 mg/kg x2 with (n=5) or without (n=8) rabbit ATG 2.5 mg/kg x2. Prophylaxis of GVHD was CSP alone. Results. Engraftment was rapid (median, 11 days) in all cases, and there was no TRM. Acute GVHD of grade II–IV developed in 7, and chronic extensive GVHD in 5. Eleven patients achieved CR after RIST, and 6 relapsed or progressed, among whom 2 achieved CR after cessation of CSP, donor lymphocyte infusion and local irradiation, and have been disease-free for more than 1 year. Ten patients are alive, 9 without disease, with median follow-up time of 26 mos (range, 4–45 mos). HTLV-I proviral titers determined using real time PCR decreased after RIST and became undetectable in 8 out of 13 patients. In 3, including one transplanted from an HTLV-I carrier donor, anti-HTLV-1 antibody transiently decreased and became nearly undetectable. Conclusions. RIST is feasible and safe in ATL patients, and it has not only an anti-ATL but also an anti-HTLV-I activity. This is the first report documenting the efficacy of RIST for ATL in terms of survival and remission durability. Figure Figure

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Luznik Leo ◽  
Chen R. Allen ◽  
Kaup Michele ◽  
Bright C. Emilie ◽  
Bolanos-Meade Javier ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Gvhd ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
The Impact

Abstract Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

Late Pulmonary Dysfunction in Long-Term Survivors after allogeneic Hematopoietic Stem Cell Transplantation with Intensified Conditioning Regimen Including Thiotepa, Cyclophosphamide, and Total Body Irradiation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2137-2137
Author(s):  
Satomi Ito ◽  
Maki Hagihara ◽  
Kenji Motohashi ◽  
Atsuo Maruta ◽  
Yoshiaki Ishigatsubo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Pulmonary Dysfunction ◽  
Hematopoietic Stem ◽  
Related Donor ◽  
Total Body ◽  
Long Term Survivors

Abstract Background: Late pulmonary dysfunction is a clinical problem influencing on quality-of-life (QOL) in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). In this study we retrospectively assessed pulmonary function test (PFT) in patients surviving 5 years or more after HSCT with intensified conditioning regimen and identified pre-and post-transplant risk factors. Methods: Sixty-five long-term survivors transplanted between May 1994 and March 2003 (minimum 5 years follow-up after HSCT) were included in this analysis. There were 36 males and 29 females. Median age was 39 years, with a range of 16 to 53 years. All patients were transplanted because of hematologic malignancies (20 patients with AML, 16 with ALL, 9 with MDS, and 20 with CML). The pre-transplant conditioning regimen consisted of thiotepa (200 mg/m2 for 2 days), cyclophosphamide (2,000–2,250 mg/m2 for 2 days), and total body irradiation (12.5 Gy in five fractions). The prophylaxis of graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine or tacrolimus. Bone marrow (BM) from related donor or unrelated donor, and peripheral blood stem cell (PBSC) from related donor were transplanted in 33 patients, 22, and 10, respectively. PFT was performed pre-conditioning and then post-transplant at 3 months, 1 year, and thereafter annually. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC ratio were used to measure ventilatory capacity. Vital capacity (VC) and total lung capacity (TLC) were used to measure lung volumes. Diffusion capacity for carbon monoxide (DLCO) was determined by using a carbon monoxide single-breath technique with correction for hemoglobin concentration. Results: Seven (11%) patients showed abnormalities in PFT after HSCT. Temporary abnormality (restrictive pattern) within 1 year was detected in 2 patients. Five patients developed late-onset and continuous abnormality (restrictive pattern in 2 patients, obstructive in 2, and mixed in 2) with a cumulative incidence of 8%. These were clinically diagnosed as having bronchiolitis obliterans in 3 patient and interstitial pneumonia in 1. DLCO was significantly lower after transplantation of PBSC than after BM (P=0.02 at 3 year and P=0.00 3 at 5 year). More than 40 years old, female, high risk of disease status, and abnormal PFT pre-transplant were related with a decline of PFT within 1 year after HSCT, but there were no association with PFT abnormality at 3 or 5 years. The cumulative incidence of late PFT abnormality in patients with CML was significantly higher than that in those with other than CML (P=0.01).Other factors including age, sex, smoking, disease status, and donor sources were not significant for developing late pulmonary dysfunction. Extensive chronic GVHD was associated with late PFT abnormality with statistical significance (P=0.002 for VC and P=0.01 for FEV1). Three of 7 patients receiving immunosuppressant at 5 years after HSCT had pulmonary complication. Conclusions: The results showed relatively a low incidence of PFT abnormality in long-term survivors who received HSCT with intensified conditioning regimen. However, late pulmonary dysfunction lowers QOL in survivors despite long-term remission of leukemia Longer follow-up should be needed to determine whether more patients with chronic GVHD will develop PFT abnormality.

Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using Alemtuzumab and Cyclophosphamide as Conditioning Regimen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3198-3198
Author(s):  
Fernanda Lodi ◽  
Gustavo Teixeira ◽  
Antonio Vaz Macedo ◽  
Rosana Lamego ◽  
Simone Silva Magalhaes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Median Number ◽  
Off Label Use ◽  
Hematopoietic Stem ◽  
Off Label

Abstract Abstract 3198 Poster Board III-135 Introduction Cyclophosphamide (Cy) with/without antithymocyte globulin (ATG) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (AlloHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). In developing countries, and particularly in Brazil, ATG costs limit its use in AlloHSCT for SAA patients. Alternative low-cost regiments, like busulfan (BU) with Cy as conditioning regimen is still associated with a significant rate of rejection, especially in heavily transfused patients, and long-term infertility. Alemtuzumab (Cam) was reported as an alternative to ATG for SAA patients, with similar activity and a lower cost. Material and Methods In order to study the effect of the combination of Cy and Cam, we reviewed all AlloHSCT performed for SAA using this conditioning regimen. Between April 2007 and Mai 2009, fifteen patients with SAA (defined by Camitta criteria) underwent an AlloHSCT in our institution. Median age at transplantation was 25 (range 5-42) years. All but one patient had positive CMV serology. Median number of transfusions was 20 (range 10-67). One patient received a second AlloHSCT due to a late (> 4 years) graft rejection. Patients received an unmanipulated bone marrow (n=11) or peripheral blood (n=4) graft as stem cell source and all but one patient were transplanted with an HLA-identical sibling. Median number of nucleated cell infused was 2.86 (range 1.65-6.50)x10 8/kg. Cyclosporin alone (n=10) or in combination with methotrexate (n=5) was used as GVHD prophylaxis. Results Thirteen out of 15 patients presented neutrophil recovery with a median time to > 0.5×10 9 neutrophil/L of 23 (range 13-30) days. Platelet recovery (> 20×10 9 platelets/L) occurred in thirteen patients with a median time of 16.5 (range 9-45) days. Acute graft versus host disease (GVHD) was observed in just one patient (grade II). None of 12 patients alive 100-days after AlloHSCT presented chronic GVHD. Seven patients presented CMV reactivation. One patient did not engrafted and other presented a late (14 months) rejection. One patient became pregnant after alloHSCT and gave birth to a healthy child. With a median follow-up of 315(range 4-782) days, two patients died and the estimate 1-year overall survival rate is 87%. One patient died due to complications of a CNS bleeding that occurred hours before marrow infusion and the other of GI infection while still on neutropenia. Conclusion Use of cyclophosphamide and alemtuzumab as conditioning regimen is a valid option in SAA patients undertaking AlloHSCT, with significant lower rates of acute and chronic GVHD. Nevertheless, a longer follow-up is required to properly evaluate rejection incidence. Disclosures Off Label Use: Drug: Alemtuzumab Off-label Use: Aplastic Anemia.

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