Faculty Opinions recommendation of A phase II study of sirolimus, tacrolimus and rabbit anti-thymocyte globulin as GVHD prophylaxis after unrelated-donor PBSC transplant.

2012 ◽  
Author(s):  
Nelson Chao
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis

scholarly journals A phase II study of sirolimus, tacrolimus and rabbit anti-thymocyte globulin as GVHD prophylaxis after unrelated-donor PBSC transplant

2012 ◽  
Vol 48 (2) ◽  
pp. 278-283 ◽  
Author(s):  
S K Khaled ◽  
J Palmer ◽  
T Stiller ◽  
D Senitzer ◽  
R Maegawa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis

Rituximab for Graft-Versus-Host-Disease-Prophylaxis after Allogeneic Stem Cell Transplantation Given as Treatment of High Risk Relapse of Aggressive Lymphoma: Results of a Randomized Phase II Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1974-1974 ◽  
Author(s):  
Bertram Glass ◽  
Justin Hasenkamp ◽  
Anke Görlitz ◽  
Peter Dreger ◽  
Jörg Schubert ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
B Cell ◽  
Phase Ii ◽  
Progressive Disease ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Randomized Phase Ii ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Background: High dose therapy (HDT) followed by autologous stem cell support has poor outcome in patients with primary progressive lymphoma or relapse after primary HDT. Allogeneic SCT may help these patients by exerting an GVL effect. Its use however is hampered by high incidence of severe GVHD and non-relapse mortality in this population. Rituximab has been claimed to reduce the incidene of GVHD without negative impact on the relapse rate. Patients and Methods : We initiated a randomized phase II study using intermediate conditioning (Fludarabine 125 mg/m2, Busulfan 12 mg/kg and cyclophosphamide 120 mg/kg) followed by GVHD prophylaxis with short term mycophenolat mofetil plus tacrolimus. Anti-thymozyte globulin (ATG) was given due to center decision. Patients were randomized to receive two times four doses of rituximab (375 mg/m2) post transplant starting day +21 and day +175 or no additional GVHD prophylaxis. From June 2004 to July 2007 sixty five patients with aggressive NHL were enrolled and 59 were eligible for analysis. Thirty one pts had diffuse large B cell NHL, 3 patients follicular lymphoma grade 3, 7 pts blastic mantle cell lymphoma, 2 pts aggressive marginal zone lymphoma, 2 patients lymphoblastic B cell lymphoma, and 12 T cell lymphoma. 42 (71%) pts received at least one cycle of HDT and autologous SCT prior to alloSCT; 78% had early relapse ( < 12 months) or primary progressive disease, 59% chemo-refractory disease and 48% had progressive disease with high or high intermediate age adjusted IPI immediately prior to conditioning. Results: Allo-PBPC were obtained from HLA-identical siblings in 17 pts, from matched unrelated donors in 32 pts and from one locus mismatched unrelated donors in 10 pts. 33 patients did receive ATG. Median observation time of surviving patients is 1,8 years. 30 pts died, in 19 patients death was attributed to treatment related causes. After one year, estimated overall survival is 49%, progression free survival is 39%, relapse rate is 28 % and incidence of GVHD > grade 1 is 73%. The last documented lymphoma progress occurred at day 288 after alloSCT. There are no significant differences in OS, PFS and GvHD in relationship to the application of Rituximab. Conclusion: Intermediate intensity conditioning followed by allogeneic SCT is a valuable treatment option in patients with high-risk relapse of aggressive NHL. The incidence of GVHD and non-relapse mortality is high. On the background of this very high basic incidence of GVHD, we did not find a significant impact of post transplant rituximab on GVHD, relapse rates or survival, respectively. Therefore, ATG will be added as an obligatory part of the conditioning regimen in the next study phase in additional 30 patients

scholarly journals Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Jie-ling Jiang ◽  
Wen-hui Gao ◽  
Li-ning Wang ◽  
Ming Wan ◽  
Ling Wang ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Primary Data ◽  
Post Transplantation ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Number Of Patients

The PT-Cy was considered as one of the mainstay protocol for graft verus host disease (GVHD) prophylaxis. Recent study demonstrated that PT-Cy combined with other immunosuppressants could further reduce the incidence of GVHD and improve the GVHD and relapse free survival (GRFS). In this prospective phase II study, we evaluated the effect of a new GVHD prophylaxis consist of PT-Cy combined with tacrolimus and low dose anti-thymoglobulin (ATG). A total of 23 patients were enrolled including 20 patients with acute lymphoblastic leukemia (ALL) and three patients with T cell lymphoma. The median age was 29 years (range, 16~58 years). Patients with HLA-matched related donor (MSD, n=7) received PT-Cy combined with tacrolimus, while patients with HLA matched unrelated (MUD, n = 2) or haplo-identical (Haplo, n = 14) donor received additional ATG at 2.5 mg/kg on day 15 or day 22 after engraftment of neutrophils. As to the acute GVHD (aGVHD), only three patients developed grade I (n = 1) or grade II (n = 2) aGVHD with 100-day incidence of all aGVHD and II-IV aGVHD at 13.0 ± 5.1% and 9.1 ± 6.1% respectively. Only two patients had mild and one had moderate chronic GVHD (cGVHD), with 1-year incidence of cGVHD and moderate/severe cGVHD at 15.2 ± 8.7% and 4.6 ± 4.4% respectively. A high incidence of CMV reactivation was documented (14/16 with MUD/Haplo donor and 2/7 with MSD) with only 1 CMV disease documented. There were two EBV reactivation without post-transplantation lymphoproliferative disease (PTLD) documented. With a median follow-up of 303 days (range, 75~700 days), three patients relapsed leading to 1-year cumulative incidence of relapse (CIR) at 12.8 ± 9.2%. Only one patient died of CMV pneumonia on day 91 with both 100-day and 1-year non-relapse mortality (NRM) at 4.6 ± 4.4%. The 1-year overall survival (OS), event-free survival (EFS) and GRFS were 95.5 ± 4.4%, 82.6 ± 9.5%, and 68.0 ± 11.3% respectively. Based on Simon's stage II design, our primary data showed that the PT-Cy+tacrolimus ± ATG protocol was promising in preventing aGVHD and cGVHD, which may translate into low NRM without increased CIR. Further clinical trial with large number of patients should be warranted. This trial was registered at www.clinicaltrials.gov as #NCT 04118075.

Once Daily Busulfan and Fludarabine Is Well Tolerated and Effective in Older Heavily Treated Patients Prior to Unrelated Donor Allogeneic Peripheral Blood Stem Cell Transplant.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4950-4950
Author(s):  
Grant W. Potter ◽  
Carlos Bachier ◽  
Brad Smith ◽  
Maureen Hougham ◽  
C.F. LeMaistre ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Phase Ii Study ◽  
Unrelated Donor ◽  
Once Daily ◽  
Donor Chimerism ◽  
Gvhd Prophylaxis ◽  
Co Morbidity ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Reduced-intensity (RI) preparative regimens are used to treat patients (pts) unable to receive standard myeloablative allogeneic hematopoietic stem cell transplants (HCT) due to risk factors such as older age, prior treatments, and co-morbidity. We report the results of a prospective phase II study using a RI regimen and unrelated donor HCT. The RI regimen consisted of intravenous busulfan (Bu) 3.2 mg/kg daily for 2 doses, fludarabine 30mg/m2 daily for 5 doses, and ATG 15mg/kg daily for 4 doses. GVHD prophylaxis was tacrolimus and methotrexate 15mg/m2 on day 1, and 10 mg/m2 on days 3 and 6. Twenty-one patients (median age 60, range 39–67) with acute myelogenous leukemia (n=10), non-Hodgkin’s lymphoma (n=5), chronic lymphocytic leukemia (n=2), myelodysplasia (n=2), and multiple myeloma (n=2) were admitted to the study between 2002 and 2007. Nineteen pts were HLA matched with unrelated donors at A, B, C, DR, and DQ, and two pts had unrelated donors mismatched at one HLA class I allele. Nine pts had one or more autologous HCTs prior to beginning the study. Bu pharmacokinetics (pk) were performed on each dose of Bu for the first 3 pts and revealed a median Bu AUC of 5620 uM*min (range 4717–7148), Cmax 3.13 mcg/ml (range 2.68–4.62) and clearance 86.8 ml/min/kg (range 76.2–98.7). Engraftment, toxicity and follow up data is available on 20 pts. Grade II or higher regimen related toxicity (RRT) was reported in seventeen (85%) pts; gastrointestinal (n=14), mucositis (n=7), hepatic function (n=4), fever and infection (n=3), pulmonary function (n=2), and renal function (n=1). Veno-occlusive disease did not manifest in any pts. Six pts did not receive the full prescribed dosage of ATG because of ATG related toxicities, including fever and chills, hypotension, capillary leak syndrome, and elevated bilirubin levels. One pt’s ANC never dropped below 0.5 x 109/L, and in the remaining nineteen patients the median day of engraftment was 15 days. Nineteen (95%) of twenty pts achieved 100% donor chimerism by day 80. Three pts subsequently lost donor chimerism and one never achieved higher than 90% donor chimerism; all 4 pts relapsed. Thirteen pts (65%) developed grade II or higher overall acute GHVD and chronic GVHD developed in five pts. Treatment related mortality (TRM) was 15% (95% confidence interval [CI], 5%–40%) at 3 months, and 35% (95% CI, 17%–63%) at 12 months. The most common cause of TRM was GVHD and infection. Actuarial overall survival at 3 years was 52% (95% CI, 27%–71%). All six pts who received reduced ATG dosages developed acute GVHD and one had relapse of disease, while of the remaining fourteen pts who received full ATG dosages 7 developed acute GVHD and 5 had relapse of disease. In conclusion, this small phase II study of a once daily Bu and fludarabine RI regimen and unrelated donor HCT demonstrated good long term survival and disease control. Once daily Bu pk studies demonstrated no unexpected AUC or clearance parameters. Significant TRM still exists with this RI regimen in this heavily treated older pt population, and future use of a co-morbidity scoring tool may help select pts more suitable for this regimen. ATG significantly contributed to RRT, while GVHD and its treatment and complications primarily resulted in the TRM. Removing ATG and using other measures for GVHD prophylaxis and treatment may improve this RI regimen.

Improved Outcome of Reduced Toxicity Fludarabine, Cyclophosphamide Plus Thymoglobulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of Two Multicenter Prospective Studies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 220-220
Author(s):  
Hyoung Jin Kang ◽  
Ji Won Lee ◽  
Hyery Kim ◽  
Kyung Duk Park ◽  
Hee Young Shin ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Phase Ii ◽  
Graft Failure ◽  
Phase Ii Study ◽  
Conditioning Regimen ◽  
Severe Aplastic Anemia ◽  
Unrelated Donor ◽  
Once Daily ◽  
Conditioning Regimens ◽  
Reduced Toxicity

Abstract Abstract 220 Introduction: Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic modality for severe aplastic anemia, but optimal conditioning regimen for the HSCT with an unrelated donor has not been defined yet. As the thymoglobulin had been found to be more effective among many kinds of anti-thymocyte globulins, and fludarabine based conditioning regimens without total body irradiation have been reported to be promising for transplantation from unrelated donors in SAA, combination of fludarabine, cyclophosphamide and thymoglobulin conditioning regimens had been tried to reduce GVHD and to allow good engraftment. Our previous phase II study (study 1) of fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen resulted in successful engraftment (100%), but treatment-related mortality (TRM) occurred in 9 (32.1%) patients (NCT00737685, Biol Blood Marrow Transplant. 2010.16;1582). As cyclophosphamide is more toxic than fludarabine with similar effect, then we performed a new phase II study (study 2) with reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen by reducing dosage of cyclophosphamide and increasing dosage of fludarabine (NCT00882323). Patients and Methods: Twenty-eight and 31 patients were enrolled in study 1 and 2, respectively. In study 1, cyclophosphamide (50 mg/kg once daily i.v. on days −9, −8, −7 & −6), fludarabine (30 mg/m2̂ once daily i.v. on days −5, −4, −3 & −2) and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2 & −1) were used for the conditioning regimen. For study 2, cyclophosphamide was reduced to 60 mg/kg once daily i.v. on days −8 & −7, and fludarabine was increased to 40 mg/m2̂ once daily i.v. on days −6, −5, −4, −3 & −2. Thymoglobulin (2.5 mg/kg once daily i.v. on days −4, −3 & −2) was also used. Results: Donor type hematologic recovery was achieved in all patients of study 1 (100%) and study 2 (100%). Events were occurred in 10 patients of study 1. Nine patients developed TRM, which included thrombotic microangiopathy (N=2), pneumonia (N=1), myocardiac infarction (N=1), post-transplantation lymphoprolifarative disease (N=3), and chronic GVHD-associated complications (N=2). Delayed graft failure occurred in 1 patient at 37 months after HSCT. In study 2, 2 patients had events. One patient developed TRM (pneumonia) and delayed graft failure occurred in 1 patient at 4 months after HSCT. Overall survival rate of study 2 (96.7%) was significantly higher than that of study 1 (67.9%) (P=0.005). Event free survival of patients was significantly better in study 2 (93.3%) compared to that of study 1 (64.3%) (P=0.014). Conclusions: Reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen showed promising results with same successful engraftment and less TRM compared to the previous combination and was optimal for the unrelated donor transplantation in severe aplastic anemia. Disclosures: No relevant conflicts of interest to declare.

High Rates of Severe aGVHD with Tacrolimus and Mycophenolate Mofetil in a Large Cohort of Related and Unrelated Allogeneic Transplant Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1951-1951
Author(s):  
Zaid Al-Kadhimi ◽  
Zartash Gul ◽  
Wei Chen ◽  
Daryn Smith ◽  
Abhinav Deol ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Phase Ii ◽  
Causes Of Death ◽  
Secondary Malignancy ◽  
P Value ◽  
Unrelated Donor ◽  
Phase Ii Trials ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
One Year

Abstract Abstract 1951 Both acute and chronic graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in patients (pts) undergoing allogeniec hematopoietic stem cell transplantation (allo-HCT). Tacrolimus and mycophenolate mofetil (Tac-MMF) have shown encouraging results as GVHD prophylaxis in few prospective phase II trials with reduced intensity preparative regimens. Perkins et al. in a randomized phase II trial with myeloablative preparative regimen reported 11 and 26% incidence of grade III-IV aGVHD in related and unrelated donor transplants respectively. Methods We retrospectively evaluated clinical outcomes in a cohort of 414 consecutive pts who underwent related or unrelated allo-HCT with Tac-MMF for GVHD prophylaxis. Consecutive pts were transplanted with myeloablative or low intensity preparative regimens between January 2005 and June 2011 at Karmanos Cancer Center. Study end points were: Overall survival (OS), progression free survival (PFS) (Kaplan Meir), cumulative incidence (CI) of acute and chronic GVHD, relapse, CMV infection and non-relapse mortality (NRM). Results Pt characteristics are summarized in Table 1. There were 211 pts who underwent allo-HCT from a related donor (RD) and 203 patients who had allo-HCT from an unrelated donor (UD). Sixty three pts (31%) of the UD were 7/8 HLA matched. Median follow up of all patients was 60 months with 95% confidence interval (95%CI) 54.4 – 64.7 months. The CI of aGVHD for grades II-IV was 47.4% (95%CI 40.5–54.0), 55.2% (95%CI 48.0–61.7) in RD and UD groups respectively. The CI of aGVHD grades III-IV was 22.3% (95%CI 16.9–28.1), 36.5% (95%CI 29.9–43.1) in RD and UD groups respectively (Gray's test p-value 0.0007). The CI of cGVHD at 60 months was 56.2% (95%CI 48.7–63.1), 66.3% (95%CI 58.8–72.7) in RD and UD groups respectively (Gray's test p-value 0.015). The CI of severe cGVHD (NIH grade3) at 60 months was 28.1% (95%CI 22.2–34.3), 26.1% (95%CI 20.3–32.3) in RD and UD groups respectively. The CI of bronchiolitis obliterans at 60 months was 14.0% (95%CI 9.7 –19.1), 11.6% (95%CI 7.6–16.6) in RD and UD groups respectively (NS). The CI of CMV reactivation at 60 months was 27.2% (95%CI 21.3–33.4), 23.2% (95%CI 17.6–29.2) in RD and UD groups respectively (NS). NRM at 60 months was 32.5% (95%CI 25.9–39.2), 46.5% (95%CI 39.3–53.4) in RD and UD groups respectively (Gray's test p-value 0.001). The CI of relapse was 22.4% (95%CI 16.7–28.5) for UD and 28.8% (95%CI 22.6–35.2) for RD. One year survival was 61% (95%CI 55–68), 55% (95%CI 48–62) in RD and UD groups respectively. One year PFS was 55% (95%CI 48–62), 48% (95%CI 41–55) in RD and UD groups respectively. Five year OS was 43% (95%CI 35–51), 34% (95% CI 27–41) in RD and UD groups respectively. Causes of death for the RD group (n=115) were as follows: GVHD 49%, relapse 42%, sepsis 3%, multi-organ failure (MOF) 3%, Diffuse alveolar hemorrhage 2%, and secondary malignancy 3%. As for the UD group (n=133) causes of death were: GVHD 57%, relapse 29%, sepsis 7%, MOF 4%, graft failure 2%, and secondary malignancy 1%. Uni-variate and multi-variate analysis is being performed to evaluate disease risk, donor status, and regimen intensity as predictors of GVHD and survival. Conclusion: The use of Tac-MMF for GVHD prophylaxis was associated with higher than previously reported incidence of severe aGVHD both in RD and UD allo-HCT. Furthermore, we observed a higher incidence of severe aGVHD, cGVHD and NRM in the UD group compared to RD. GVHD was the leading cause of mortality in both groups. Disclosures: No relevant conflicts of interest to declare.

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