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.

The Use of Sirolimus Combined with Tacrolimus and Low-Dose Methotrexate Is Effective in Preventing Graft-Versus-Host Disease after Unrelated Donor Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2866-2866
Author(s):  
Ryotaro Nakamura ◽  
Roberto Rodriguez ◽  
Auayporn Nademanee ◽  
Joycelynne Palmer ◽  
David Senitzer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Serum Level ◽  
Low Dose ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Dose Methotrexate ◽  
Gvhd Prophylaxis ◽  
Full Intensity ◽  
Reduced Intensity

Abstract The use of sirolimus combined with tacrolimus and low-dose methotrexate recently showed a promising result in preventing GVHD after unrelated donor hematopoietic stem cell transplantation (Antin et al. Blood2003; 102: 1601). We studied this approach in 33 patients who received an unrelated donor transplant after full-intensity conditioning or reduced intensity conditioning from April 2005 to March 2006. All patients gave written informed consent for City of Hope protocols approved by the local institutional review board. Patient age ranged from 21 to 65 (median 46). Ten were female and 23 were male. The cohort consisted of 12 patients with AML, 9 with NHL, 6 with ALL, and the remaining 6 with other diagnosis (MDS=2, MPD=2, CML=1, HD=1). Patients were conditioned with either full-intensity regimen (FTBI-VP16=8, FTBI-Cy=6, BuCy=2) or reduced-intensity regimen using fludarabine (125mg/m2) plus melphalan (140mg/m2) (n=17) and received either a bone marrow graft (n=8) or peripheral blood stem cell graft (PBSC: n=25). GVHD prophylaxis consisted of tacrolimus (target serum level 5–10 ng/ml) and sirolimus (target serum level 3–12 ng/ml) started on day -4, and methotrexate 5mg/m2 for 3–4 days (days 1, 3, 6, +/− 11). High-resolution (HR) molecular HLA typing was performed for class I and II. Twenty pairs were in HR molecular match in all 10 antigens (HLA-A, B, C, DR, and DQ), five were in HR molecular 6/6 match (mismatch in C and/or DQ), and the remaining 8 pairs had a molecular mismatch in HLA-A (n=4), B (n=3), and DR (n=1). Eight transplants were from female donors to male recipients. After a median follow up of 7 months (range: 3–15), 26 patients are alive. Causes of death include relapse (3), VOD (2), and sepsis with multiorgan failure associated with grade 4 GVHD (1). The probabilities of 1-year overall survival, disease-free survival, and relapse were 74% (95%CI: 59–85%), 59% (95%CI: 41–75%) and 28% (95%CI: 16–45%), respectively. The probability of transplant-related mortality was 9% (95%CI: 5–18%) at 100 days and 19% (95%CI: 10–32%) at 1 year. Thrombotic microangiopathy was observed in two patients and were reversible. The probability of grade 2–4 acute GVHD was 44+9% (grade 3–4: 24+8%). Of 26 patients evaluable, 12 developed chronic GVHD (7=extensive, 5=limited). There was no difference in GVHD between full-intensity transplants and reduced-intensity transplants. There was a trend for reduced grade 2–4 acute GVHD in HR 10/10 match transplants (n=20: 31%) compared with the others (n=13: 62%, p=0.08). The current data compare favorably to our historic control (n=181: reduced intensity=98, full-intensity=83) using tacrolimus plus methotrexate or cyclosporine plus MMF with the incidence of grade 2–4 acute GVHD at 64% (p=0.02). In summary, our result show the combination of sirolimus, tacrolimus and low-dose methotrexate is associated with improved GVHD prophylaxis and acceptable toxicity. However, transplants others than 10/10 HR molecular match require further improvement.

scholarly journals Bone marrow transplantation in Fanconi anemia using matched sibling donors

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 2050-2054 ◽  
Author(s):  
M Kohli-Kumar ◽  
C Morris ◽  
C DeLaat ◽  
J Sambrano ◽  
M Masterson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Feasible Option ◽  
Matched Sibling ◽  
Low Incidence

Abstract Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.

Sirolimus and Tacrolimus as Graft-vs.-Host Disease Prophylaxis in Allogeneic Stem Cell Transplantation: The Dana-Farber Cancer Institute Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1227-1227
Author(s):  
Corey Cutler ◽  
Shuli Li ◽  
Haesook T. Kim ◽  
Edwin Alyea ◽  
Vincent Ho ◽  
...  
Keyword(s):  
Stem Cells ◽  
Overall Survival ◽  
Stem Cell ◽  
Serum Level ◽  
Acute Gvhd ◽  
Cell Function ◽  
Peripheral Blood Stem Cells ◽  
Gvhd Prophylaxis ◽  
Blood Stem Cells

Abstract Sirolimus is a novel immunosuppressant similar to tacrolimus, however, sirolimus inhibits T cell function uniquely via FKBP12/mTOR and can impair dendritic cell function. Sirolimus acts synergistically with tacrolimus and has a non-overlapping toxicity profile, making their use in combination attractive. We began employing sirolimus as GVHD prophylaxis in 2000, and herein describe our experience with this compound in the myeloablative transplant setting. Methods: Two clinical trials were performed using sirolimus (target serum level 3–12 ng/ml) and tacrolimus (target serum level 5–10 ng/ml) as primary GVHD prophylaxis. Cytoxan (1800 mg/m2/d x 2) and TBI (14 Gy, 7 fractions) was the conditioning regimen used in all patients. Trial 1 enrolled 76 patients who received HLA-matched, unrelated or 1-Ag mismatched related or unrelated bone marrow or peripheral blood stem cells. Abbreviated methotrexate (20 mg/m2 total) was routinely given post-transplant. Trial 2 enrolled 53 patients who received HLA-matched, related peripheral blood stem cells. No methotrexate was given post-transplant. Results: The median times to neutrophil engraftment (>500/ml) after transplantation were 17 (range 11–32) and 14 (range 9–17) days for trials 1 and 2 respectively. The median times to platelet engraftment (>20,000/ml) after transplantation were 29 (range 11–98) and 12 (range 10–47) days for trials 1 and 2. Grade II–IV acute GVHD occurred in 35% and 19% of patients in the two trials. Grade III–IV acute GVHD occurred in 21% and 4% of patients in the two trials. The median time to first hospital discharge was 33 and 19 days from transplantation for trials 1 and 2. Seven patients in trial 1 (9%) and 3 patients in trial 2 (6%) did not survive to first hospital discharge. The non-actuarial incidence of chronic GVHD in the two trials was 49 and 44%, respectively. Treatment-related mortality at 100 days was 13% and 6% in the trials. At two years, the relapse-free and overall survival estimates for trial 1 are 46 and 48% (Median follow-up of survivors: 27 months). One year relapse-free and overall survival estimates for trial 2 are 71% and 75% (Median follow-up of survivors: 15 months). Overall survival at 2 years is 72%. Toxicity related to the addition of sirolimus was modest. Among all patients (n=129), VOD occurred in 16 patients (12%), idiopathic pneumonia syndrome occurred in 9 patients (7%) and thrombotic microangiopathy occurred in 13 patients (10%). Conclusions: Sirolimus, when added to tacrolimus after allogeneic stem cell transplantation is effective for GVHD prophylaxis. Engraftment is prompt, the incidence and severity of acute GVHD are reduced and transplant-related morbidity and mortality is reduced, regardless of stem cell source and methotrexate use. Early survival estimates are excellent due to reduced GVHD and transplant-related toxicity. Sirolimus is worthy of broader study in allogeneic transplantation.

Low-Dose Methotrexate as Salvage Therapy for Refractory Graft-Versus-Host Disease (GVHD) after Reduced-Intensity Conditioning (RIC) for Allogeneic Stem Cell Transplantation (allo-SCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1802-1802
Author(s):  
Mohamad Mohty ◽  
Hugues de Lavallade ◽  
Catherine Faucher ◽  
Sabine Furst ◽  
Jean El-Cheikh ◽  
...  
Keyword(s):  
Side Effects ◽  
Salvage Therapy ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Risk Population ◽  
High Morbidity ◽  
Dose Methotrexate ◽  
Grade 3

Abstract Background. RIC regimens are increasingly used for allo-SCT. Although such regimens are associated with a relatively low early transplant-related mortality (TRM) in comparison to standard myeloablative allo-SCT, GVHD remains a matter of concern. Of note, corticosteroid-resistant GVHD is associated with high morbidity and mortality, and therapeutic options are limited for those patients. Furthermore, patients undergoing RIC allo-SCT are older than patients undergoing myeloablative allo-SCT, and are thus more exposed to the side effects and complications of long term corticosteroids (CS) administration. Low dose methotrexate (MTX) therapy is a well established modality for prophylaxis of GVHD after standard myeloablative allo-SCT. However, little is known about the role of this drug in the treatment of CS-resistant GVHD. Patients and Methods. The aim of this pilot single center study was to investigate the role and benefit of MTX in a curative setting after failure of CS treatment in 20 consecutive patients undergoing RIC allo-SCT. 20 patients experiencing severe GVHD received IV infusions of low dose MTX (5 mg/m2/infusion) at weekly intervals, for at least four weeks. Reasons for MTX administration were: refractory acute GVHD (after at least one week of 2 mg/Kg CS administration), CS-refractory chronic GVHD, chronic GVHD exacerbation after CS taper, or CS side effects and complications (CS-induced diabetes requiring insulin therapy, severe metabolic or psychiatric disorders). Responses to low dose MTX infusions were assessed one month after the last infusion in each involved organ. Results. 12 patients were treated for severe acute GVHD, while 8 patients received MTX for extensive chronic GVHD. Median age of patients was 51 (range, 22–60). Median time of administration of MTX was day +89 (range, 32–300) after allo-SCT. Of note, none of the patients received any other concomitant therapy for refractory GVHD. 13 patients responded to MTX administration (65 %) with 5 complete responses (25%). Among the 12 patients treated for acute GVHD, 7 responded (58%) of whom 5 CRs (42%). 3 patients did not respond and died from resistant GVHD. Interestingly, 5 patients from the group of grade 3–4 acute GVHD responded. Among the 8 patients treated for chronic GVHD, 6 were responders (75%). In addition, MTX allowed a significant reduction of CS daily dosage ranging from 25% to 80%, as assessed one month after the last administration of MTX. With a median follow-up of 287 days, no increase of CS therapy was necessary among these 6 MTX-responding patients. In the whole study population, toxicity of low dose MTX administration was low (transient and mild reversible cytopenia in 3 cases, 15%). Among the 20 patients, 14 are still alive (70%) with a median follow-up of 293 (range, 65–513) days. Overall, 2 patients died of progressive disease, while 4 patients died from refractory GVHD. Conclusions. In this study, the global response rate of severe GVHD to low dose MTX was impressively high (65%) if considered in terms of salvage therapy in this relatively elderly and high risk population. Low dose MTX appears to be a well-tolerated, inexpensive and likely steroid-sparing agent that is worthy of further investigation in prospective trials for treatment of refractory GVHD, but also as frontline therapy in combination with CS.

HLA-DP Mismatches Increase the Risk of Acute GVHD after Unrelated Donor Hematopoietic Transplantation (UDT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3125-3125 ◽  
Author(s):  
Marcos de Lima ◽  
Simrit Parmar ◽  
Ping Liu ◽  
Poliana A. Patah ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value <0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. AGVHD-free survival was calculated from transplant date to date of development of grade II–IV GVHD or completion of 100 days of follow-up. Results: Median age was 48 yrs (range, 14–72). Diagnoses were MDS (n=5), AML (n=58), and CML (n=21). 54 pts (64%) were beyond 1st CR; all CML pts were in >1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% < 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

scholarly journals Low Dose Antithymocyte Globulin (ATG) for Graft-Versus-Host Disease (GVHD) Prophylaxis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5788-5788 ◽  
Author(s):  
Anand Tandra ◽  
Leland Metheny ◽  
David Yao ◽  
Paolo F. Caimi ◽  
Lauren Brister ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Lymphoproliferative Disorder ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hla Typing ◽  
Viral Reactivation ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract ATG appears to reduce the incidence of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Potential risks of this strategy include viral reactivation, delayed immune recovery and increased relapse rates. The ideal dosing of rabbit ATG in this context is largely unknown. We therefore hypothesized that low dose ATG would reduce the incidence of acute and chronic GVHD in matched unrelated donor (MUD) transplants without compromising survival and relapse rate. A retrospective analysis was performed of a cohort of high-risk MUD HSCT recipients treated since year 2013, when our practice changed to include rabbit ATG at 3 mg/Kg for all MUD transplants at the Case Medical Center in Cleveland, Ohio. Herein we present the results of this analysis. Methods. 58 MUD transplants were performed between years 2013 and 2016, with a median follow up of 262 days post-transplant. All donor-recipient pairs were matched by high resolution HLA typing at HLA-A, -B, -C, and DRB1, (8/8 matches) with the exception of 4 pairs (7/8 matches. Median age was 56 years (range, 53-64). Underlying diagnoses were AML (n=26), MDS (13), CML (n=5), NHL (n=9), Hodgkin's lymphoma (n=2), Multiple Myeloma (n=1) and myeloproliferative disorders (n=2). Preparative regimens were ablative in 26 cases (45 %) and of reduced intensity in 31 cases (55 %). Graft source was bone marrow (n=5) and peripheral blood (n=53). All but 4 pts received GVHD prophylaxis with tacrolimus, and mini-methotrexate (5 mg/m2 on days +1, +3, +6 and +11), in addition to rabbit ATG 3 mg/Kg divided in two doses on days -2 and -1 pre HSCT. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human Herpes Virus (HHV6) PCR were conducted thrice weekly during the first 100 days after HSCT. Results. The 100-day cumulative incidence of grade II-IV acute GVHD was 41% (95% CI: 29-57; Fig 1), while the cumulative incidence of grade III-IV acute GVHD was 18% (95% CI: 9-35; Fig 2). 1-year cumulative incidence of chronic GVHD was 27% (95% CI: 17-42; Fig 3). At 180 days, the incidence of CMV viremia (defined as more than 1,000 copies/mL) was 25% (95% CI: 16-40), while the incidence of EBV and of HHV6 viremia was 35% (95% CI: 24-51) and 14% (95% CI: 8-27), respectively. There was no instance of EBV-related lymphoproliferative disorder. 3-year overall survival estimate is 48% (95% CI: 34-62). Cumulative incidence of Non-relapse mortality (NRM) and relapse at 1 year was 21% (95% CI: 12-37) and 44% (95% CI: 29-65), respectively. Conclusion. Our study shows that low dose rabbit ATG appears to reduce chronic GVHD rates without a major effect on acute GVHD incidence. CMV, EBV and HHV6 reactivation did occur, albeit at rates that are somewhat lower than those historically reported, without EBV-driven lymphoproliferative disorder. Disclosures Caimi: Genentech: Speakers Bureau; Roche: Research Funding; Novartis: Consultancy; Gilead: Consultancy.

A Phase I/II Trial of Bortezomib, Tacrolimus and Methotrexate for Prophylaxis of Acute Graft Versus Host Disease after HLA Mismatched Reduced Intensity Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1158-1158
Author(s):  
John Koreth ◽  
Kristen Stevenson ◽  
Haesook T Kim ◽  
Vincent T Ho ◽  
Corey S Cutler ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Graft Versus Host ◽  
Dose Methotrexate ◽  
Gvhd Prophylaxis ◽  
Level 1

Abstract There remains a need for better control of acute graft versus host disease (GVHD) after HLA mismatched peripheral blood stem cell (PBSC) allogeneic transplantation. Bortezomib is a small molecule proteasome inhibitor with immunomodulatory properties, and preclinical data indicate utility in GVHD control after allogeneic transplantation. We report on Phase I of a Phase I/II trial of bortezomib, tacrolimus and low dose methotrexate for GVHD prophylaxis after HLA mismatched reduced intensity conditioning (RIC) PBSC transplantation for patients with hematologic malignancies. Dose limiting toxicity (DLT) by day 45 after PBSC infusion is the primary endpoint, evaluating both acute bortezomib toxicity (e.g. neuropathy) and impact on stem cell function. Secondary endpoints include incidence of acute and chronic GVHD. Patients with 1–2 locus antigen/allele mismatch (HLA-A, -B, -C, -DRB1) are eligible. Pretransplant conditioning consists of busulfex (0.8 mg/kg/d) and fludarabine (30 mg/m2/d) each for 4 days. GVHD prophylaxis is bortezomib (dose level cohorts of 1, 1.3 or 1.5 mg/m2 on days +1, +4, +7), tacrolimus (days −3 to +180) and low dose methotrexate (5 mg/m2 on days +1, +3, +6, +11). 13 patients were enrolled on the bortezomib dose finding Phase I portion of the study. At bortezomib dose level 1, one of 5 patients had a possible DLT, with poor engraftment likely related to progression of underlying MDS/AML. At bortezomib dose level 1.3, none of 3 patients had a DLT. At bortezomib dose level 1.5, two of 5 patients had a possible DLT. One patient failed to engraft in the setting of minimally treated myeloproliferative disease; the other had graft rejection in the setting of persistent CLL post transplant. Bortezomib dose level 1.3 is considered the MTD, and 6 additional patients have been enrolled at this dose on the expanded Phase I/II portion of the study thus far. Overall, the 19 patients on study have a median follow-up of 12 months. No neurotoxicity has been noted. No platelet or neutrophil nadir was noted in 8 patients. The median time to neutrophil engraftment (ANC &gt;500) was 13 days in 7 patients experiencing a nadir; and the median time to platelet engraftment (Plts &gt;20,000) was 19 days in 8 patients with a nadir. Grade 2–4 acute GVHD has occurred in 2 of 17 evaluable patients (one each at bortezomib dose level 1 and 1.5), for a 180 day cumulative incidence of 14%, with relapse or death as a competing risk. Chronic GVHD has occurred in 6 of 12 evaluable patients, for a 1 year cumulative incidence of 50%. Overall and relapse free survival at 1 year are 73% and 58% respectively. In summary, GVHD prophylaxis with bortezomib, tacrolimus and low dose methotrexate after busulfex/fludarabine RIC PBSC transplantation is well tolerated. The low rate of acute GVHD in the HLA mismatched context is encouraging, and additional accrual is ongoing.

Low Incidence of Acute Graft-VS.-Host Disease (GVHD) Using Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) after Matched Sibling Donor (MSD) Non-Myeloablative Stem-Cell Transplants (NST) Conditioned with Fludarabine (FLU) and Low-Dose Total Body Irradiation (TBI).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5065-5065
Author(s):  
Yago Nieto ◽  
Nigel Patton ◽  
Timothy Hawkins ◽  
Ruth Spearing ◽  
Scott I. Bearman ◽  
...  
Keyword(s):  
Low Dose ◽  
Acute Gvhd ◽  
Multiorgan Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Large Cell ◽  
Survival Times ◽  
Gvhd Prophylaxis ◽  
Cell Transplants ◽  
Low Incidence

Abstract Randomized studies after conventional allografting showed that in combination with methotrexate TAC was superior to cyclosporine for prevention of acute GVHD. Using the Seattle conditioning regimen of FLU/low-dose TBI we evaluated TAC/MMF as a substitute for cyclosporine/MMF as post-grafting immunosuppression after MSD PBPC NST. Thirty-two patients (median age 57, range 32–68 years), who were poor candidates for a conventional myeloablative transplant, were enrolled. Patient diagnoses included lymphoma (N=12) (7 follicular, 2 transformed, 1 mantle-cell, 1 diffuse large cell, 1 NK), myeloma (N=12), high-grade MDS (N=5), AML (N=2), Hodgkin’s (N=1). Patients were conditioned with FLU (30 mg/m2/d x 3), TBI (200 cGy), were infused donor PBPCs on day 0, and received GVHD prophylaxis with TAC (0.06 mg/kg PO b.i.d. from day −3), targeting initially 10–20 ng/mL, and MMF (15 mg/kg PO b.i.d., from day 0 to +27, discontinued without taper). TAC was tapered from day +100 to +180 and from day +35 to +56, in those patients with indolent (N=25) and aggressive malignancies (N=7), respectively. Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a non-fatal graft rejection. The % patients with mixed/donor T-cell chimerism were as follows: 1 month: 77%/23%, 3 mo: 86%/14%, and 1 yr: 20%/80%. Five patients (15.6%) experienced stage II–IV acute GVHD, presenting at median day +61. Eleven patients (34%) experienced chronic GVHD (1 limited, 10 extensive) at median onset day +190. In 6 of those patients (22%), chronic CVHD was not elicited by immunosuppression withdrawal or DLI upon tumor progression. Day+100 transplant-related mortality (TRM) was 0%. Overall TRM was 9%, with 3 deaths from GVHD-related multiorgan failure on days +105, +343, and +354, respectively. At median follow-up of 19 (2–41) months, 20 patients (62.5%) were alive, 17 patients (53%) remained progression-free, 13 of them (41%) in complete remission. Median progression-free and overall survival times were 21 and 33 months, respectively. Conclusion: TAC/MMF after a MSD NST provides effective acute GVHD prophylaxis, and is associated with an excellent early safety profile. As compared to reported outcomes with cyclosporine/MMF, acute GVHD incidence appeared lower and onset was delayed.

scholarly journals CD34+ Cell Dose Effects on Clinical Outcomes of Patients with Acute Myeloid Leukemia after T-Replete Haploidentical Allogeneic Hematopoietic Stemcell Transplantation Using Peripheral Blood Stem Cells. a Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4586-4586
Author(s):  
Enrico Maffini ◽  
Myriam Labopin ◽  
Didier Blaise ◽  
Fabio Ciceri ◽  
Zafer Gulbas ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Group ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Peripheral Blood Stem Cells ◽  
Gvhd Prophylaxis ◽  
Cd34 Cells ◽  
Blood Stem Cells

The absolute number of infused CD34+ donor cells represents a critical step towards the achievement of a meaningful marrow engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). Previous observations have reported controversial conclusions regarding the impact of CD34+ donor cell doses and post-transplant clinical end-points. The vast majority of analysis conducted so far have considered myeloablative and reduced-intensity conditioning allogeneic HSCT setting, with HLA-matched sibling and/or unrelated donors. The T-cell replete haploidentical setting has not been extensively studied yet. We conducted a retrospective analysis on 414 adult patients (median age 54 years; range, 18-74) with acute myeloid leukemia (AML) in first (70%) and second (30%) complete remission who had received a T-cell replete allogeneic HSCT from a haploidentical donor, using peripheral blood stem cells (PBSC), between 2006-2018, based on ALWP-EBMT registry data. Median donor age was 37 years (range, 20-71). Time from disease diagnosis to HSCT was 6.3 months (range, 1.3-97.9). Seventy-three (18%) patients had secondary-AML. Eighty-seven patients (21%) had unfavorable cytogenetics. Karnofsky performance-status at the time of HSCT was ≥ 90 in 318 (77%) patients. Graft vs. host disease (GVHD) prophylaxis was post-transplant cyclophosphamide (PT-Cy)-based in 293 (71%) patients and anti-lymphocyte serum (ATG)-based in 121 (29%) patients. Conditioning was myeloablative in 179 (43%) patients and reduced-intensity in 235 (57%) patients. Median number of infused CD34+ cells was 6.58 x 106/kg (range, 2.2-31.2). Thirteen patients (3.2%) experienced graft failure while the remaining 399 (96.8%) engrafted uneventfully. Neutrophils engraftment at day 30 was 91.2% (95% Confidence interval [CI]: 88 - 93.6) while sustained platelets engraftment (>20.000/uL at 6-months) was observed in 83.7% (95% CI: 79.6 - 87). Median time to neutrophils and platelets engraftment were 20 (range, 10-79) and 21 days (range, 1-37) respectively. After a median follow-up of 23.3 months (range, 12.1-41.8) 2-year overall survival (OS) was 64.5 % (95% CI 59.3-69.7) with a leukemia-free survival (LFS) of 57.3 % (95% CI 51.8-62.7) and non-relapse mortality (NRM) of 23.3 % (95% CI: 19.0-27.7). The cumulative incidence of grade II-IV and III-IV acute GVHD at day-100 were 32.3 % (95% CI: 27.8 - 36.9) and 14.6 % (95% CI: 11.3 - 18.2), respectively. Incidence of 2-years chronic GVHD overall and extensive were 36.3 % (95% CI: 30.9 - 41.6) and 14.4 % (95% CI: 10.7 - 18.6), respectively. GVHD-free/relapse-free survival was 43.5 % (95% CI: 38 - 48.9) at 2-years. We found the optimal CD34+/kg threshold defining high-dose (n= 334) versus low-dose (n= 80)to be 4.96 x 106, using the Hothorn and Zeileis method (Hothorn, T. and Zeileis, A. Generalized maximally selected statistics. Biometrics 2008;64(4):1263-1269). Patients in the high-dose group experienced higher rates of engraftment compared to those in the low-dose group both for neutrophils (92.1% vs. 87.3%, p= 0.005) and platelets (86% vs. 73.3%, p= 0.001) while median time to neutrophils engraftment was 19 days (range, 10-79) in the high-dose group and 22 days (range, 14-46) in the low-dose group (p= 0.0001). Recipients of > 4.96 x 106/kg CD34+ cells experienced lower NRM (hazard ratio [HR] 0.48; 95% CI:0.29-0.75) and prolonged LFS (HR 0.62; 95% CI 0.43-0.90) and OS (HR 0.59; 95% CI:0.40-0.87) than recipients of ≤ 4.96 x 106/kg CD34+cell dose. Patients who received ATG as GVHD prophylaxis experienced less grades II-IV acute GVHD respect those in the PT-Cy cohort (HR 0.56; 95% CI: 0.36-0.87) without any differences in grades III-IV acute GVHD incidence at day 100 between the two groups. On Cox analysis, a female donor to male recipient combination was associated with higher extensive chronic GVHD incidence compared to other donor-recipient sex combinations, with CD34+ categorized according to the optimal threshold of 4.96 x 106 (HR 2.21; 95% CI:1.23-3.97; p= 0.008). AML patients who underwent a PBSC T-cell replete HSCT from haploidentical donors receiving ≥ 4.96 x 106CD34+/kg cells experienced a lower NRM and extended survival rates compared to those receiving ≤ 4.96 x 106/kg CD34+. The latter findings may have a significant practical impact and can guide prospective approaches. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Abatacept Is Effective for Gvhd Prophylaxis after Unrelated Donor Stem Cell Transplantation (URD SCT) for Severe Sickle Cell Disease (SCD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 370-370
Author(s):  
Alexander I. Ngwube ◽  
Niketa C. Shah ◽  
David Jacobsohn ◽  
Edward Dela Ziga ◽  
Shalini Shenoy
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Low Incidence ◽  
One Year

Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year overall survival (OS) and event-free survival (EFS) of 79% (95% CI 59-90) and 69% (95% CI, 48-82) respectively following reduced intensity conditioning (RIC).1 Though the RIC approach provided successful engraftment in the majority, the transplant approach was not considered safe for widespread adoption due to high rates of graft-versus-host disease (GVHD) especially in children &gt;13 years, a predominant cause of mortality. Strategies to minimize GVHD were essential if URD SCT was to be considered with curative intent in SCD. Aim/Method Multicenter trial (NCT03128996) with the primary objective of determining EFS in non-malignant disorders at one-year was amended as follows. The phase I SCD cohort included conditioning with hydroxyurea, proximal alemtuzumab, fludarabine, and melphalan in patients with 8/8 HLA-matched URD (-A, -B, - C and -DRB1).1 Thiotepa (8 mg/kg) was added in 7/8 HLA-mismatched SCT. GVHD prophylaxis included a calcineurin inhibitor and methotrexate as previously described. Abatacept (10 mg/kg) was administered on days -1, +5, +14, +28, +60, +100, +180, +270 and +365 based on efficacy described against acute GVHD with early dosing after SCT for malignant disorders.2,3 The latter 3 doses were omitted in cord transplant recipients. Result Thirteen children (7-21 years) underwent SCT (8/8 URD marrow- 7; 7/8 URD marrow or cord-6) primarily for stroke (N=6), ≥3 severe vaso-occlusive pain crises (N=4) or ≥2 acute chest syndrome episodes per year (N=3). The conditioning regimen was well tolerated. One patient had primary graft rejection after CMV infection (7%) and had autologous recovery. All other patients engrafted; neutrophils at median of 18 days (10-24), platelets at median of 28 days (16-39) and are surviving free of SCD with median follow-up of 12 months (range 4-59). Myeloid lineage donor chimerism was &gt;95% and lymphoid was 39%- 100% at day+100. Two-year OS and EFS was 100% and 92.3% (95% CI, 6.57-35.7), respectively. The day+100 incidence of grade II-IV and III-IV acute GVHD incidence was 23% and 15% respectively. One-year incidence of chronic GVHD was 38%. However, only one patient (7%) developed extensive cGVHD. One patient (7%) developed posterior reversible encephalopathy syndrome and recovered. Viral replication in blood was detected in 7 of 13 patients (7 CMV, 1 EBV reactivation). No patient developed EBV PTLD or required EBV-related intervention. Conclusion In comparison to previous experience1 with RIC and URD SCT, our early observations are (1) a lower incidence of PRES (7 vs 34%) (2) low incidence of severe acute GVHD (15% vs 17% grade III -IV) despite mismatched donors, (3) low incidence of extensive chronic GVHD (7% vs 38%) and (4) no mortality despite patient age (10/13 were &gt;13 years old). We attribute this gain to avoiding steroid use, and the benefit of including abatacept into the treatment regimen. The engraftment, safety, and immune reconstitution profile continue to be monitored in this ongoing trial now accruing in a Phase II cohort. As we and others work toward expanding donor options for SCD transplants, we submit that all alternate donor transplants for severe SCD are experimental and should be performed on clinical trials that track success and pitfalls. Reference: 1. Shenoy S et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016 Nov 24; 128(21): 2561-2567. 2. Koura et al. In vivo T cell costimulation blockade with abataceptfor acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant. 2013 Nov; 19(11): 1638-49. 3. Watkins BK et al. T cell co-stimulation blockade with CTLA-4 Ig (Abatacept) for acute GVHD prevention in HLA-matched and mismatched unrelated donor transplantation: Results of a Phase 2 trial. Abstract 65. ASTCT Meetings, Houston 2019. Figure Disclosures Shah: Jazz pharmaceuticals: Speakers Bureau. OffLabel Disclosure: Abatacept, FDA approved for rheumatoid arthritis is a fusion protein that inhibits T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs).It is used for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation in this study

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