Optimal Conditioning Regimen for Haplo-Identical Stem Cell Transplantation in Adult Patients with Acquired Severe Aplastic Anemia: Prospective De-Escalation Study of TBI and ATG Dose

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2196-2196
Author(s):  
Sung-Eun Lee ◽  
Sung Soo Park ◽  
Young-Woo Jeon ◽  
Jae-Ho Yoon ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Adult Patients ◽  
Free Survival ◽  
Group 4 ◽  
Optimal Conditioning ◽  
Group 2 ◽  
Group 1

Abstract Background Recent advances in controlling graft failure and graft-versus-host disease (GVHD) due to barrier of HLA incompatibilities in haplo-identical stem cell transplantation from related mismatched donor (Haplo-SCT) extended its application to severe aplastic anemia (SAA). Therefore, studies for searching optimal conditioning regimen and strategy of graft manipulations for SAA patients who receive Haplo-SCT are needed. This prospective study was aimed to explore the optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with SAA who received Haplo-SCT. Methods We have explored a safe and sufficient dose of ATG in combination with 800 cGy TBI and fludarabine (Flu, 30 mg/m2/day) for 5 days using step by step dose de-escalation based on the transplant-related mortality (TRM) and toxicity. The dose of ATG was de-escalated from 10 mg/kg (group 1), 7.5 mg/kg (group 2), to 5 mg/kg (group 3) and from October 2014, the TBI dose also reduced to 600 cGy with fixed dose of Flu and ATG (5mg/kg) (group 4). If any patient developed TRM with engraftment in each group, we moved to next group. For GVHD prophylaxis, a combination of tacrolimus and short-course methotrexate was used. G-CSF mobilized PBSCs were used as stem cell source without manipulation. Considering the importance of both survival and GVHD rate when testing conditioning regimen, GVHD-free survival, defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, or death was addressed. Results Twenty-nine patients including 18 men and 11 women were enrolled. The median age was 31 (17-52) years. Median CD34+ cells transplanted were 5.84x106/kg (1.45-16.2). All patients achieved primary engraftment. Thirteen patients (7 of 10 in the group 1-3, 6 of 19 in the group 4) had CMV DNAemia requiring pre-emptive therapy including 3 patients with CMV disease (2 pneumonia, 1 colitis). Three patients (2 in the group 1, 1 in the group 2) developed EBV-associated PTLD, of whom two patients with monomorphic type received rituximab and chemotherapy. The incidence of acute GVHD (grade ≥2) and chronic GVHD (≥ moderate) were 24% and 17%, respectively. With a median follow-up of 41.4 (31.9-48.9) months in the group 1-3 and 10.1 (1.3-20.6) months in the group 4, probability of overall survival (94.1% in the group 4 vs. 70% in the group 1-3, P = 0.292) and GVHD-free survival (73.3% in the group 4 vs. 50% in the group 1-3, P = 0.161) were improved in the group 4. Conclusions This study explored the optimal conditioning with step by step de-escalation dose of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/low-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA. Disclosures No relevant conflicts of interest to declare.

Is Antilymphocyte Globulin Useful in Conditioning Regimen of Unrelated Donor Hematopoïetic Stem Cell Transplantation?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2067-2067
Author(s):  
Helene Esperou ◽  
Marie Lorraine Appert ◽  
Ibrahim Yacoub Agha ◽  
Noel Milpied ◽  
Norbert Ifrah ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Allelic Differences ◽  
Group 2 ◽  
Grade Iii ◽  
Group 1

Abstract Between 1998 and 2004, 2141 allogeneic hematopoietic stem cell transplantations with unrelated donor (excluding cord blood) have been recorded on the SFGM-TC data base. The lack of unique behavior in regard of Anti Lymphocyte Globulin (ALG) use in unrelated donor transplants allowed us to perform a retrospective study to assess the influence of ALG in such grafts. To avoid biaises we excluded T cell depletion or monoclonal antibody use, reduced intensity conditioning and focused only on patients (pts) with acute leukemia (AL) and myelodysplasia (MDS). So we defined a study population of 553 pts. In addition, in order to analyze the actual impact of ALG on wellknown targets (engraftment, acute GvHD, relapse, survival) we choose to keep only the cases in which was available the allelic HLA typing (4 digits) for the recipient and the donor, i.e. 250 pts. There were 106 females and 144 males, allografted in 29 centers. The median age was 23 years (1–62) and there were 77 children under 15. There were 223 AL - myeloid n=120, lymphoid n=103 - and 27 MDS. The source of cells was bone marrow for 190 pts and peripheral mobilized stem cells for 60. One hundred and ninety-three pts received a conditioning regimen including Total Body Irradiation. Ninety-five pts received ALG (mainly Thymoglobulin Mérieux-Genzyme Lyon France at various doses) for a median of 3 days (group 1) and 155 did not (group 2). There were 189 donor/recipient pairs strictly HLA-matched 10/10, 49 with one allelic difference (HLA A n=13; HLA B n=8; HLA C n=13; HLA DRB1 n= 5; HLA DQB1 n=10 ), 11 with 2 allelic differences and 1 with 3 allelic differences. 238 pts have sustained engraftment at a median time of 20 days (9–41) without any influence of ALG use (97% vs 94% NS). Overall survival at 3 years was 45% in group 1 and 52% in group 2 (NS). The incidence of acute GvHD (grade II to IV) was similar in the two groups (59% vs 54%), but the incidence of acute GvHD (grade III to IV) was lower in group 1 (21% vs 32% p=0.03). Use of ALG did not affect rate relapse (18% vs 20% NS). In a multivariable analysis including HLA disparities, patient age, use of ALG, two factors appear as predictive for grade III–IV GvHD: HLA-identity (p=0.05) and use of ALG (p=0.02). These factors are not significant for survival in the same multivariable analysis but in this allelic matched population, the influence of ALG should be analyzed in regard of exact dose of ALG.

Multi-Center Phase II Study of CAMPATH-1H Dose De-Escalation Prior to Nonmyeloablative HLA-Identical Sibling Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1055-1055
Author(s):  
Ronjon Chakraverty ◽  
Nilusha Manji ◽  
Richard Clark ◽  
Charles Crawley ◽  
Peter Johnson ◽  
...  
Keyword(s):  
Total Dose ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Significant Risk ◽  
Post Transplantation ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Inclusion of CAMPATH-1H as part of a Fludarabine/Melphalan conditioning regimen is effective at preventing GVHD and reducing non-relapse mortality (NRM)following allogeneic stem cell transplantation. However, these benefits are offset by high rates of infection and potentially a loss of graft-versus-tumor effects. When used at a total dose of 100mg, CAMPATH-1H antibody can still be detected at levels in excess of those required to induce ADCC for several weeks. We reasoned that a reduction in the dose of CAMPATH-1H would permit improved immune reconstitution post-transplantation. We report here the analysis of a national, multi-center trial in which the total dose of CAMPATH-1H was reduced step-wise in separate cohorts from 60mg to 20mg prior to HLA-identical sibling transplantation (n=106). Eligibility criteria included patients with haematological malignancies who were aged 18–65, who had a life expectancy >3 months and who were not suitable for standard myeloablative conditioning. Primary endpoints included PK data, chimerism, NRM and incidence of GVHD or infection. The study received IRB approval and all patients gave informed consent. Four total doses of CAMPATH-1H were tested in consecutive cohorts: group 1, 60mg split between d-2 and d-1 (n=26); group 2, 40mg split between d-2 and d-1 (n=27); group 3, 30mg d-1 (n=28); and group 4, 20mg on day -1 (n=25). 97/106 patients recruited to the study are evaluable with a median follow up of 12 months. Median age was 50 (range 19–64). No major differences were identified in patient characteristics between each cohort. 1-year OS and PFS for the whole population was 80.8% and 67.2% respectively. Peak CAMPATH-IH levels (ug/ml) measured by ELISA on day 0 (n=5 each group) were 7.7 ±1.1 in group 1, 4.3 ±0.7 in group 2, 4.9 ±0.8 in group 3 and 2.7± 0.7 in group 4 (p<0.05 groups 1 vs. each group 2–4). By day 28, CAMPATH-1H levels had fallen substantially in all groups, but especially groups 3/4: 1.1 ±0.4 in group1, 0.6 ±0.1 in group 2, 0.1 ±0.06 in group 3 and 0.1 ±0.06 in group 4 (p<0.05 group 1 vs. each group 3 and 4). In groups 3 and 4, 40% of patients had undetectable CAMPATH-1H levels by day 28. Chimerism data was available in 78 patients and of these, 1 patient showed autologous reconstitution, 52 were mixed chimeras and 25 were full chimeras, with no differences between the groups. Day 100 NRM was 4% in group 1, 8% in group 2, 0% in group 3 and 12% in group 4. Grade III-IV GVHD was 0% in group 1, 4% in group 2, 0% in group 3 and 11% in group 4 (p=0.09 group 1 vs. 4). It is noteworthy that 2 patients in group 4 died of complications secondary to grade IV GVHD, although no patients died of this complication in any of the other cohorts. There were no significant differences in the rates of initial CMV reactivation between the groups, or in the rates of CD4 reconstitution. Cumulative incidences of chronic GVHD at 1-year were 55% and 30% in groups 1 and 2, although further follow up is required in later cohorts. We conclude that significant de-escalation of the CAMPATH-1H dose prior to HLA-identical sibling transplantation is feasible without increasing NRM, although reductions below 30mg are associated with a clinically significant risk of severe acute GVHD. Further studies are warranted to determine whether reductions in CAMPATH-1H dosage will translate into improvements in progression-free survival.

scholarly journals Busulfan (Bu) and Cyclophosphamide (Cy) Based Conditioning Regimen Still Holds the Promise of Being a Safe and Efficacious Regimen for Allogeneic Transplantation in Patients with Transfusion Dependent Thalassemia (TDT) Even in High Risk

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 949-949
Author(s):  
Pallavi Mehta ◽  
Aakanksha A Singh ◽  
Neha Yadav ◽  
Narendra Agrawal ◽  
Rayaz Ahmed ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Mixed Chimerism ◽  
Class Iii ◽  
Free Survival ◽  
Grade 3

Abstract Introduction: Allogeneic stem cell transplantation (HSCT) is a potential curative treatment for TDT. BuCy based regimen has been used widely as a standard myeloablative chemotherapy. However, the use of treosulfan based conditioning regimen has increased over the last decade (Choudhary D et al BBMT 2013). We analysed the safety and efficacy of BuCy based vs Treosulfan/Thiotepa/Fludrabine (Treo/Thio/Flu) regimens in TDT between September 2013 and March 2021. Method: This is an observational retrospective hospital record-based study approved by Institutional Review Board. Regimen used: Treo/Thio/ Flu : Thiotepa 8 mg/kg , treosulfan 14 g/m2/day for 3 days, and fludarabine 40 mg/m2/day for 4 days . Flu/Bu/Cy/ATG : Fludrabine 30mg/ m2/ day for 6 days ,Antithymocytoglobulin 4.5mg/kg in 3 days , Busulfan (per oral) 14mg/kg ( boys) and 12mg/kg (girls) in 4 days, Cyclophosphamide 40mg/kg/day ( boys)and 50mg/kg/day ( girls) for 4 days. Statistical Analysis: Fisher's exact test was used for discrete variables and t-test was used for continuous variables. Log-rank test was used for the difference in survival between the groups. P value &lt; .05 was considered statistically significant. Cox regression for survival analysis was also used for time to event data of the predicted variables. Results: As shown in Table 1, 74 patients were enrolled, out of which 35 (47.2%) patients received BuCy based regimen whereas 39(52.7%) patients received Treo/Thio/Flu. All were fully HLA matched. Median age was 5.5 (1-12) years and 9 (1-15) years respectively. According to Lucarelli classification, number of patients with Class I, II, III were 17, 12, 6 in BuCy group vs 2, 14,18 in Treo/Thio/Flu group respectively. When stratified according to Matthew classification, 06 (17.1%) and 11 (28.2%) patients were in class IIIB respectively (Mathews V et al, BBMT 2007). Source of graft was bone marrow in BuCy group vs peripheral blood stem cell (PBSC) in Treo/Thio/Flu group. Mean CD34 cell dose was 3.82(2.2-9.1) vs 5(1.65-8.01) 106/kg in BuCy vs Treo/ Thio/Flu group respectively. Neutrophils and platelets engrafted at median of 16 days (14-21) and 16 days (9-47 ) in BuCy and 15 days (10-20) and 13 days (9-41) in Treo/ Thio/ Flu. Median duration of follow-up was 28 (23-32.9) months. Two (5.7%) patients had rejection (primary=1, secondary=1) in BuCy group whereas none in Treo/Thio/Flu. Five (14.3%) vs 10 (25.6%) patients developed grade ¾ oral mucositis respectively where 1 patient in each group belonged to Class III. Sinusoidal obstruction Syndrome (SOS) was observed in 02 (5.7%) vs 04 (10.3%) patients (p=0.047) respectively, with no patients affected in Class III. BuCy group had 04(11.4%) patients with acute GVHD, including one patient with grade 3. Treo/Thio/Flu group had 15(38.5%) patients with acute GVHD including 4 patients with grade 3 which had significant impact on survival (p=0.038). We also observed chronic GVHD in 04(11.4%) and 11(28.2%) patients respectively which was mainly limited stage in former and extensive in later which impacted the survival (p=0.031). CMV viremia was observed in 14 (40%) vs 8 (20.5%) patients respectively. We also encountered significant infections in both groups {21 (60%) vs 17 (43.6%)}, however, difference was not statistically significant. Four (5.1%) patients had transplant related mortality (TRM) in Treo/Thio/Flu group, in contrast to none in BuCy group. Commonest cause of death was sepsis. Mixed chimerism was commonly seen in BuCy group {20 (57.1%)} vs Treo/Thio/Flu group {12(30.1%)}.(Table 2) At last follow up, all alive patients except two patients with rejection are transfusion independent. Five-year Thalassemia-free survival (TFS) and overall survival (OS) of entire cohort was 94%+3% and 93%+4% respectively. Estimated OS and Event free survival (EFS) of BuCy vs Treo/Thio/ Flu was 100% vs 89.7% (p=0.060) and 93.9% vs 89.7% (p=0.472) respectively.(Figure 1) Discussion: We observed significant difference in TRM, acute and chronic GvHD and SOS favoring the BuCy group even in class III. On the contrary, we encountered rejections(n=2) and increased number of mixed chimerism in BuCy group which corroborates with previous literature (Fouzia N et al, BMT 2018). Conclusion: In our experience BuCy based conditioning regimen is a safe and effective regimen even in high risk class III TDT, with less TRM in comparison to Thio/Treo/Flu regimen. However, one needs to be vigilant for rejections and mixed chimerism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Investigating the Relationship between CD34+and CD3+ Cell Doses, One-Year Graft-Versus-Relapse-Free-Survival, Graft-Versus-Host Disease, and Overall Survival in Haploidentical Hematopoietic Stem Cell Transplantation: A Single Center Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2051-2051 ◽  
Author(s):  
Mindy Hsiao ◽  
Anastasia Martynova ◽  
George Yaghmour ◽  
Chris Foss
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Optimal Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Improved Outcomes ◽  
The Mean ◽  
Related Mortality

Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. As the number of haplo-HCT's rises, investigating the factors that may affect outcomes is necessary in order to improve overall survival and reduce transplant-related mortality. The optimal dose of CD34+ cells used during haplo-HCT to ensure favorable outcomes using PTCy has not yet been reported though a range of 2 to 5.00x106 cells/kg is commonly used.Furthermore, the optimal dose of CD3+ cells is unknown however recent data has suggested less than 3.00x108 cells/kg may prevent the development of acute GVHD. The importance of studying the impact of CD34+/CD3+ cell dosing may help to improve outcomes in this setting. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 21) who received haplo-HCT from 2014 to 2019. The primary end-point assessed was 1-year GVHD-free/relapse-free survival (GRFS) defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. Secondary end-points included 1-, 2-, and 3-year relapse-related mortality (RRM) and overall survival (OS) in addition to 1-year transplant related mortality (TRM) and incidence of both acute and chronic GVHD. Results: A total of 67 adult haplo-HCT recipients were reviewed. Of the patients evaluated, approximately 50% (n = 33) were male and 49% (n = 32) were female. The age range was 21-71 years old (median = 44), and the most common underlying hematologic disorders included AML (40%), ALL (38%), aplastic anemia (7.7%), and others (MDS, lymphoma, myelofibrosis, and HLH) (13.8%). 67% of patients received myeloablative conditioning regimens while 33% received reduced intensity regimens. 70% (n = 47) of patients received peripheral blood as a stem cell source with 30% (n = 20) receiving bone marrow. The mean CD34+ dose infused was 6.07x106 cells/kg and the mean CD3+ dose was 2.94x108 cells/kg. The mean time to recovery of platelets, neutrophils, and lymphocytes was 25, 18, and 37 days respectively. CD34+ stem cells ≥5.00x106 cells/kg was significantly associated with shorter time to lymphocyte recovery (p = 0.0265) though recovery less than 30 days was not significantly associated with OS (p = 0.5268). Incidence of 1-year GRFS was 71% (n= 46) and 1-, 2-, and 3-year RRM were 4.6%, 6%, and 7.7% respectively. 1-year TRM was 15.3% with 50% of deaths from acute GVHD. 1-, 2-, and 3-year OS were 80%, 78%, and 77% respectively. Factors significantly associated with increased mortality included use of RIC regimen (p = 0.004) and disease status at time of transplant (p = 0.04). Cumulative incidence of GVHD was 63% (n = 42) with 33% (n = 22) and 30% of patients (n = 20) with acute and chronic GVHD respectively. Lack of mild chronic GVHD was associated with increased mortality (p = 0.0029) and use of a myeloablative regimen (p = 0.0029) was significantly associated with GVHD. Subgroup analysis of those who received CD34+ dose ≥7.00x106 cells/kg (n = 24) and ≥10x106 cells/kg (n = 7) were found to have 1-year OS of 87.5% and 85.7% compared with 77% and 80% in those that received lower doses (p= 0.2229 and p = 1.00) respectively however this was not found to be significantly associated with increased incidence of GVHD, relapse, or mortality. Discussion: Our results demonstrate improved outcomes specifically 71% survived 1 year without experiencing at least 1 GRFS event compared with 24-35% reported by CIBMTR, Holtan et al 2015, and Solh et al 2016 with 3-year OS of 77% when compared with a previously reported 48%. The mean CD34+ cell dose of our population is higher than the standard range which may account for the improved outcomes however the dosing of CD34+/CD3+ cells were not significantly associated with our primary and secondary end-points. It was significantly associated, however, with shorter time to lymphocyte recovery, a factor that has been reported to be associated with decreased RRM and therefore improved OS. Furthermore, subgroup analysis of higher CD34+ dose did show a better 1-year OS though this was not statistically significant. Limitations of this study include small sample size and short follow-up period. Further research with a prospective study identifying the optimal CD34+/CD3+ cell dose in addition to comprehensive evaluation of immune recovery is warranted in order to improve haplo-HCT outcomes. Figure Disclosures Yaghmour: Jazz Pharmaceutical company: Consultancy, Speakers Bureau; Astella company: Speakers Bureau; Takeda: Speakers Bureau.

P1031The impact of the duration of atrial fibrillation persistence for arrhythmia free survival in patients undergoing catheter ablation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Furukawa ◽  
T Yamada ◽  
T Morita ◽  
S Tamaki ◽  
M Kawasaki ◽  
...  
Keyword(s):  
Catheter Ablation ◽  
Outcome Data ◽  
Free Survival ◽  
Group 4 ◽  
Kaplan Meier ◽  
Group 3 ◽  
Group 2 ◽  
Af Recurrence ◽  
Group 1

Abstract Background Catheter ablation (CA) for atrial fibrillation (AF) is a curable treatment option. However, AF recurrence after CA remains an important problem. Although the success rate has been improved after catheter ablation (CA) in patients with paroxysmal AF (PAF), outcome data after CA for persistent AF (PeAF) are highly variable. Previous studies showed the PeAF is one of independent predictors for AF recurrence in comparison to PAF. However, there are little information available on the prognostic significance of AF duration after CA for AF. The aim of this study is to evaluate the impact of AF duration on long-term outcomes of AF ablation in patients with PeAF compared with PAF. Methods We enrolled 778 consecutive patients, who were referred our institution between August 2015 and December 2017 for undergoing the first time CA for AF. We divided 5 groups (Group 1; PAF (n=442), Group 2; PeAF duration ≤6 months (n=198), Group 3; PeAF duration of 6 months to 2 years (n=87), Group 4; PeAF duration of 2–5 years (n=30) and Group 5; PeAF duration ≥5 years (n=21)). All patients followed up for at least 1 year. Outcome data on recurrence of AF after ablation were collected. Results There were no significant differences in baseline clinical characteristics before CA among 5 groups, except for the prevalence of congestive heart failure, left atrial diameter and left ventricular ejection fraction. During a mean follow-up period of 511±298 days, 217 patients had AF recurrence. Kaplan-Meier analysis revealed that AF recurrence was significantly higher in group 2 compared to group 1 (31% vs 20%, p=0.002) and in group 4 compared to group 3 (83% vs 30%, p<0.0001). However, AF recurrence was no significantly differences between groups 2 and 3 (31% vs 30%, p=0.76) and between groups 4 and 5 (83% vs 81%, p=0.45). Of 217 patients with AF recurrence, 154 patients had undergone multiple procedures. After last procedures, during a mean follow-up period of 546±279 days, 61 patients had AF recurrence. Kaplan-Meier analysis revealed that AF recurrence was significantly higher in group 2 compared to group 1 (10% vs 3%, P=0.0005) and in group 4 compared with group 3 (35% vs 10%, p=0.0001). However, AF recurrence was no significantly difference between groups 2 and 3 (10% vs 10%, p=0.91) and between groups 4 and 5 (47% vs 35%, p=0.47). AF Free Survival Curve Conclusion Although patients with PeAF within 2 years had significantly higher AF recurrence compared to PAF, AF ablation might still be a good contributor as the first line approach to improve outcomes in patient with PeAF within 2 years.

Effect of Rituximab on the Incidence of GVHD in Lymphoma Patients who Received the BEAM-Conditioning and an Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4980-4980
Author(s):  
Issa F. Khouri ◽  
Rima M. Saliba ◽  
Daniel R. Couriel ◽  
Grace-Julia Okoroji ◽  
Sandra Acholonu ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Control Group ◽  
Study Group

Abstract It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings. To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below: Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4     (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9     range (1–8) (1–9) Median follow-up 17 38     range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01 Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.

One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 965-965
Author(s):  
David Valcarcel ◽  
Fangyu Kan ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R Spellman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Related Donor ◽  
Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

Outcome of Patients Aged ≥60 After Allogeneic Hematopoietec Cell Transplantation: Age Has No Impact on Survival

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3540-3540 ◽  
Author(s):  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
Wolfgang A. Bethge
Keyword(s):  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Allogeneic Hct ◽  
Kaplan Meier ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Abstract 3540 Historically, allogeneic hematopoietic cell transplantation (HCT) has been offered only to patients with good performance status and below the age of 60. However, the peak incidence of most hematologic malignancies is above 60 years of age. The introduction of reduced intensity conditioning (RIC) regimens enabled successful allogeneic HCT in patients with considerable comorbidities and older than 60 years. The impact of age on outcome of allogeneic HCT in patients ≥60 years has not been evaluated extensively. We retrospectively analyzed 109 consecutive patients (f=43, m=66) aged≥60 who received allogeneic HCT 2000–2010 at our institution. Median age of the patients was 65 years (range, 60–76). Patients were grouped in two cohorts depending on age: group 1 aged 60–65 years (n=60, median age=63) and group 2 aged 66–76 years (n=49, median age=68). Diagnoses were acute leukemia (AML n=65, ALL n=1), myelodysplastic syndrome (n=14), osteomyelofibrosis (n=7), non-Hodgkin lymphoma (n=9), multiple myeloma (n=8), aplastic anemia (n=1), chronic myeloid leukemia (n=2) and chronic lymphatic leukemia (n=2). At time of HCT, 41 of the patients were in complete remission (CR), 68 in partial remission (PR) (group 1: CR 21, PR 39; group 2: CR 20, PR 29) and 18 patients had a preceding HCT, 14 in group 1. Conditioning regimens were grouped in high (TBI/Bu+Cy, n=5, all group 1), intermediate (FLAMSA, Flu/Mel/BCNU, n=28, group 1=11, group 2=17), low (FLU+alkylans, n=48, group 1=32, group 2=16) and minimal (2GyTBI/Flu, n=28, group 1=12, group 2=16) intensity. Intermediate intensity conditioning was particularly used for high risk patients in PR (25/28). 22 patients were transplanted from matched related (MRD), 46 from matched unrelated (MUD) and 41 from mismatched unrelated donors (MMUD). Kaplan-Meier-estimated 3-year overall survival (OS) was 45% for all patients, 32% for group 1 and 62%, for group 2, respectively (p=0.02), with more patients with high risk constellation in group 1. 3-year OS for patients transplanted with MUD was 57%, with MMUD 46% vs. with MRD 0% (p=0.01). Non-relapse-mortality was 28% for all patients, 40% in group 1 and 12% in group 2, probably due to the higher intensity in conditioning in group 1. The outcomes with intermediate, low and minimal intensity conditioning were comparable, while all patients after high intensity conditioning died. Table 1 describes Kaplan-Meier estimated 3-year-OS and statistical univariate analysis by log-rank test in the different subgroups. Table 1. 3-year OS (in%) All Group 1 Age 60–65 Group 2 Age 66–76 Remission CR 52 p=0.25 31 p=0.76 77 p=0.15 PR 40 32 50 Conditioning high 0 p=0.5 0 p=0.08 – p=0.38 intermediate 52 50 53 low 48 43 57 minimal 45 17 67 Donor MRD 0 p=0.01 0 p=0.06 73 p=0.45 MUD 57 53 65 MMUD 46 40 33 GVHD acute no 18 p=0.003 13 p=0.008 33 p=0.27 ≥II 43 53 58 chronic no 39 p=0.25 36 p=0.70 52 p=0.08 limited 52 30 100 extensive 50 30 67 In group 1 the outcome of minimal conditioning was inferior compared to intermediate and low conditioning while patients in group 2 had a better outcome with minimal vs. low and intermediate conditioning. Incidences of acute GVHD ≥II, limited and extensive chronic GVHD (cGVHD) were 10%, 28% and 13%, respectively. In group 1, acute GVHD ≥II occurred in 13% and cGVHD in 35%, in group 2 in 5% and 41% of the patients, respectively. Acute GVHD ≥II was associated with inferior outcome (3-year OS of 18% vs. 43%, p=0.003) while cGVHD had a positive impact on OS. In group 2 patients with limited cGVHD showed better 3-year OS than patients without cGVHD (67% vs. 52%, p=0.12). Age alone had no major impact on outcome of allogeneic HCT. Patients aged ≥60 seemed to benefit from the use of MUD rather than an older MRD. Chronic GVHD had a positive influence on survival. Our data indicate that the regimen used should be tailored to disease risk and patient performance status. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Stem Cell Tranplantation (allo-SCT) for Adult Patients with Active Refractory/Relapsed Hematological Malignancies: a Survey From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3456-3456
Author(s):  
Patrice Chevallier ◽  
Noel Milpied ◽  
Karin Bilger ◽  
Gérard Socié ◽  
Ibrahim Yakoub-Agha ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Best Supportive Care ◽  
Adult Patients ◽  
Peripheral Blood Stem Cells ◽  
Hematological Diseases

Abstract Abstract 3456 Patients with active refractory/relapsed hematological diseases have a very poor outcome. Best supportive care or investigational therapies in phase 1 trials are usually proposed to these patients. However, some previous data suggested that allo-SCT might be an efficient therapy even in the setting of chemorefractory disease, because long-term immune-mediated disease control can be achieved in some patients after allo-SCT. The aim of this study was to evaluate on a large series the outcome of adult patients with active refractory/relapsed hematological diseases at time of allo-SCT and to determine which sub-group would most benefit from such approach. Between 2005 and 2009, 861 patients with various hematological diseases (AML, n=323; ALL, n=43; MDS, n=129, CMML, n=12; MPS, n=110; CML, n=28; NHL, n=100; HL, n=40; myeloma, n=36; CLL, n=24; and other, n=16) were treated with allo-SCT, and reported to the SFGM-TC Registry. Per study criteria, all patients presented with active refractory or relapsed disease at time of transplant. This series included 517 males (60%) and 344 females (40%). The median age at transplant was 50 (range, 16–71) years. The median interval between diagnosis and transplant was 17 (range, 1–99) months. 32% of patients failed at least one prior SCT (Autologous or allogeneic prior to allo-SCT). 350 (41%) patients received allo-SCT from an HLA-matched sibling donor, while the remaining 59% received an allogeneic graft from a matched unrelated or mismatched donor. The stem cell source was mainly peripheral blood stem cells (n=617; 72%). Bone marrow was used in 139 patients (16%), and cord blood in 107 patients (12%). Myeloablative conditioning regimen was used in 328 patients (38%), and various reduced-intensity regimens were used in other cases (62%). With a median follow-up of 290 (range, 1–1854) days after allo-SCT, engraftment was observed in 88% of cases. Grade II-IV and grade III-IV acute GVHD occurred in 35% (n=301) and 17% (n=144) of patients, respectively. Chronic GVHD was observed in 185 patients (21%; limited: n=77; extensive: n=82; missing data: n=24). At last follow-up, 347 patients (40%) were still alive (of whom 297 were in CR; 86%). 246 patients (28.5%) died of disease progression, and 232 patients died of transplant-related causes (NRM: 27%). The Kaplan-Meier (KM) estimates of overall survival (OS) at one and 2 years were 39% (95%CI, 36–43%) and 31% (95%CI, 28–35%), respectively. Of note, in patients with lymphoma (n=140), OS at 1 and 2 years were 57% (95%CI, 48–66%) and 49% (95%CI, 40–58%) versus 36% (95%CI, 32–40%) and 27% (95%CI, 23–31%), respectively, in all other diagnoses (P=0.00004). In a Cox multivariate analysis accounting for relevant factors, a diagnosis of lymphoma (NHL or Hodgkin) was the most significant factor associated with improved survival (RR=1.68; 95%CI, 1.3–2.2; P=0.0001). Despite its retrospective nature and the inherent selection biases, in case of availability of suitable donor, this data support the use of allo-SCT in adult patients with active refractory/relapsed hematological diseases, especially in patients with lymphomas. Results are expected to be further improved with the advent of novel conditioning regimens and maintenance therapies after transplant that are currently tested as part of prospective studies. Disclosures: No relevant conflicts of interest to declare.

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