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.

Improved Outcome After Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RI-HCT) for Myelodysplastic Syndrome (MDS) Using Tacrolimus/Sirolimus-Based Gvhd Prophylaxis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2771-2771 ◽  
Author(s):  
Ryotaro Nakamura ◽  
Joycelynne Palmer ◽  
Pablo Parker ◽  
Anthony Stein ◽  
Tracey Stiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
One Year ◽  
The Impact ◽  
Bone Marrow Blasts ◽  
Improved Outcome

Abstract Abstract 2771 Poster Board II-747 We previously reported an encouraging result with RI-HCT for MDS (Bone Marrow Transplant 2007; 40:843-50) using flugarabine/melphalan conditioning and cyclosporine (CSA)/mycophenolate (MMF) as GVHD prophylaxis. In order to further improve upon the outcome in the RI-HCT setting, we initiated a series of clinical trials at City of Hope National Medical Center designed to evaluate the impact of tacrolimus (FK)/sirolimus (SIRO)-based GVHD prophylaxis. Here we report the combined, updated results from a consecutive case-series of 89 patients with MDS (including AML progressed from MDS) who underwent RI-HCT from 2000 to 2008 and received either CSA/MMF (n =44) or FK/SIRO (n=45)-based GVHD prophylaxis. All patients received fludarabine 125 mg/m2 plus melphalan 140 mg/m2 followed by an allogeneic HCT (peripheral blood: n=83, bone marrow: n=6) from an HLA-identical sibling (SIB: n=35) or unrelated donor (MUD: n=54). Additional ATG was given to 12 patients. For MUD transplants a short course of methotrexate was added to CSA/MMF or FK/SIRO. The median age was 59 years (range: 20-71) and 31 (35%) patients were female, 58 (65%) were male. Diagnoses at transplant were RA (n=21), RARS (n=1), RAEB/RAEBT (n=36), and AML from prior MDS (n=31). Cytogenetic risk was low in 15 (17%), intermediate in 37 (41.5%), high in 37 (41.5%) patients. By IPSS criteria (for MDS only), 2 patients had low, 24 had int-1, 20 had int-2, and 12 had high-risk MDS. Twenty-seven patients had therapy-related MDS including 14 with prior autologous HCT. The median follow-up time for surviving patients was 39 months (range: 24-68) for the CSA/MMF group and 17 months (range: 4-39) for the FK/SIRO group. All but two patients (1 in CSA/MMF, 1 in FK/SIRO) engrafted with the median neutrophil recovery at 15 days (range: 11-55). The baseline patient, disease and transplant characteristics were similar between CSA/MMF and FK/SIRO, except for an increased percentage of therap-related MDS in the CSA/MMF group (43% vs. 18%, p<0.01). The median donor chimerism by STR at day 30 post-transplant was 100% in both groups (p=0.6). FK/SIRO was associated with a significantly reduced one-year non-relapse mortality (NRM) (11.4%) compared with CSA/MMF (36.2%, p=0.01). This improvement in NRM translated into a trend for improved overall survival (81.4% vs. 52.3%, p=0.1) and disease-free survival (72.2% vs. 52.3%, p=0.08) at one year. While we observed no significant difference in acute GVHD grade II-IV between CSA/MMF and FK/SIRO, FK/SIRO was associated with a significant reduction in grade IV GVHD (0% versus 26%, p<0.01) and a trend for III-IV GVHD (31% vs. 55%, p=0.1). There was no significant difference in chronic GVHD between FK/SIRO (60%) and CSA/MMF (56%, p=0.8). In multivariate analysis, the use of FK/SIRO was independently associated with improved NRM after adjusted for donor type, therapy-related MDS, %bone marrow blasts, and HLA match status (Table). In conclusion, FK/SIRO-based GVHD prophylaxis was associated with an improved outcome after RI-HCT for MDS attributable to the reduced risk for severe acute GVHD.Variables for NRMHazard Ratio (95% CI)p-valueDe novo (n=62) Therapy-related (n=27)baseline 0.75 (0.31–1.89)0.55Sibling donor (n=35) Unrelated donor (n=54)baseline 2.17 (0.70–6.74)0.18Bone marrow blasts < or =10% (n=67) Bone marrow blasts >10% (n=22)baseline 2.13 (0.92–4.96)0.08HLA match (sibling donor or 10/10 MUD, n=72)HLA < mismatch MUD (<10/10 match, n=17)baseline 6.26 (2.11–18.55)0.001FK/SIRO (n=45) CSA/MMF (n=44)baseline 6.58 (2.15–20.14)0.001 Disclosures: Off Label Use: cyclosporine, cellcept, tacrolimus, sirolimus, and methotrexate for GVHD prophylaxis.

Efficacy of Reduced Induction Chemotherapy and Early Transplantation in ALL Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4487-4487
Author(s):  
Ardeshir Ghavamzadeh ◽  
Amir Hooshang Pourkhani ◽  
Kamran Alimoghaddam ◽  
Mohammadreza Ostadali Dehaghi ◽  
Amir Ali Hamidieh ◽  
...  
Keyword(s):  
Overall Survival ◽  
Causes Of Death ◽  
Disease Free Survival ◽  
P Value ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
One Year ◽  
And Control ◽  
Disease Free

Abstract Abstract 4487 Eighty percent of acute lymphoblastic leukemia (ALL) patients achieve a complete remission (CR) but only 30–40% are long-term survivors. Hematopoietic stem cell transplantation (HSCT) is only curable treatment in ALL patients. However, the efficacy of induction, consolidation chemotherapy and early hematopoietic stem cell transplantation remain unclear. Therefore, at our center, patients with newly diagnosed ALL, are randomly divided into 2 arms from 2008 to 2011. Patients in the study arm received reduced induction chemotherapy (Vincristine 1 mg/m2 every week for 4 weeks plus Dexamethasone 24mg/d for 28 days) and undergone early HSCT after disease stabilized within 15–30 days without intention of achieving complete remission (CR). The control arm received conventional chemotherapy (routine induction and then consolidation) followed by HSCT. Both arms received Busulfan (4mg/kg for 4 days) plus Cyclophosphamide (60mg/kg for 2 days) as a conditioning regimen. The GVHD prophylaxis consisted of Methotrexate plus Cyclosporine. Here, we compare the efficacy of these two kinds of treatment. A total of 89 patients enrolled in the study. Seventeen patients allocated to the study arm and 72 others allocated to the control arm. The median age was 22 years (range: 16–33) in the study arm and 22 years (range: 3–49) in the control arm. All patients underwent Allogeneic HSCT with peripheral blood source. The median waiting time from diagnosis to HSCT was 708 days (range: 45–219) in the control arm. In the study arm, 13 patients (76%) were in CR1.The median follow-up time was 15.5 months (range: 1–30) in the study arm and 10.2 months (range: 1–34) in the control arm. Relapse occurred in 2 (11.7%) and 6 (8.3%) patients of the study and the control arms, respectively. Five patients (29.4%) of the study arm and 10 patients (13.5%) of the control arm were died. The causes of death were GVHD and sepsis in 4 (80%) patients and relapse in 1 (20%) patient in the study arm. The causes of death were GVHD in 6 (60%) patients and relapse in 4 (40%) patients in the control arm. One-year overall survival was 75% and 83.7% in study and control arms, respectively (Fig 1, P-value: 0.212). One-year disease-free survival was 75% and 81.1% in study and control group, respectively (Fig 2, P-value: 0.273).Figure 1.Overall Survival of ALL Patients in Study arm vs. Control armFigure 1. Overall Survival of ALL Patients in Study arm vs. Control armFigure 2.Disease-free Survival of ALL Patients in Study arm vs. Control armFigure 2. Disease-free Survival of ALL Patients in Study arm vs. Control arm Reduced induction followed by early transplantation without consolidation reveals no significant statistical different outcome compared with routine treatment. This result might be due to small size of patients and short time of follow-up. A study with more cases and long time follow-up is recommended. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of Extracorporeal Photopheresis in Prevention of Graft-Versus-Host Disease in Patients Treated with Allogeneic Hematopoietic Stem Cell Transplantation: A Randomized Controlled Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 102-102
Author(s):  
Maryan M Ali ◽  
Tobias Gedde-Dahl ◽  
Marit B Veierød ◽  
Geir E Tjønnfjord ◽  
Per Ole Iversen
Keyword(s):  
Hematological Malignancy ◽  
Intervention Group ◽  
Study Groups ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Randomized Controlled ◽  
Gvhd Prophylaxis ◽  
One Year ◽  
And Control

Abstract Introduction In many patients diagnosed with a hematological malignancy, the disease cannot be totally eradicated by conventional therapeutic approaches, and for them allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option. A major complication of allo-HSCT is graft-versus-host disease (GvHD), affecting about 50% of transplant recipients. In addition to increased risk of death and long-lasting debilitating conditions, severe GvHD also impairs health-related quality of life. High-dose systemic steroids is the first line treatment for GvHD, but treatment failure is common, and steroid-refractoriness is a major cause of non-relapse mortality after allo-HSCT. While there is no established second line GvHD-treatment, extracorporeal photophoresis (ECP) has emerged as an attractive and increasingly applied alternative, partly due to its favourable safety profile. However, the use of ECP in preventing GvHD is sparse and data are inconclusive due to lack of randomized controlled trials (RCT). We therefore conducted a RCT to study if ECP given post transplantation could prevent the development of GvHD. Methods Between June 2017 and February 2020, we enrolled 157 patients (&gt; 18 years) diagnosed with a hematological malignancy and treated with an allo-HSCT in first remission into an intention-to-treat open RCT. Ethical and IRB approvals were granted, and the RCT was registered with Clinical Trials (ID NCT03204721). The sample size (76 in intervention group and 81 controls) was calculated based on a reduction of 25% in the total number of patients diagnosed with any form of GvHD within the first year of allo-HCST (primary end-point) as clinically relevant. The patients were stratified according to whether they received myeloablative or reduced intensity conditioning (Table 1), and they were given GvHD prophylaxis as shown in Table 1. ECP (Therakos Cellex ®, Mallinckrodt Pharm., NJ) was initiated when patients had engrafted (i.e. leukocytes &gt; 1 x 10 9/L and platelets &gt; 20 x 10 9/L), and, according to the study protocol, we planned for ECP on two consecutive days/week for two weeks, then weekly for four weeks to a total eight treatments for each patient in the intervention group. Chi-square test was used to test differences between the two study groups. Results Table 1 shows that patient characteristics were well balanced among the two study groups. Four patients did not receive ECP while 39 received all the eight treatments. One year after allo-HCST, the proportion of GvHD was 45/76 (59%) in the intervention group and 52/81 (64%) in the controls (p=0.52). There were no significant differences between the intervention and control group regarding development of acute (45% vs. 48%) or chronic (39% vs. 40%) GvHD. Neither did we detect any statistical differences between the two study groups regarding organ involvement or severity of the GvHD manifestations (data not shown). During the one-year observation period, 16/76 (21%) and 10/81 (12%) relapsed in the intervention and control group, respectively (p=0.14). The corresponding numbers of deaths were 12/76 (16%) and 16/81 (20%), respectively (p=0.52). Six patients in the intervention group experienced mild to moderate temporary, adverse events that could possibly be related to the ECP-procedure. Conclusion In this first RCT addressing ECP as GvHD prophylaxis in allo-HSCT for hematological malignancy, we found no significant difference in the numbers, types, organ involvement, or severity of GvHD between the intervention and the control group. Thus, our study does not support the use of ECP as an adjunct to GvHD-prophylaxis based on cyclosporine and methotrexate, mycophenolate mofetil, or sirolimus. However, ECP did not seem to be harmful in this setting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4879-4879
Author(s):  
Omar Albanyan ◽  
Hyejeong Jang ◽  
Seongho Kim ◽  
Andrew Kin ◽  
Asif Alavi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Matched Donor

Abstract Introduction: Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment. Methods: We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis. Results: From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant). Conclusion: Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

Quadruple Therapy with CsA, MTX, MMF and ATG and Triple Therapy with CsA, MTX and ATG for Preventing Graft-Versus-Host Disease in Unrelated Donor Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5296-5296 ◽  
Author(s):  
Zhiping Fan ◽  
Zhengshan Yi ◽  
Qifa Liu ◽  
Jing Sun ◽  
Dan Xu ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Genetic Loci ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Significant Difference ◽  
Disease Free

Abstract Objective To explore the effective protocol for graft-versus-host disease (GVHD) prophylaxis in unrelated donor hematopoietic stem cell transplantation (URD-HSCT). Methods 31 patients with leukemia received URD-HSCT, of whom 16 received quadruple therapy (quadruple group) with CsA, MTX, MMF and ATG for GVHD prophylaxis and 15 received triple therapy (triple group) with CsA, MTX and ATG. 22 patients were matched in all HLA genetic loci with donors, seven were mismatched in one HLA genetic locus, 1 in two HLA genetic loci, and 1 in three HLA genetic loci. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 17 cases and modified BuCY conditioning regimen (hydroxyurea, busulfan, Ara-C, Cyclophosphamide) in the other 14 cases. Immune reconstitution of quadruple group and triple group at 1,3, 6, 9,12 month after transplantation were examined by flow cytometer, and the diference of the two group were estimated with Independent-Samples T test. The incidence of GVHD of the two group was esitimated with Mann-Whitney Test. Kaplan-Meier survival analysis model was used to estimate the overall survival and the disease-free survival (DFS). Results Immune reconstitution after transplantation of quadruple group and triple group have no significant difference (P&gt;0.05). Acute GVHD (aGVHD) occurred in 9 patients (56.25%) of the quadruple group and in 11 (73.33%) of the triple group, respectively. The incidence of acute GVHD (aGVHD) differed little between the two group (P=0.238). The incidence ofIII~IV°aGVHD in the two group were 6.30% and 26.67%, respectively, and there was no significant difference (P=0.122). 6 patients had chronic GVHD (cGVHD), in the16 cases who could be followed up in quadruple group, 3 of the 11 patients who could be followed up in triple group developed cGVHD postoperatively (P=0.580). Four patients of quadruple group died of hemorrhagic cystitis, mycotic pneumonia, tuberculosis and relapse, respectively. 3 patients of triple group died of GVHD, and the other 3 died of GVHD associated interstitial pneumonia, cytomegalovirus (CMV) pneumonia and pneumocystis carinii infection. The lethality of GVHD of quadruple group and triple group were 0%,26.7%, respectively, and there was significant difference(P=0.027). The one-year disease-free survival rate was 75% and 60% in patients of the quadruple and the triple group, respectively, and significant difference was not noted (P= P=0.188). Conclusion Compared with triple therapy with CsA, MTX and ATG, CsA+MTX+MMF+ATG procedure dose not worsen the immune reconsititution after transplantation. It can’t decrease the incidence and severity of aGVHD, but can lower the lethality of GVHD in URD-HSCT. The quadruple procedure may lead to higher relapse rate after URD-HSCT.

A Randomized 3-Arm Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute Graft-Versus-Host Disease (GVHD) After Unrelated Donor Hematopoietic Cell Transplantation (HCT) Using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies: A Multi-Center Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 348-348 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Barry Storer ◽  
Lars Vindelov ◽  
Amelia Langston ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Phase Ii ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Sequential Trials

Abstract Abstract 348 We previously reported results of 3 sequential trials of GVHD prophylaxis with mycophenolate mofetil (MMF) BID/TID and cyclosporine (CSP) BID with various taper schedules in patients (pts) with advanced hematologic malignancies given unrelated G-CSF-mobilized peripheral blood stem cell (PBSC) grafts after fludarabine 90 mg/m2 and 2 Gray total body irradiation. Cumulative incidences of grades II-IV acute GVHD in the 3 trials were 52, 53 and 77%, respectively. The goal of the current protocol was to evaluate, in a phase II randomized 3-arm study, which drug combination or schedule was most promising in preventing acute GVHD. Tacrolimus (Tac) was used in place of CSP and each of the 3 arms used MMF TID until day 30 and then BID, but the subsequent duration of MMF varied. In Arm1, pts received Tac until day 180 and MMF until day 96. In Arm2, Tac was given until day 150 and MMF until day 180. In Arm3, Tac was given until day 150 and MMF until day 180 with the addition of rapamycin from days -3 through 80. One hundred seventy-five pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study between Jan/05 and Aug/09, and results on the first 159 pts (Arm1 n=56; Arm2 n=51; Arm3 n=52) are reported here with a median follow-up of 18.4 months for surviving pts. The median age of pts was 60 (range 13-75) yrs. Sixty-six (42%) had previous autologous (n=55) or allogeneic (n=11) HCT. All pts were matched for HLA-DRB1 and -DQB1 at the allele level: 16 had single allele mismatches at HLA-A, -B or –C and the remainder (n=143) were fully HLA-matched. Diagnoses included AML (n=72), NHL (n=36), MM (n=19), ALL (n=10), CLL (n=9), MDS (n=8), HL (n=4), and CML (n=1). Randomization was based upon transplant center (FHCRC vs other), number of prior chemotherapy treatments (0-2 vs 3+), and age (<55 vs 55+ years). The pts received PBSC grafts containing a median of 7.9 ×106 CD34 and 2.8 × 108 CD3 cells/kg. Sustained donor engraftment occurred in 99.4% of pts. The day-150 cumulative incidences of grades II-IV (figure 1) and III-IV acute GVHD were as follows: Arm1: 56%, 9%; Arm2: 52%, 12%; and Arm3: 45%, 10%, respectively. Chronic GVHD requiring therapy was as follows: Arm1: 44%, Arm2: 35%, and Arm3: 55% of pts. The 6-month nonrelapse mortality was 6% in Arm1, 8% in Arm2, and 2% Arm3. The 2-year Kaplan-Meier estimates of relapse and nonrelapse mortality (figure 2) were as follows: Arm1: 27%, 24%; Arm2: 39%, 19%; and Arm3: 30%, 15%, respectively (overall 32% and 20%, respectively). The 2-year overall and progression-free survivals were as follows: Arm1: 49%, 41%; Arm2: 42%, 37%; Arm3: 55%, 41%, respectively (overall 48% and 40%, respectively). The addition of rapamycin to MMF and Tac (Arm3) resulted in the lowest incidence of grades II-IV acute GVHD (p=0.09 compared to reference Arm1), without a significant difference in chronic GVHD. While the phase II design of the study was not powered to show statistical differences between the 3 arms, the lower incidence of grades II-IV acute GVHD combined with the low morbidity and nonrelapse mortality in Arm3 using MMF, Tac and rapamycin is encouraging and warrants further study. Disclosures: Off Label Use: Fludarabine - conditioning prior to HCT. Mycophenolate mofetil - immunosuppression after HCT. Tacrolimus - immunosuppression after HCT. Rapamycin - immunosuppression after HCT..

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