A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4200-4200 ◽  
Author(s):  
Amin M. Alousi ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Borje S Andersson ◽  
Issa Khouri ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Control Group ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Matched Sibling ◽  
And Control

Abstract Abstract 4200 Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period. Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results: The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion: Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors. Disclosures: Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

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

scholarly journals Outcomes of Allogeneic Hematopoietic Cell Transplantation with Cord Blood Versus Mismatched Unrelated Donor with Post-Transplant Cyclophosphamide in Acute Myeloid Leukemia: An Analysis from the ALWP of the EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Bhagirathbhai Dholaria ◽  
Myriam Labopin ◽  
Jaime Sanz Caballer ◽  
Annalisa Ruggeri ◽  
Jan J. Cornelissen ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Matched Pair ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Matched Pair Analysis ◽  
Grade Ii

Background Haploidentical allogeneic hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) has greatly expanded potential donor options for patients (pts) without a fully HLA-matched donor. However, an HLA-mismatched unrelated donor (UD) or cord blood transplantation (CBT) are valid options for pts who do not have an haploidentical-related or a fully HLA-matched donor. The incorporation of PTCy with mismatched UD allo-HCT is associated with reduced risk of non-relapse mortality (NRM) and graft-versus-host disease (GvHD) (Jorge et al., BBMT, 2018). No previous study has compared outcomes of these two graft sources in contemporary era. In this study, we compared the outcomes of CBT versus (vs) single antigen-mismatched (HLA 9/10) UD allo-HCT with post-transplant cyclophosphamide (PTCy) in pts with acute myeloid leukemia (AML). Methods Pts with AML who underwent a first CBT without PTCy (N=902) or allo-HCT from a 9/10 UD with PTCy (N=280) between 2010 to 2019 were selected from The European Society of Blood and Marrow Transplantation (EBMT) registry. We excluded pts who had ex vivo T cell depletion. The median pt age was comparable between CBT and UD cohort [51 years (y) vs. 52 y, p=0.09]. The recipients of CBT had a longer median follow up (47 vs. 19 months, p&lt;0.01) compared to UD. The cytogenetic risk category was good in 68 (6%), intermediate in 514 (46%), poor in 184 (16%) and unknown in 416 (35%) pts. Pre-HCT disease status was first complete remission (CR1) in 701 (59%), CR2 in 279 (24%) and advanced (non-CR1/CR2) in 202 (17%) pts. Myeloablative conditioning (MAC) was used in 47% of the total pts and the use of MAC was comparable between the study cohorts (p=0.21). In vivo T cell depletion was used more frequently with CBT compared to UD (40% vs. 26%, p&lt;0.01). A Cox regression multivariate (MV) analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score based 1:1 matching of pts with known cytogenetic risk. Propensity score was based on pt age, gender, Karnofsky performance score, cytogenetic risk group, pre-HCT disease status and intensity of conditioning regimen. Results In the univariate analysis, day +180 incidence of grade II-IV acute GvHD was 36% vs. 32% (p=0.07) and grade III-IV acute GvHD was 15% vs. 11% (p=0.16) for CBT and UD cohorts, respectively. The 2-y incidence of total chronic GvHD was 26% vs. 32% (p=0.20) and extensive chronic GvHD was 12% vs. 12% (p=0.83), respectively. CBT was associated with higher incidence of graft failure (11% vs. 4%, p&lt;0.01) and higher 2y NRM (30% vs. 16%, p&lt;0.01) compared to UD. CBT resulted in lower leukemia free survival (LFS) (43% vs. 61%, p&lt;0.01), overall survival (OS) (47% vs. 63%, p&lt;0.01) and GvHD-free, relapse-free survival (GRFS) (34% vs. 47%, p&lt;0.01). There was no difference in 2y relapse incidence (RI) between study cohorts (28% vs. 23%, p=0.24). There were more infection-related deaths in CBT compared to UD allo-HCT recipients (31% vs. 24% of total reported deaths). Among CBT recipients, 3 pts died from graft failure and 5 pts died from lymphoproliferative disorder. In the MV analysis (Table 1), CBT was associated with higher risk of grade II-IV acute GvHD [hazard ratio (HR)=1.32, 95% confidence interval (CI):1-1.74,p&lt;0.05], NRM [HR=2.09, 95% CI:1.46-2.99, p&lt;0.0001], and RI [HR=1.35, 95% CI: 1-1.83, p=0.05] which resulted in inferior LFS [HR=1.68, 95% CI:1.34-2.12,p&lt;0.0001], OS [HR=1.7, 95% CI:1.33-2.17, p&lt;0.0001] and GRFS [HR=1.49, 95% CI:1.21-1.83,p&lt;0.0001] compared to UD. The chronic GvHD did not differ between the study cohorts [HR=0.94, 95% CI: 0.68-1.3, p=0.69]. Older age and advanced disease status were associated with poor OS. These results were confirmed in a matched-pair analysis, which compared 177 pairs of CBT vs. 9/10 UD allo-HCT pts. CBT was associated with higher 2y NRM (HR=1.96, p&lt;0.01), RI (HR=2.01, p&lt;0.01), and lower LFS (HR=1.98 p&lt;0.01), OS (HR=1.82, p&lt;0.01) and GRFS (HR=1.77, p&lt;0.01) (Figure 1). Grade II-IV acute (HR=1.33, p=0.13) and total chronic (HR=1.02, p=0.93) GvHD rates were comparable between the cohorts. Conclusions In this large registry-based observational study, CBT was associated with inferior LFS, OS and GRFS due to higher NRM and RI compared to 9/10 UD allo-HCT with PTCy. In the absence of a fully matched or haplo donor, 9/10 UD allo-HCT with PTCy may be preferred over CBT in pts with AML. A prospective study is needed to validate our findings. Disclosures Dholaria: Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&J: Research Funding; bms: Research Funding. Labopin:Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte Corporation: Honoraria. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Mobilized Peripheral Blood Stem Cells (PBSC) Compared with Bone Marrow (BM) as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced Intensity Conditioning (RIC-alloSCT) in Patients with Acute Myeloid Leukemia (AML) in Complete Remission (CR): a Retrospective Analysis From the ALWP of EBMT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 527-527
Author(s):  
Arnon Nagler ◽  
Myriam Labopin ◽  
Avichai Shimoni ◽  
Dietger Niederwieser ◽  
Nadezda Basara ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Published Data ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Data Set ◽  
Advanced Phase ◽  
Unrelated Donors

Abstract Abstract 527 RIC-alloSCT is being increasingly used for AML patients with high comorbidities not eligible for standard myeloablative conditioning. Few published data advocate the use of PBSC instead of BM in RIC in the HLA identical sibling setting, however only scarce data is availabel in RIC-alloSCT using unrelated donors. Moreover, sometimes volunteer donors are reluctant to use G-CSF. Therefore, we compared outcomes of PBSC vs. BM RIC-alloSCT, using the EBMT ALWP data set. Between 2000 and 2008, 803 patients with AML in CR underwent RIC-alloSCT from HLA compatible unrelated donors with PBSC (690) or BM (113) grafts. Recipient‘s age was higher in the PBSC vs. BM groups 57y (range, 19-77) and 52y (range, 18-76), respectively (P<0.0001), while gender was comparable between the 2 groups. Leukemia features were also comparable between the PBSC vs. BM groups, such as WBC at diagnosis (10.4×109/L vs. 8.6×109/L), cytogenetics–good risk (6.7% vs. 9.6%), intermediate risk (73.9% vs. 75%) and poor risk (19.4% vs. 15.4%) as well as for FAB classification. Disease status at RIC-alloSCT was not statistically different between the 2 cohorts: in the BM group 57% were in first CR and 43% in second CR compared to 64% and 36% in the PBSC group, respectively (p=0.13). Time from diagnosis to transplant was 239d in PBSC group vs. 332d in the BM group (P<0.0001) and low-dose TBI-based conditioning was more frequently used in PBSC (33.2%) compared to 6.2% in the BM group (P<0.0001). Donor gender and CMV serostatus were not statistically different in both groups. There was a difference in year of transplant as it was 2006 (2000-2008) vs. 2005 (2000-2008) for the PBSC vs. BM RIC-alloSCT (P<0.001). Results: Engraftment was achieved in 95% of the patients in both groups. Acute GVHD grade > II was significantly higher in the PBSC group, 28% compared to 12% in BM group, (P<0.0001). Similarly, chronic GVHD (2y) was higher in the PBSC with 55±3% vs. 48±9% in the BM group, respectively (P=0.05). The 2-year probabilities of LFS and relapse incidence were 44±3% and 38±3% for the PBSC transplants in comparison to 42±6% and 51±7%, for the BM group (NS), while, non relapsed mortality was significantly higher for the PBSC vs. BM group, 29±3% vs. 14±5%, respectively (P=0.007). In multivariate analysis, after statistical adjustments of differences, the PBSC group was associated with a higher incidence of aGVHD (II-IV) (HR=3.2, p=0.01), higher NRM (HR=2.6, p=0.005), a trend of decreased relapse incidence (HR 1.47, p=0.06) and no statistical difference of LFS between the two groups (p=0.62). In conclusion: 1) The vast majority (86%) of the unrelated RIC - alloSCT for AML performed in Europe are from PBSC rather than from BM grafts. 2) Our results indicate significantly higher incidence of acute GVHD and NRM, but not statistically different LFS comparing unrelated PBSC to BM grafts following RIC conditioning. Therefore, there is no disadvantage for using unrelated BM rather than unrelated PBSC grafts in the RIC-alloSCT setting. Whether PBSC should be preferred in advanced phase of the disease, where outcome is dominated by relapse incidence, need to be further investigated. Disclosures: No relevant conflicts of interest to declare.

Reduced Intensity Conditioning Combined with Post-Transplant Cyclophosphamide for Graft Vs. Host Disease Prophylaxis In Older-Aged or Medically Frail Patients with Advanced Hematological Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2341-2341
Author(s):  
Amin M Alousi ◽  
Borje S. Andersson ◽  
Rima M. Saliba ◽  
Wendeline Botnick ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Phase Ii Trial ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Graft Vs Host Disease ◽  
Matched Sibling ◽  
Grade 3

Abstract Abstract 2341 Graft-vs-Host Disease (GVHD) remains a common complication following matched sibling and unrelated (MUD) donor hematopoietic cell transplant (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (Cy) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and Cy. Herein, we report the results of a phase II trial exploring a reduced intensity conditioning (RIC) regimen combined with post-transplant Cy in BM and peripheral blood (PB) HCT recipients. Methods: Fludarabine (Flu) was administered at a dose of 40mg/m2 over 1hr followed by intravenous Bu over 3 hrs targeting a daily AUC of 4,000 microMol-min on days −6 to −3. Recipients of MUD's received ATG on days −3 to −1 (total dose 4mg/kg). Cy was given as sole GVHD prophylaxis at a dose of 50mg/kg on days +3 and +4. Results: 31 pts with a median age of 62 yrs (range, 39–71) received a matched sibling (n=11) or unrelated donor (n=20) graft from BM (n=22) or PB (n=9) for the following diagnoses: AML/ MDS (n=25), CLL+MDS (n=2), CLL (n=1), NHL+MDS (n=1), NHL (n=1) and ALL (n=1). Disease status at the time of HCT was induction failure, relapsed and/ or chemotherapy-refractory disease in 23 pts with the remaining pts in high-risk CR1 (n=5), CR2 (n=2) or CR3 (n=1). The median co-morbidity score was 3 (range, 0–7) and 7 pts had a prior HCT (autologous n=4, allogeneic n=3). Median days to ANC > 0.5 × 109/L and platelet count >20 × 109/L were 17 (range, 13–38) and 24 (range, 11–57), respectively. Primary and secondary graft failure occurred in 1 and 2 pts, respectively. Mucositis (grade 2: n=19, grade 3: n=4) and hemorrhagic cystitis (grade 2: n=10, grade 3: n=4, grade 4: n=2) were the most common toxicities. Day 100 non-relapse mortality was 6% (95% CI, 2–25). The cumulative incidence (C.I.) of acute GVHD grades II-IV and III-IV was 56% (95% CI, 40–79) and 13% (95% CI, 5–33) which includes 4 cases of late acute GVHD. Rates of acute GVHD did not differ between PB or BM recipients (55% vs. 58%, p-value 0.9). C.I. of chronic GVHD was 11% (95% CI, 4–32). With a median follow-up of 10 months (range, 4–20), 1-yr overall and progression-free survival (PFS) was 56% (95% CI, 35–73) and 43% (95% CI, 21–63), respectively. For pts with AML/MDS, 1- yr PFS for pts in CR1, any CR and relapsed/refractory disease were: 100%, 66% (95% CI, 16–91) and 40% (95% CI, 20–60), respectively. Conclusion: This phase II trial of RIC with BU/Flu combined with post-transplant Cy was well tolerated and resulted in favorable survival and good disease-control in this high-risk, older-age population. Rates for acute GVHD appear comparable to historical rates with calcineurin-inhibitor based regimens, while rates for chronic GVHD appear to be lower. Rates for acute GVHD were similar for PB and BM grafts supporting the inclusion of PB grafts in future trials using post-transplant Cy as the basis for the GVHD prophylaxis regimen. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Combination of ATG and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Peripheral Blood Stem Cell Transplants for High-Risk Hematological Malignancies- a Single Centre Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4569-4569
Author(s):  
Shruti Prem Sudha ◽  
Eshetu G Atenafu ◽  
Queralt Salas Gay ◽  
Zoe Evans ◽  
Zeyad Al-Shaibani ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Persistent Disease ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Donor Type

Abstract Background ATG and post-transplant cyclophosphamide (PT-Cy) have been individually shown to be efficacious in reducing rates of GVHD in HLA matched and mismatched transplants. We adopted a combination regimen of ATG and PT-Cy for GVHD prophylaxis for matched unrelated donor (MUD) transplants in our centre to decrease the rates of acute and chronic GVHD. Patients and methods Pre-transplant conditioning consisted of iv Fludarabine (30mg/m2/day) for 4 days, iv Busulphan (3.2 mg/kg/day for 2 days), and low dose TBI (200cGy on day-1). GVHD prophylaxis was with Thymoglobulin 4.5mg/kg over 3 days (day-3 to -1), PT-Cy 50 mg/kg/day on days+3 and +4 and cyclosporine from day+5 (taper started by day+45 in patients without GVHD). The stem cell source was G-CSF stimulated peripheral blood stem cells (PBSC) in all patients. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan Meir method. Among variables included in Cox regression analysis to identify predictors of survival were age, pre-transplant remission status, occurrence of CMV infection, donor type (10/10 vs 9/10), and occurrence of acute or chronic GVHD. Results A total of 102 patients (median age 59y, range 22-74y) with high-risk hematological malignancies (AML-55, MDS-20, MPD-9, ALL-5, CML-4, lymphoma-6, CMML-3) were treated with this protocol. Unrelated donors were 9/10 matched in 26 patients, and the rest were 10/10 matched. At a median follow-up of 12 months (range 0.5 to 31 months), the 1year OS and PFS were 66.5% (95% CI -57% -76%) and 57.6% (95% CI 47.6% -67.6%) respectively. The 1year OS for 10/10 transplants was 72.3% (95%CI 61.7%- 82.9%), which was significantly higher than that for 9/10 transplants at 50% (95%CI 30.4%- 69.6%, p=0.016). The 1year PFS for 10/10 donor transplants was 65.5% (95% CI-54.3%- 76.7%) which was significantly higher than that for 9/10 transplants at 34.6% (95%CI 16%- 53.2%, p=0.004). The 9/10 matched patients had significantly higher relapses (hazard ratio 3.2, 95%CI 1.4-7.1, P=.005) than 10/10 matched patients. There were five graft failures (one primary and four secondary). The non-relapse mortality (NRM) was 17.6 %. The overall incidence of acute GVHD was 40% (grade 3-4 acute GVHD was seen in 14.8% patients). The overall incidence of chronic GVHD was 19.6% (moderate/severe NIH stage chronic GVHD was seen in 8.8% patients). The overall relapse rate was 23.3%. CMV re-activation was seen in 50 (49%) patients, and EBV re-activation in 20 (19.6%) patients, and 10 (9.8%) patients were diagnosed with post-transplant lympho-proliferative disorder (PTLD). In univariate analysis, adverse predictors of survival were a) persistent disease at the time of transplant, b) absence of chronic GVHD, and c) 9/10 donor type. In multivariable analysis, the only independent predictors of survival were a) persistent disease at time of transplant [hazard ratio 6.96, 95% CI 1.97-24.7, p=0.003], and b) donor type 9/10 vs 10/10 [HR 2.59, 95% CI 1.15-5.8, p=0.022]. Conclusion Our experience shows that PT-Cy and ATG can be combined for GVHD prophylaxis in MUD PBSCTs with low rates of Gr3-4 acute GVHD and chronic GVHD, and acceptable NRM and relapse rates. There were high rates of viral reactivation including PTLD. Figure. Figure. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4655-4655 ◽  
Author(s):  
Kavita Raj ◽  
Eduardo Olavarria ◽  
Diderik-Jan Eikema ◽  
Liesbeth C de Wreede ◽  
Linda Koster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

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.

Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 730-730 ◽  
Author(s):  
Edwin P. Alyea ◽  
Shuli Li ◽  
Haesook Kim ◽  
Corey Cutler ◽  
Vincent Ho ◽  
...  
Keyword(s):  
Serum Level ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Dose Methotrexate ◽  
Gvhd Prophylaxis ◽  
Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

Outcomes of c Hematopoietic Stem Cell Transplantation (HCT) after Non-Myeloablative Conditioning in Relapsed, Refractory, or Transformed Indolent Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3124-3124 ◽  
Author(s):  
Andrew R. Rezvani ◽  
Brenda M. Sandmaier ◽  
Barry Storer ◽  
Michael Maris ◽  
Edward Agura ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Aggressive Lymphoma ◽  
Optimal Timing ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Allogeneic Hct ◽  
Grade 3

Abstract Sixty-two patients (pts) with chemotherapy-refractory indolent or transformed NHL were treated at 10 centers with allogeneic HCT from related (n=34) and unrelated (n=28) donors after 2 Gy total body irradiation with or without fludarabine. Diagnoses included follicular lymphoma (FL) (n=54, including 10 with grade 3 FL), small lymphocytic lymphoma (n=6), and marginal zone lymphoma (n=2). Median age was 54 years (range 33–66 years), and median time from diagnosis to HCT was 4.4 years (range 0.5–18.5 years). Sixteen pts had histologically documented transformation to diffuse aggressive lymphoma prior to HCT. Twenty-seven pts (44%) had failed autologous HCT. Disease status at the time of HCT was complete response (CR, n=16), partial response (PR, n=22), refractory (n=13), untested relapse (n=9), or unknown (n=2). Eleven of the 28 unrelated donor/recipient pairs (39%) had HLA mismatches: 2 at a single allele, 7 at a single antigen, and 2 at an antigen and an allele. One pt had non-fatal graft rejection from a 1-antigen-mismatched unrelated donor. Median follow-up of survivors after HCT was 36.6 months (range 2.3–60 months). Responses (CR [n=18] and PR [n=7]) were seen in 25 of 44 (57%) pts with evaluable disease prior to HCT, while 5 had stable disease, 9 progressed, and 5 were not evaluable due to early non-relapse mortality (NRM) on d27–d108. Two of 16 pts (13%) transplanted in CR relapsed; one was treated with donor lymphocyte infusion and achieved a persistent CR. The incidences of acute GVHD grades II–IV, III–IV, and chronic GVHD were 63%, 19%, and 53%, respectively. At 3 years, the risks of relapse/progression and NRM were 19% and 42%, respectively. There was a trend toward increased mortality with unrelated donors (HR 1.87 [0.9–3.7, p=0.08]). Progression-free and overall survival (PFS and OS) were significantly better in the non-transformed group (see tables 1 and 2). Table 1. Outcomes Non-transformed Transformed Relapse 6/46 (13%) 6/16 (38%) NRM 20/46 (43%) 6/16 (38%) 3-year OS 24/46 (52%) 4/16 (25%) 3-year PFS 20/46 (43%) 4/16 (25%) Table 2. Hazard Ratios (HR) for Transformed vs. Non-Transformed Pts HR (95% CI) p All-cause Mortality 2.39 (1.2–4.9) 0.02 Relapse/progression 4.75 (1.5–15) 0.01 Grade 3+ acute GVHD 1.84 (0.5–6.3) 0.35 Extensive chronic GVHD 1.96 (0.8–5.0) 0.18 Figure Figure Allogeneic HCT after non-myeloablative conditioning can produce durable responses and prolonged survival in pts with refractory indolent or transformed NHL. Pts transplanted before histologic transformation had significantly better outcomes. Future efforts will focus on reducing NRM and identifying optimal timing of HCT.

A Randomized Prospective Multicenter Phase III Trial Comparing Standard GvHD Prophylaxis with Cyclosporine and Methotrexate with Additional Pretransplant ATG Fresenius (ATG-F) in Allogeneic Stem Cell Transplantation from Matched Unrelated Donors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 57-57 ◽  
Author(s):  
Jürgen Finke ◽  
Wolfgang Andreas Bethge ◽  
Claudia Schmoor ◽  
Hellmut Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Chronic Gvhd ◽  
Group Versus ◽  
Phase Iii ◽  
Control Group ◽  
Phase Iii Trial ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Treatment Comparisons ◽  
Grade Iii

Abstract Graft versus host disease is a major cause of morbidity and mortality after allogeneic stem cell transplantation from unrelated donors. Strategies using intensified GvHD prophylaxis including T cell depletion did not result in better outcome due to increased risks of infection and relapse. The use of ATG in the conditioning regimen for in vivo-Tcell depletion for GVHD prophylaxis has been reported by several groups but not been tested in a large prospective randomized trial. Here we report on results from the first large prospective, randomized, multicenter, open-label, phase III trial comparing standard GvHD prophylaxis with cyclosporine A (CyA) and short course methotrexate (Mtx) days +1, +3, +6, +11 (15/10/10/10 mg/m2) with or without 3×20mg/kg ATG-Fresenius (ATG-F) after a median follow-up time of two years. Between 2003 and 2007, 201 patients, median age 40 (range 18–60) years with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94), were transplanted from HLA-A and -B (2 digit), DRB1, DQB1 (4 digit) identical unrelated donors after highdose myeloablative conditioning with marrow (n=37) or PBSC (n=164) grafts. Median follow up time was 732.5 (25%-quartile 604, 75%-quartile 1097) days. For treatment comparisons with regard to the occurrence of aGvHD grade III-IV or death within 100 days post Tx, logistic regression adjusted for status of disease, source of stem cells, and center was used. For treatment comparisons with regard to time-to-event variables, cumulative incidence rates considering relapse and death as competing events were estimated, and Cox regression modelling the event-specific hazard rates and adjusting for status of disease and source of stem cells was used. Engraftment with WBC &gt; 1000/μl was achieved in 97% in the ATG-F group after median 26 days, and in 95% in the control group after median 19 days (p&lt;0.0001). At day +100, the rate of patients experiencing the primary efficacy endpoint-severe aGvHD (grade III–IV) or death - was 21.4% in the CyA/Mtx/ATG-F arm versus 33.7% in the CyA/Mtx only arm (p=0.1286). Incidence of grade III–IV acute GvHD was 11.7% in the ATG-F arm and 24.5% in the control group (p=0.054), grade II–IV aGvHD was 33.0% vs. 51.0% (p=0.0108), and grade I–IV aGvHD was 56.3% vs. 74.5% (p=0.0073). Incidence of chronic GvHD (limited and extensive) after two years was 30.8% in the ATG-F group versus 58.8% in the control group (p&lt;0.0001). Incidence of extensive chronic GvHD after two years was 12.2% in the ATG-F group versus 42.6% in the control group (p&lt;0.0001). Disease-free survival (DFS) after two years was 51.6% in the ATG-F and 47.5% in the control group (p=0.65). Incidence of relapse/progression after two years was 28.9% in the ATG-F and 23.6% in the control group (p=0.55). Incidence of death without former relapse/progression (TRM) after two years was 19.6% in the ATG-F and 28.9% in the control group (p=0.198). Overall survival (OS) after two years was 59.2% in the ATG-F and 51.9% in the control group (p=0.47). Number of infections per follow up year was 4.54 in the ATG-F and 4.76 and in the control group. The addition of ATG-F to standard CyA/Mtx prophylaxis results in decreased incidence of acute and chronic GvHD without increase of relapse or TRM rates. This is the first randomized trial answering the long-standing question regarding the beneficial effect of additional ATG-F to a standard GvHD prophylaxis. A reduction of GvHD without compromising survival could be demonstrated.

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