scholarly journals Triple Post-Transplant Cyclophosphamide (PTCY) Based Gvhd Prophylaxis for HLA Matched or HLA Haploidentical Transplants

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4881-4881
Author(s):  
Eugenio Galli ◽  
Elisabetta Metafuni ◽  
Sabrina Giammarco ◽  
Maria Assunta Limongiello ◽  
Idanna Innocenti ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Age Over 60 ◽  
Disease Free ◽  
Related Mortality

Abstract We report a retrospective analysis of 198 consecutive allogeneic stem cell transplant (HSCT) recipients, who received post transplant cyclophosphamide (PTCY), cyclosporine and mycophenolate mofetile as g raft-versus-host-disease (GVHD) prophylaxis. The donor was either HLA matched (n=78) (siblings -32- or unrelated -46) , or a haploidentical relative (HAPLO) (n=120). End points of the study were acute and chronic GVHD, transplant related mortality (TRM), relapse, disease free survival (DFS) and graft versus host and relapse free survival (GRFS). The two groups were comparable except for an older age (49 vs 56 years) in the haplo-HLA group. The diagnosis was mainly acute leukemia (57%), myelofibrosis (21%) or lymphoma (12%). Conditioning was myeloablative in 77% and 73% respectively (p=0.57). Acute GVHD grade II-IV developed in 10% of the HLA matched transplants vs 27% in the HAPLO group (p=0.005). The latter also had more moderate-to-severe cGVHD (4% vs 23%, p<0.001). The cumulative incidence of transplant related mortality (TRM) at 1 year for the HLA matched vs HAPLO patients, was 10% vs 21% (p=0.04) (Fig.1) , with age over 60 years being the major negative predictor in multivariate analysis. Relapse at 1 year was 24% for HLA matched vs 10% for HAPLO transplants (p=0.051) (Fig.1). Disease free survival (DFS) at 1 year was 65% and 68% in matched and HAPLO patients, respectively (p=0.85) (Fig.1) and GRFS 55% vs 49% (p=0.18). In multivariate analysis, age over 60 years was the strongest predictor of DFS and GRFS (HR 1.73, p=0.03 and HR 1,65, p= 0.02). In conclusion: when using the same triple PTCY based GVHD prophylaxis, HLA matched grafts are associated with significantly less acute and chronic GvHD, if compared with HAPLO grafts. There is a trend for reduced TRM at 1 year, especially in chronic myelo-lymphoproliferative disorders, and a trend for increased relapse, resulting in identical disease free survival. Figure 1 Figure 1. Disclosures Laurenti: Gilead: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

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

Unmanipulated Haploidentical Bone Marrow Transplantation and Post-Transplant Cyclophosphamide for Hematologic Malignanices Following A Myeloablative Conditioning.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3034-3034
Author(s):  
Andrea P Bacigalupo ◽  
Anna Maria Raiola ◽  
Alida Dominietto ◽  
Maria Teresa Van Lint ◽  
Francesca Gualandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Myeloablative Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Active Disease ◽  
Related Mortality

Abstract Abstract 3034 Despite a large number of unrelated donors (UD), not more than 30% of patients who have activated a donor search, undergo an allogeneic UD stem cell transplant. HLA haploidentical family members are being increasingly considered as an alternative donors, both using T cell depleted or T cell replete grafts. Post-transplant high dose cyclophosphamide (PT-CY), introduced by the Baltimore group, has shown very promising results following non myeloablative conditioning regimens. We are now reporting 50 patients with high risk hematologic malignancies, who received a myeloablative regimen, followed by unmanipulated haploidentical bone marrow transplant (hBMT) and PT-CY. The myeloablative conditioning consisted of thiotepa (10 mg/kg), busulfan (9,6 mg/m2̂), fludarabine (150 mg/m2̂)(n=35), or total body irradiation (9,9–12 Gy), fludarabine (120 mg/m2̂) (n=15). The median age was 42 years (18–66); 23 patients were in remission and 27 had active disease; 10 patients were receiving a second allograft. Graft versus host disease (GvHD) prophylaxis consisted in PT-CY on day+3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median nucleated cell dose was 3.6 ×108̂/kg (range: 1,4 – 7,7). The median time to neutrophil counts of >0.5×109/L was 18 days (range, 13–30 days) and to platelet counts of >20×109/L 23 days (range, 14 – 58 days), respectively. There was no correlation between infused number of nucleated cells and days of neutrophil engraftment. The cumulative incidence of engraftment was 90%for neutrophils and 86% for platelets. Three patients died before engraftment, and 2 patients had autologous recovery: 45 patients (90%) had full donor chimerism on day +30. The cumulative incidence of grade II-III acute GvHD was 12%, and of moderate chronic GvHD 10%. With a median follow up for surviving patients of 333 days (149–623), the cumulative incidence of transplant related mortality is 18%, and the rate of relapse 26%. The actuarial 22 months disease free survival is 68% for patients in remission and 37% for patients with active disease (p<0.001). Causes of death were pneumonia (n=3), haemorrhage (n=3), sepsis (n=3) and relapse (n=7). In conclusion, a myeloablative conditioning regimen followed by h-BMT with PT-CY, results in a low risk of acute and chronic GvHD and encouraging rates of transplant related mortality and disease free survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcomes for Allogeneic Hematopoietic Cell Transplantation for AML and High-Grade MDS in Older Adults in the Era of T-Replete Haploidentical Donor Grafts. a Single Center Multivariate Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4665-4665
Author(s):  
Zain Bashey ◽  
Scott R. Solomon ◽  
Lawrence E. Morris ◽  
H. Kent Holland ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Older Patients ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Patient Characteristics ◽  
High Grade ◽  
Free Survival ◽  
Disease Free

Abstract Introduction: Outcomes for non-transplant therapy in older adults (age> 60 years) with AML or high-grade MDS have historically been poor. Allogeneic hematopoietic cell transplantation (allo-HCT) may improve these outcomes. However, many older patients will lack suitably HLA-matched sibling donors (MRD). Furthermore, many patients from ethnic minorities will lack an optimally matched unrelated donors (MUD). Additionally, the greater incidence and severity of chronic GVHD typically seen following MUD transplants may be particularly difficult to tolerate in older patients. T-replete haploidentical donor transplants (HAPLO) using post-transplant cyclophosphamide to mitigate alloreactivity may provide a suitable donor option for some older patients. However, no detailed comparison of outcomes after HAPLO to MRD and MUD donors in elderly patients with AML and high-grade MDS have been reported in the modern era.. Methods: We analyzed outcomes of patients aged > 60 years with AML or high-grade MDS who received an allo-HCT at our center between 2005 and 2015. Ex-vivo T-cell depleted transplants and cord blood transplants were excluded. Supportive care measures were identical between the three donor groups. Patient characteristics and outcome parameters were extracted from our institutional database where they had been prospectively entered. Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) were calculated and the cumulative incidence method with competing risks was used to calculate rates of non-relapse mortality (NRM) and relapse. Cumulative incidences of acute and chronic GVHD were estimated with death being treated as the competing risk. Cox proportional hazards models, stratified on the three transplant donor groups, were developed using OS, DFS, NRM and relapse as endpoints and other parameters as covariates. GVHD was prospectively documented by a single dedicated nurse using established criteria including NIH consensus criteria for chronic GVHD and rates calculated using the cumulative incidence method. Results: Patient characteristics (n=127, 33 HAPLO, 37 MRD, 57 MUD) were as follows: median age 64 (60-77); male 57%; regimen- myeloablative (24%) non-myeloablative (76%); graft- PBSC (80%) BM (20%); Diagnoses- AML 59%, MDS 41%; DRI- low (2%), intermediate (58%), high (39%), very high (1%); Sorror HCT-comorbidity index 0-2 (46%), >3 (54%); Median HLA mismatches were 5/10 (range 2/10 to 5/10) for HAPLO patients. Estimated rates of OS, DFS, NRM and relapse for the entire group at 2 years were 60%, 49%, 18%, and 33%. When compared to MRD and MUD, HAPLO patients had similar characteristics but were less likely to have myeloablative conditioning (6% vs. 32% and 30% respectively for MRD and MUD, p=0.016) and were more likely to have a BM graft (52% vs. 0% and 21%, p<0.001). Median follow-up of surviving patients following MRD, MUDT and HAPLO transplants were 34m, 26m and 17m. For MRD, MUD, and HAPLO transplants respectively, estimated outcomes are as follows: TRM at 1year: 14%, 14% and 9% and 2yrs 17%, 23%, 9%, Relapse at 1year - 25%, 34%, 22% and 2 yrs -32%, 34%, 33%; OS at 1 yr 72%, 72%, 77% and 2 yrs - 62%, 55% , 67%. DFS at 1 yr - 61%, 52%, 69% and 2 yrs - 51%, 43%, 58% (Fig 1.) (p=NS for all endpoints on pointwise and global comparison). The cumulative incidences of acute GVHD at 180 days were: grade 2-4 - 27%, 37% and 39%; grade 3-4 - 8%, 18% and 15% (p=NS for all) and chronic GVHD at 2 yrs were: moderate to severe - 38%, 35%, 15% (p=0.028 MUD vs HAPLO, p=0.026 MRD vs HAPLO); severe - 12%, 11%, 0% (p=0.030 MUD vs HAPLO, p=0.009 MRD vs HAPLO). On multivariable Cox analysis, donor type was not a significant predictor of OS, DFS, NRM or relapse (Table 1). Conclusions: The results show that in the current era, using predominantly non-myeloablative conditioning regimens, 2 year OS and DFS rates of 60% and 49% with a NRM <20% can be achieved in patients aged >60 years who undergo allo-HCT for AML and high-grade MDS. Outcomes of patients transplanted from HAPLO donors are comparable to those from matched donors although the rate of clinically significant chronic GVHD appears significantly less following HAPLO transplants, which may translate to an improved quality of life. Figure 1 Figure 1. Figure 2 Figure 2. Table 1 Multivariate Analysis on Overall Survival, Disease Free Survival, Transplant Related Mortality and Relapse Table 1. Multivariate Analysis on Overall Survival, Disease Free Survival, Transplant Related Mortality and Relapse Disclosures No relevant conflicts of interest to declare.

Analysis of 120 Pediatric Patients with Non-Malignant Disorders Transplanted Using Unrelated Plasma Depleted Cord Blood and the Role of Post-Thaw Wash

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4406-4406
Author(s):  
Joseph Rosenthal ◽  
Tang-Her Jaing ◽  
Lee Lee Chan ◽  
Gretchen Eames ◽  
Michael L. Graham ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cord Blood ◽  
Cumulative Incidence ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Related Mortality

Abstract Unrelated cord blood (UCB) is an important stem cell source for unrelated hematopoietic cell transplantation of patients with non-malignant disorders. Cell dosage is a critical factor for successful UCB hematopoietic stem cell transplantation (HSCT). The red cell reduced (RCR) and post-thaw wash techniques that are widely used incur significant nucleated cell loss. Three strategies were employed to maximize cell dose and improve outcome–use of cord blood processed with plasma depletion without red blood cell reduction (PD CB), avoidance of post-thaw wash, and the use of double cords (2X) when necessary. A CIBMTR-audited analysis was performed on all 120 pediatric patients with non-malignant disorders transplanted with PD CB at 29 U.S. and 17 international centers. Transplant characteristics: median age 3.5 years (range 0.1–14); median patient weight 15 kg (range 4–61); male 58%. The majority of patients (n=58; 55%) were Asian. Twenty-two (21%) patients were Hispanic, 15 (14%) were Caucasian, 6 (6%) were African-American, and three (3%) were of Middle Eastern background. HLA ABDR matches: 6/6–26; 5/6–48; 4/6–47; 3/6 or 2/6–6; median pre-freeze nucleated cell dose 10.5×107/kg; median pre-freeze CD34+ dose 3.7×105/kg; non-myeloablative regimen 24%; 58% infused without post-thaw wash (NW). Myeloid engraftment defined as ANC≥500 and 6-month platelet engraftment defined as ≥ 20K and ≥ 50K are 89±8%, 88±8%, and 84±6% respectively. The median time to myeloid and platelet engraftment are 21 days (range 11–64), 49 days (range 13–155), and 61.5 days (range 21–205) respectively. No major adverse event was observed in either the W or the NW group. The cumulative incidence of reported grade II–IV acute GVHD was 38±5%, and 19±4% had grade III–IV acute GVHD. 36±6% developed limited chronic GVHD, and 12±4% developed extensive chronic GVHD. With a median follow-up of 329 days (range 3–1928 days), the Kaplan-Meier estimates of 1-year TRM, OS and diseasefree survival were 20±6%, 88±6% and 72±6% respectively. Foregoing post-thaw wash for PD CB transplantation improved neutrophil (RR=1.75; p=0.01) and platelet engraftment (RR=1.72; p=0.02) and reduced TRM (RR=0.38; p=0.04). This series demonstrated that unrelated PD CB transplantation can be performed safely and effectively in children with life-threatening, non-malignant disorders. Additionally, the results demonstrate possible improvement in myeloid and platelet engraftment, overall and disease-free survival when post-thaw wash is not employed. Table 1. Summary of overall results Outcome All Patients N = 120 Washed CB N = 48 Unwashed CB N = 71 RR (Wash=Ref) P-value ANC500 Engraftment Cumulative Incidence Median # Days to Engraftment 87±6% d+21 86±9% d+25 89±8% d+19 1.75 0.01 Platelet 20K Engraftment Cumulative Incidence Median # Days to Engraftment 81±6% d+49 75±9% d+52 88±9% d+43 1.72 0.02 Autologous Recovery 3±2% 2±2% 4±3% 1.06 0.95 Acute GvHD II–IV Acute GvHD III–IV 38±5% 19±4% 31±7% 17±6% 45±7% 21±6% 1.74 1.38 0.11 0.50 Chronic GvHD Limited Chronic GvHD Extensive 36±6% 12±4% 14±6% 19±6% 60±10% 6±4% 5.69 0.24 &lt;0.001 0.08 Transplant-Related Mortality–100 Day Transplant-Related Mortality–3 Yr 10±3% 20±4% 11±5% 34±8% 9±4% 11±4% 0.38 0.04 Overall Survival–1 Yr Overall Survival–3 Yr 79±4% 79±4% 66±8% 66±8% 88±4% 88±4% 0.43 0.06 Disease-Free Survival–1 Yr Disease-Free Survival–3 Yr 72±5% 70±6% 58±9% 51±10% 84±5% 84±5% 0.48 0.07

scholarly journals Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1259-1259
Author(s):  
Doris M. Ponce ◽  
Rodney Sparapani ◽  
Junfang Chen ◽  
Vanderson Rocha ◽  
Daniel H. Fowler ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Disease Status ◽  
Free Survival ◽  
Grade Ii ◽  
Disease Free ◽  
Grade Iii

Abstract Background: Cord blood (CB) is routinely used as an alternative stem cell source for the treatment of children with acute leukemia and has been associated with high rates of disease-free survival (DFS). However, one controversial issue in pediatric CB transplantation is the role of anti-thymocyte globulin (ATG) as immunoprophylaxis. While inclusion of ATG in the conditioning may decrease the risk of graft-versus-host disease (GVHD), it could potentially abrogate graft-versus-leukemia effects and increase the risk of opportunistic infections. Thus, we compared outcomes in a uniform group of pediatric patients with acute lymphoblastic leukemia (ALL) who underwent myeloablative CB transplantation with or without ATG. Methods: Patients with ALL in morphologic remission (CR1 n=106, CR2 n=146, CR3 n=45) aged ≤ 20 years transplanted between 01/2007-12/2011 with high-dose total body irradiation-based conditioning and single or double unit CB grafts were eligible for analysis. CB units were 4-6/6 HLA-A,-B at the antigen-level, -DRB1 allele matched to the recipient and had CB unit with cryopreserved total nucleated cell dose of ≥ 2.5 x107/kg/unit. Cox regression models were built to evaluate potential differences in outcome in ATG versus non-ATG CB transplant recipients. The primary endpoint was 3-year DFS. Results: Of 297 patients, 92 received ATG and 205 did not. Age and disease status were similar in each group whereas ATG recipients were less likely to be CMV seropositive and more likely to receive single unit CB grafts. While neutrophil engraftment was similar in each group, the risk of day 100 grade II-IV acute GVHD [30% (95%CI: 21-40) versus 54% (95%CI: 47-61), p = 0.0002] and 3-year chronic GVHD [22% (95% CI: 14-31) versus 43% (95% CI: 36-50), p = 0.0008] were decreased in ATG recipients. However, day 100 grade III-IV aGVHD was comparable: 11% (95%CI: 5-18) in ATG versus 17% (95%CI: 12-23) in non-ATG recipients, p = 0.15]. The 3-year TRM was similar in both groups: 16% (95%CI: 10-25) in ATG versus 17% (95%CI: 13-23) in non-ATG recipients (p = 0.98). Relapse was also similar in ATG and non-ATG recipients: 17% (95%CI: 10-23) versus 27% (95%CI: 21-34, p = 0.12), respectively. In multivariate analysis, negative CMV serostatus was associated with reduced TRM risk [HR 0.55 (95%CI: 0.30-0.98), p = 0.004] whereas remission status CR2 or CR3 significantly increased relapse risk [HR 2.18 (95%CI: 1.22-3.89), p = 0.008], but inclusion of ATG had no effect on either outcome. With a median follow-up of survivors of 36 months (range 5-72), the 3-year DFS was 66% (95%CI: 56-76) and 55% (95%CI: 48-62) in ATG and non-ATG recipients, respectively (p = 0.23, Figure 1). The distribution of causes of death was similar in each group. In multivariate analysis, treatment failure risk was increased in patients transplanted in CR2 or CR3, but the inclusion of ATG had no effect (p = 0.24) (Table 1). Conclusion: Inclusion of ATG in pediatric myeloablative CB transplant for ALL is associated with a decreased risk of grade II-IV acute GVHD and chronic GVHD but not severe grade III-IV acute GVHD. There was no difference in 3-year DFS in each group and multivariate analysis revealed ATG inclusion had no impact upon treatment failure risk. These results indicate that optimization of both ATG and non-ATG conditioning platforms are needed in order to further improve CB transplantation survival in children with ALL. Unanswered questions include the impact of the formulation, dose and timing of ATG administration. These findings cannot be extrapolated for other diagnoses, reduced intensity conditioning, or adults. Table 1 Hazard ratio(95% confidence interval) p-value ATG use Conditioning without ATG Conditioning with ATG 1.00 0.78 (0.52 – 1.18) 0.24 Disease status CR1 CR2, CR3 1.00 2.01 (1.31 – 3.08) 0.001 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4662-4662
Author(s):  
Jacopo Peccatori ◽  
Serena Albanese ◽  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Fabio Giglio ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.

Risk Factors for Graft-versus-Host Disease (GVHD) Following Myeloablative HLA-Identical Sibling Transplantation with Allogeneic Peripheral Blood Stem Cells (PBSC): An Analysis of 546 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3318-3318
Author(s):  
Mohamad Mohty ◽  
Keyword(s):  
Risk Factors ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Individual Patient Data ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Post Transplant ◽  
Factors Associated ◽  
Disease Free

G-CSF-mobilized PBSCs are increasingly used in allogeneic transplantation. In comparison to bone marrow (BM), PBSCs have been shown to allow faster engraftment, but also can lead to more chronic GVHD. Our current knowledge of risk factors for GVHD is based primarily on historical analyses performed using BM as the stem cell source. This analysis sought to identify potential risk factors predicting for the development of acute and chronic GVHD after related HLA-identical PBSC transplantation (PBSCT). We analyzed the outcome of 546 patients who were part of an international database bringing together individual-patient data from nine randomized trials. Median age of recipients was 39 years. 180 (33%) patients had acute myeloid leukemia (AML), 237 (43%) had chronic myeloid leukemia (CML) and 129 patients had other hematological malignancies. 398 (73%) patients had standard risk disease at time of PBSCT and 218 (41%) patients received TBI-based myeloablative conditioning. 312 (57%) patients received short-course methotrexate (days 1, 3, 6) as GVHD prophylaxis, while 234 (43%) received long-course methotrexate (days 1, 3, 6, 11). 190 (35%) patients received G-CSF post-transplant. An ANC of >500/μL was reached at a median of 16 (range, 8–50) days. Platelet recovery occurred at a median of 15 (range, 5–376) days. The incidence of grades II-IV acute GVHD was 44% (95%CI, 40–48%), while the incidence of extensive chronic GVHD was 40% (95%CI, 36%–44%). In a Cox multivariate analysis, the incidence of acute GVHD was significantly associated with age (P=0.001; RR=1.60 for age >40; 95%CI, 1.2–2.1), and TBI-based conditioning (P=0.0009; RR=1.7; 95%CI, 1.2–2.2). The main risk factors associated with an increased risk of extensive chronic GVHD in a Cox multivariate analysis were grade II-IV acute GVHD and a female donor (P=0.009; RR=1.5; 95%CI, 1.1–2.0; and P<0.0001; RR=2.2; 95%CI, 1.6–2.9 respectively). At a median follow-up of 35 months, disease-free survival (DFS) was significantly higher in patients with extensive chronic GVHD compared to patients without extensive chronic GVHD (P=0.03). G-CSF post-transplant (P=0.0027; RR=1.9; 95%CI, 1.2–2.9), disease status at transplant ((P<0.0001; RR=2.9 for advanced diseases; 95%CI, 1.9–4.3), and a diagnosis of acute leukemia (AML or ALL; P<0.0001; RR=3.5; 95%CI, 2.2–5.6) were the major factors associated with worsened disease-free-survival. In conclusion, although the use of PBSCs is associated with more frequent and clinically more severe chronic GVHD, this large-scale analysis based on individual-patient data demonstrates that some risk factors for GVHD after PBSCT are qualitatively comparable to those observed with BM-derived stem cells and might be determinant for the ultimate outcome. Most importantly, extensive chronic GVHD is associated with significantly improved DFS, while the use of G-CSF post-transplant might be detrimental.

scholarly journals Allogeneic Hematopoietic Stem-Cell Transplantation in Patients with GATA 2 Deficiency: Influence of Donor Stem Cell Source and Post-Transplantation Cyclophosphamide

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Diana X. Nichols-Vinueza ◽  
Nirali N. Shah ◽  
Jennifer Cuellar-Rodriguez ◽  
Thomas R. Bauer ◽  
Katherine R. Calvo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Immune Reconstitution ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Gata2 Deficiency ◽  
Disease Free ◽  
Grade Iii

Background: We recently reported on the single-institution experience with allogeneic hematopoietic stem cell transplantation (HSCT) in 22 consecutive patients with GATA2 deficiency or the MonoMAC syndrome and observed a disease-free survival of nearly 90%. However, despite 10/10 HLA match of matched related donors (MRD) and matched unrelated donors (URD), there was a 25% incidence of grades III-IV acute graft-versus-host disease (GVHD) with tacrolimus/methotrexate (Tacro/MTX). In contrast, there was no grade III-IV acute GVHD in the haploidentical related donor (HRD) recipients, all of whom received GVHD prophylaxis with post-transplantation cyclophosphamide (PT/Cy) followed by tacrolimus/mycophenolate (tacro/MMF). Based on this initial experience, the protocol was subsequently amended to incorporate PT/Cy in all patients. We now report on this expanded cohort of a total of 59 patients, representing the largest experience with HSCT for GATA2 deficiency. Methods: This single-institution study was conducted at the National Institutes of Health Clinical Center between 2013 and 2020 (ClinicalTrials.gov Identifier: NCT01861106). Patients between 12 to 60 years of age were eligible if they had a deleterious mutation in the GATA2 gene, or clinical picture of the MonoMAC syndrome. Although the primary endpoints were engraftment and reversal of the clinical phenotype, a secondary endpoint was added to determine if PT/Cy in the MRD and URD reduced the incidence of grade III-IV aGVHD without compromising the overall and disease-free survival. Immune reconstitution at 100 days, 6, 12, 24, 36 months was analyzed. Results: 59 patients (median age at diagnosis 24 years; IQR 20-32) with GATA2 deficiency or the MonoMAC syndrome underwent allogeneic HSCT. MRD and URD recipients received busulfan for four days (targeted to an AUC 3600-4800) and fludarabine, whereas HRD recipients received two days of low dose cyclophosphamide, 5 days fludarabine, 200cGY total body irradiation, and two or three days of busulfan depending upon the presence or absence of clonal cytogenetic abnormalities. Donor sources included: 11 MRD, 31 URD, and 17 HRD. Median follow-up was 2 years [IQR 1-4], 88% (52/59) are currently alive. Seven deaths have occurred, including: persistent AML (n=1); infection (n=4); poor graft function and cardiac arrest (n=1) and from HPV-associated metastatic cancer (n=1). All of the patients who received HRD transplant are alive. Median time to neutrophil engraftment was 15 days (IQR 13-17) and 19.5 days (IQR 16-25) for platelets. Ninety three percent (55/59) of patients had blood test results after 100 days post-transplant to assess immune reconstitution; eighty one percent (45/55) had normal absolute monocyte counts, 67% (37/55) had normal absolute NK cell counts and 89% (49/55) had normal B cells counts. There was one case of primary graft failure in a recipient of an URD-transplant, and one secondary graft rejection in a recipient of HRD-transplant. Fifty-four percent (32/59) of patients had pre-HSCT myelodysplastic syndrome (MDS), and only two relapsed post-HSCT. Forty two percent (25/59) had abnormal cytogenetics pre-HSCT; amongst 23 patients with serial pre/post bone marrow cytogenetic evaluations, 19 had established normal cytogenetics post-HSCT. Forty five percent (19/42) of MRD/URD patients received Tacro/MTX for GVHD prophylaxis, and 31.5% (6/19) developed grade III-IV acute GVHD (aGVHD). In contrast, 55% (23/42) MRD/URD patients received PT/Cy for GVHD prophylaxis, and none developed grade III-IV aGVHD (p 0.0052). Five percent (1/17) of HRD recipients developed grade III-IV aGVHD. Forty two percent (8/19) of MRD/URD patients who received post-transplant Tacro/MTX had chronic GVHD, 4.3% (1/23) of MRD/URD patients who received PT/Cy developed cGVHD, and 5.8% (1/17) of HRD patients developed cGVHD within the first 2 years post-transplant. Conclusions: Allogeneic HSCT using a busulfan-based regimen in GATA2 deficiency results in nearly a 90% disease-free survival with long-term immune reconstitution. The use of PT-Cy reduced the risk of severe aGVHD and cGVHD and did not increase the risk of relapse or progression of MDS/AML. With earlier recognition of the disease, and the use of PT/Cy more broadly, these results are expected to continue to improve. Disclosures Notarangelo: NIAID, NIH: Research Funding.

T-Cell Replete Haploidentical Transplantation Using Post-Transplant Cyclophosphamide Results in Equivalent Non-Relapse Mortality and Disease-Free Survival Compared to Transplantation From HLA-Identical Sibling and Matched Unrelated Donors: A Stratified Cox Model Analysis of Two Hundred and Sixty Contemporaneous Allogeneic Transplants From a Single Center

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 833-833 ◽  
Author(s):  
Asad Bashey ◽  
Xu Zhang ◽  
Connie A. Sizemore ◽  
Karen Manion ◽  
Stacey Brown ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Research Funding ◽  
Disease Free Survival ◽  
Cox Models ◽  
Free Survival ◽  
Post Transplant ◽  
Haploidentical Transplantation ◽  
Disease Free ◽  
Significant Covariates

Abstract Abstract 833 HLA-identical siblings (MRD) or 10 of 10 HLA - A, B, C, DRB1 and DQB1 matched unrelated volunteers (MUD) are considered optimal donors for patients who may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). However, many patients, particularly those from ethnic minorities and mixed race backgrounds, will lack such donors. HLA-haploidentical (Haplo) relatives are available for virtually all patients. Traditional approaches to allo-HCT using Haplo donors have entailed stringent ex-vivo T-cell depletion and intense preparative regimens. Such transplants have been associated with slow immune reconstitution and a high-risk of opportunistic infections and non-relapse mortality (NRM). Recently, another approach to haploidentical transplantation using T-replete grafts and post-transplant cyclophosphamide (Cy) to prevent graft versus host disease (GVHD) and rejection has demonstrated promising results (Brunstein et al Blood 2011, vol118, p 282). Forty-Five patients underwent first allografts with a Haplo donor at our center between 02/05 and 08/10 (median age=46, range 20–73; diagnoses were AML 14, ALL 6, CML 4, MDS 4, CLL 7, NHL 4, HD 6; median KPS 90, range 70–90; CIBMTR disease risk score low 14, intermediate 7, high 24; median hematopoietic cell transplant co-morbidity index (HCTCI) score = 1, range 0–5; prior autotransplant = 7). Twenty-seven patients received a reduced-intensity conditioning regimen (RIC): fludarabine 30 mg/m2/d d −6 to −2; TBI 200cGy d-1, Cy 14.5 mg/kg/d on d-6,-5 and 50mg/kg/d on d+3,+4 with a bone marrow graft. Eighteen patients received myeloablative conditioning where the above regimen was modified by replacing low-dose TBI with iv busulfan 110–130 mg/m2/d × 4 days and bone marrow was replaced with G-CSF mobilized PBSC as the graft. Two patients receiving RIC failed to engraft and developed autologous hematopoietic recovery. All other patients engrafted with median 100% donor T-cell chimerism from initial testing at d+30. Outcomes of the Haplo transplants were compared to contemporaneous first allografts from MRD (n=115) and MUD (n=99) at our center. Median follow-up for surviving patients was 36 months (range 9–74.5 months). Cumulative probability of NRM at 36 months was 16%, 19% and 8% for MRD, MUD and Haplo respectively (p=NS) (see Fig). For both overall survival (OS) and disease-free survival (DFS), the effects of patient and disease characteristics were evaluated in Cox models with three transplant groups as strata. HCTCI score, CIBMTR risk category, type of diagnosis were identified as significant covariates on both OS and DFS, while age was significant on DFS only. The adjusted probabilities of OS and DFS were estimated from the stratified Cox models, weighted by the proportions of the significant covariates in the pooled sample. MRD had statistically superior OS to Haplo at 18 months (79% vs. 61%, p=0.033 in point wise comparison). However, adjusted OS was not significantly different between the three types of transplant at 36 months (71%, 58% and 58% for MRD, MUD and Haplo respectively (p=NS)). Adjusted DFS at 36 months was 47%, 46% and 55% respectively (p=NS) (see Fig). Ninety-three patients (35.7%) suffered relapse or progression of their malignancy at a median of 154 days post transplant (range 12–1445 days). Estimated cumulative incidence of relapse at 36 months was 35%, 38% and 36% respectively for MRD, MUD and Haplo (p=NS) (see Fig). The inverse probability of censoring weighted (IPCW) method was used to determine survival following relapse/progression in each group. Estimated survival at 1 year following relapse was 71%, 64% and 15% (p<0.0001 pointwise comparison for MRD vs. Haplo and MUD vs. Haplo). This study demonstrates that excellent NRM and DFS can be achieved using haploidentical donor transplantation with the above regimens. These outcomes are equivalent to those obtained in contemporaneously transplanted MRD and MUD at our center. T-cell replete haploidentical transplant is therefore a valid alternative for patients who lack a conventional donor. Survival following relapse/progression is inferior following haploidentical than conventional donor transplants. This may at least partly be related to the difficulty in using DLI following relapse in haploidentical transplants. Future strategies to improve outcomes following haploidentical transplants should focus on treatment approaches following relapse. Disclosures: Bashey: Otsuka America Pharmaceuticals, Inc: Research Funding. Sizemore:Otsuka America Pharmaceuticals, Inc: Research Funding. Manion:Otsuka America Pharmaceuticals, Inc: Research Funding. Brown:Otsuka America Pharmaceuticals, Inc: Research Funding. Holland:Otsuka America Pharmaceuticals, Inc.: Research Funding. Solomon:Otsuka America Pharmaceuticals, Inc: Research Funding. Morris:Otsuka America Pharmaceuticals, Inc: Research Funding.

scholarly journals Post-Transplant Cyclophosphamide and Thymoglobulin, a Graft-Versus-Host Disease Prophylaxis in Matched Sibling Donor Peripheral Blood Stem Cell Transplantations

2020 ◽  
Vol 29 ◽  
pp. 096368972096590
Author(s):  
Chutima Kunacheewa ◽  
Weerapat Owattanapanish ◽  
Chutirat Jirabanditsakul ◽  
Surapol Issaragrisil
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Free Survival ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Matched Sibling

Post-transplant cyclophosphamide (PTCy) has been explored in several types of stem cell transplantations (SCTs) and it proved highly effective in controlling graft-versus-host disease (GvHD) without aggravating relapsed disease. However, PTCy alone has resulted in inferior outcomes in matched sibling donor (MSD) employing peripheral blood (PB) SCTs. We hypothesized that adding thymoglobulin to PTCy would be able to control GvHD effectively. We retrospectively compared the use of standard GvHD prophylaxis encompassing a combination of PTCy and thymoglobulin (ATG) in patients with myeloid malignancies in a myeloablative conditioning MSD PBSCT. Forty-two patients underwent PBSCT using either methotrexate and cyclosporine (MTX/CSA, 21 patients) or PTCy and ATG (21 patients) as a GvHD prophylaxis. With median follow-ups of 71 months, the 1-year GvHD-free, relapse-free survival rates and chronic GvHD-free survival rate of the standard and PTCy/ATG groups were similar: 24% versus 37% ( P = 0.251) and 29% versus 43% ( P = 0.095), respectively. When focusing on chronic GvHD we observed that 17/35 patients (48.6%) suffered from this, 5/18 (27.8%) treated with MTX/CSA had extensive chronic GvHD, but 0/17 PTCy/ATG did. Twenty-one patients required additional GvHD treatment; 7/21 in the PTCy/ATG received only corticosteroid, while 8/14 MTX/CSA required at least 2 drugs. The 5-year overall survival rates were 52% and 52% ( P = 0.859), and the 5-year disease-free survival rates were 52% and 52% ( P = 0.862) for the MTX/CSA and PTCy/ATG groups, respectively. We conclude that PTCy in combination with ATG without immunosuppression of a calcineurin inhibitor can effectively control GvHD.

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