A Randomized Study of Cyclosporine and Methotrexate with or without Methylprednisolone for the Prevention of Graft-Versus-Host Disease: Improved Long-Term Survival with the Triple Prophylaxis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2241-2241
Author(s):  
Tapani Ruutu ◽  
Anne Nihtinen ◽  
Riitta Niittyvuopio ◽  
Eeva Juvonen ◽  
Liisa Volin
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Not Given ◽  
Term Survival ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Abstract Background: In a previously published single-center study (Blood 2000) we randomized 108 consecutive adult patients with a malignant hematological disorder undergoing allogeneic bone marrow transplantation from an HLA-identical sibling donor to receive (n=53) or not to receive (n=55) methylprednisolone (MP+ or MP-, respectively) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine A and methotrexate. MP administration was initiated on day 14 post-transplantation with 0.5 mg/kg, the dose was increased to 1 mg/kg on day 21 and thereafter tapered and discontinued on day 110. The cumulative incidence of acute GVHD was 19 % among the patients given and 56 % among those not given MP prophylaxis (p=0.0001), and that of grade II-IV acute GVHD 13 and 36 %, respectively (p=0.005). There was a non-significant trend toward a lower cumulative incidence of chronic GVHD (cGVHD) and better survival in the MP+ group. There were fewer infections and the stay at hospital was shorter among the patients given MP prophylaxis. No difference was seen in the relapse rate. We have now carried out a long-term follow-up to find out possible late effects of the intensified GVHD prophylaxis. Results: The median follow-up time of living patients was 24.5 (range 22.7-26.9) years; two patients were lost for follow-up at 37 and 80 months. In the MP+ group the overall survival (OS, p=0.021) (Figure 1) and relapse-free survival (RFS, p=0.024) were significantly higher and the non-relapse mortality (NRM) lower (p=0.003) than in the MP- group. There was a trend toward lower cumulative incidence of cGVHD in the MP+ group (36 vs. 48 %, p=0.17). The prevalence of cGVHD, analyzed with data available from ten years of scheduled follow-up, was significantly (p=0.031) lower in the MP+ group and the difference became more marked with time. Among the patients alive at ten years, none in the MP+ group but 28 % of the patients in the MP- group had active cGVHD. There was no difference in the relapse rate between the MP+ and MP- groups, the cumulative incidences were 36 and 38 %, respectively. Seven patients in each group developed a secondary malignancy, one patient in both groups had two secondary tumors. At 15 years, the survival was 55 % in the MP+ group and 47 % in the MP- group, and the NRM 21 and 30 %, respectively. Thereafter there was marked non-relapse mortality in the MP- group, eleven patients died after this time point, whereas there were no deaths during this period in the MP+ arm. At the end of the follow-up, the OS in the MP+ and MP- groups were 55 and 20 % and the RFS 54 and 18 %, respectively. The causes of the late deaths in the MP- group were: bacterial infection 3, obstructive bronchiolitis 1, acute myocardial infarction 1, intracerebral bleeding 1, sudden death of unknown cause 1, lung cancer 2, colon cancer 1, and esophagus cancer 1. Conclusion: The addition of corticosteroid to cyclosporine and methotrexate in GVHD prophylaxis, resulting in a marked decrease in the incidence of acute GVHD, did not cause adverse late effects. Long-term survival was higher among the patients given MP prophylaxis. Unexpectedly, there was marked late non-relapse mortality in the group not given MP prophylaxis, possibly contributed to by the higher prevalence of cGVHD. Disclosures No relevant conflicts of interest to declare.

Antithymocyte Globulin-Based Prophylaxis for Graft Versus Host Disease Compared to Post-Transplant Cyclophosphamide-Based Prophylaxis in Matched Unrelated Donor Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2307-2307
Author(s):  
Sara Redondo Velao ◽  
Mi Kwon ◽  
Diana Champ ◽  
MJ Pascual Cascon ◽  
Pascual Balsalobre ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION Post-transplant high-dose cyclophosphamide (PTCy) has shown to prevent graft versus host disease (GvHD) after haploidentical allogeneic hematopoietic cell transplantation (HSCT). Although less extended, its use after matched unrelated donor (MUD) HSCT in combination with additional immunosuppression has been encouraging. The aim of this study was to analyze and compare outcomes of antithymocyte globulin based (ATG) versus PTCy-based GvHD prophylaxis in matched unrelated donor HSCT. MATERIAL AND METHODS We retrospectively analyzed 51 MUD (8/8 HLA-matched) transplants performed in two Spanish centers: 25 received ATG-based prophylaxis and were performed from 2010 to 2013, and 26 received PTCy-based prophylaxis and were performed from 2013 to 2016. RESULTS Characteristics of patients and post-HSCT complications are detailed in Table 1. There were no significant differences in age, gender, diagnosis and Disease risk index. For the ATG group, conditioning regimen consisted of fludarabine combined with busulfan (80%) or melphalan (12%), and TBI plus cyclophosphamide (8%). All patients received ATG 2 mg/kg from day -4 to day -2 followed by methotrexate and cyclosporine (CsA). Conditioning regimen for patients from the PTCy group consisted of fludarabine and busulfan (85%) and thiotepa combined with busulfan and fludarabine (15%). GvHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, combined with: CsA plus MMF in 57%, CsA alone in 31%, or tacrolimus plus MMF or sirolimus in 8%, and tacrolimus alone in 4%. With a median follow-up of 58 months for the ATG group and 12 months for the PTCy group, there were no statistically significant differences in overall survival at 18 months (56% vs 85%, p=0.08), in event free survival (56% vs 68%, p=0.5), and in cumulative incidence of relapse (12% vs 18%, p=0.3). Non-relapse mortality at 12 months was significantly higher in the ATG group (32% vs 10%, p = 0.04). The ATG group presented more cases of hepatic toxicity grades I-IV and hemorrhagic cystitis than PTCy group (Table 1). Cumulative incidence of acute GvHD grades II-IV was higher in the ATG group as well as acute GvHD grades III-IV, with no differences in moderate/severe chronic GvHD incidence (Figure A). CONCLUSION In our experience, albeit differences in follow-up and limited number of patients, we conclude that PTCy combined with additional immunosuppression after MUD allogeneic HSCT offers lower rates of acute GvHD together with less toxicity and non-relapse mortality compared to ATG-based prophylaxis. Further analysis including larger series and follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation – Follow up

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 453-453 ◽  
Author(s):  
Bernhard Heilmeier ◽  
Nadine Stowasser ◽  
Gerard Socie ◽  
Maria Teresa van Lint ◽  
Andre Tichelli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Marrow Transplantation ◽  
Malignant Neoplasms ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Survivors

Abstract Patients who receive allogeneic hematopoietic stem cell transplants have an increased risk for new malignancies because of several risk factors, including conditioning with radiation and chemotherapy, immune modulation, and malignant primary disease. The frequency of and risk factors for malignant neoplasm in long-term survivors should be assessed. A former analysis of the EBMT observing the 1036 patients of this study with a median observation time of 10.7 years showed older patient age and immunosuppressive treatment of chronic graft-versus-host disease as main risk factors for secondary malignancies. We have tried to determine the cumulative incidence and define potential risk factors for new malignancies in long-term survivors after marrow transplantation in a retrospective multi center follow-up study. This study of the Late Effects Working Party was performed with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Patients were transplanted before December 1985 and had survived more than 5 years. Reports on malignant neoplasms were evaluated, and the cumulative incidence was compared to that in the matched general population. Patient age and sex, primary disease and disease stage at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. Univariate analysis was performed using the log rank test for the time until malignancy occurred; significant risk factors were studied in multivariate analysis (Cox regression). Median follow-up since transplantation was 17.9 years (range, 5 to 32.3 years). Malignant neoplasms were seen in 114 patients; the cumulative incidence was 4.0% at 10 years, 8.5% at 15 years, 14.0% at 20 years and 21.0% at 25 years. The rate of new malignant disease was 6-fold higher than that in an age-matched control population (P <0.001). The most frequent malignant diseases were neoplasms of the skin (23 patients), breast (16 patients), thyroid gland (13 patients), oral cavity (12 patients), uterus including cervix (7 patients), and glial tissue (3 patients). Median ages of patients and their donors at the time of transplantation were 21 years for both groups (range 0.5 – 52 years). Follow up data were avaible in 636 patients, 100 patients were deceased at the time of prior analysis, 300 patients were lost to follow up. Compared with the analysis of the same cohort of patients 10 years ago, the most striking increase in secondary malignancies was seen in breast cancer (4-fold), thyroid cancer (3-fold) and neoplasms of the skin and oral cavity (2-fold). In multivariate analysis patient age above 30 years (hazard ratio 1.8, 95% CI 1.2 – 2.6; p=0.006), radiotherapy for conditioning (hr 2.3, CI 1.2 – 4.3; p=0.01) and immunosuppression (hr 1.5, CI 1.0 – 2.2; p=0.05) (in particular cyclosporine or methotrexate) were risk factors for new malignancies after hematopoietic stem cell transplantation. In conclusion longer followup shows the continuous increase of the cumulative incidence of secondary neoplasms in long-term survivors. With longer follow-up a shift in the risk factors occurs: Until 10–15 years after allogeneic transplantation immunosuppression is the major risk factor for new malignancies, whereas more than 15 years after transplantation radiotherapy becomes the dominant risk factor.

The Bidirectional Relationship Between Cytomegalovirus Replication and Graft-Versus-Host Disease - a Retrospective Single Center Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2236-2236
Author(s):  
Nathan Cantoni ◽  
Hans H Hirsch ◽  
Nina Khanna ◽  
Dominik Heim ◽  
Joerg Halter ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Time Dependent ◽  
Cmv Infection ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Cmv Reactivation ◽  
Multiple Episodes

Abstract Abstract 2236 Poster Board II-213 Cytomegalovirus (CMV) infection and graft-versus host disease (GVHD) are important complications after allogeneic HSCT with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV reactivation. Data on CMV infection as a cause of GVHD, in contrast, are controversial. The association of pre-transplant CMV serology with GVHD development and reduced rates of chronic GVHD after preemptive CMV treatment are indicative of such an association. However, analyses of the direct impact of CMV infection on GVHD are rare; a recent small study found no effect of CMV replication on subsequent development of acute GVHD (Wang et al, BMT 2008). We analyzed in a single centre study the association of CMV reactivation with acute GVHD in 517 patients treated between 1993 and 2008. 59% of patients were male, median age was 42 years (range 16 to 70). Diagnoses were AML (31%), ALL (16%), CML (15%), MDS/MPN (13%), lymphoma (21%), and other (4%). Conditioning regimens were Cy/TBI ±/- etoposide (49%), Cy/Bu (17%), fludarabine and TBI (16%), or others (18%). GVHD prophylaxis consisted of CyA/MTX (78%) or CyA/MMF (21%). Donors were HLA-identical siblings (65%), other family members (4%), or unrelated donors (31%). We made use of a standardized CMV policy over the last decades. CMV reactivation was monitored using real-time polymerase chain reaction or pp65 antigenemia assay weekly in patients without infection, twice weekly in patients with CMV replication. CMV was preemptively treated with gancyclovir or foscarnet. To determine the correlation of CMV infection with acute GVHD, we used a stringent Cox regression model, in which CMV replication was modeled as a time-dependent covariate becoming positive on the day of the first detection of CMV and negative on the first negative assay thereafter. Multiple episodes of CMV replication were considered. Acute GVHD was modeled as a time-dependent covariate in models with CMV infection as endpoint. Hazard ratios (HR) were adjusted for patient age, disease, disease stage, donor type, stem cell source, conditioning regimen and GVHD prophylaxis. The analysis was restricted to the time from transplant to day 100. CMV reactivation was detected at least once in 16% (84/517) of patients at a median of 33 (range 1-95) days after HSCT. Median duration of CMV reactivation was 8.5 days (range 2-62). 19 patients showed multiple episodes of CMV replication. Donor and recipient serostatus significantly influenced the day 100 cumulative incidence of CMV infection: D-/R- (N=173) 6%; D±/R- (N=61) 10%; D±/R± (N=128) 25%; and D-/R± (N=99) 37%, p<0.001. The cumulative incidence for any acute GVHD (grade I-IV) was 67% (95% CI 56-78%) with a median onset time at day 14 (range day 5-94); the cumulative incidence for severe acute GVHD (grade II-IV) was 48% (95% CI 40-56%). When both endpoints (CMV, GVHD) were combined, 150 patients (29%) experienced neither GVHD nor CMV reactivation, 281 (54%) GVHD only, 19 (4%) CMV reactivation only, and 67 (13%) both CMV reactivation and GVHD. Of the 67 patients with both GVHD and CMV, 46 (69%) developed GVHD prior to CMV reactivation, 17 (25%) developed GVHD during CMV reactivation, and 4 (6%) developed GVHD after CMV reactivation. Cox modeling revealed that presence of GVHD grade II-IV increased the risk of CMV infection (HR 1.61, 95% CI 1.03-2.52, p=0.04). Similarly, patients were at increased risk of developing acute GVHD during phases of CMV replication (grades I-IV: HR 2.23, 95% CI 1.39-3.81, p=0.001; grades II-IV: HR 2.00, 95% CI 1.08-3.72, p=0.03). GVHD grade was not influenced by concomitant CMV reactivation (median grade II, in patients with or without CMV reactivation). The overall proportion of GVHD that occurred during phases of CMV replication was small (3% versus 64% occurring in CMV non replicating patients). Even if GVHD occurring after resolution of CMV reactivation was additionally taken into account, the majority of GVHD occurred without preceding CMV infection (63% versus 4%). These data describe the complex relationship between CMV infection and GVHD. We confirm previous studies that GVHD (and GVHD therapy) can induce CMV infection. We describe as well that patients with active CMV replication have a significantly higher risk of developing GVHD compared to patients without CMV replication. However, the proportion of GVHD that could be linked to CMV reactivation was small in this population with a low overall incidence of CMV reactivation. Disclosures: No relevant conflicts of interest to declare.

Pentostatin Therapy for Steroid-Refractory Acute Graft Versus Host Disease: Identifying Those Who May Benefit

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3136-3136
Author(s):  
Brittany Knick Ragon ◽  
Alison M Gulbis ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Partial Response ◽  
Graft Versus Host Disease ◽  
Term Survival ◽  
Graft Versus Host ◽  
Baseline Characteristics ◽  
Third Line ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Patients with steroid-refractory acute graft versus host disease (aGVHD) have dismal outcomes. Historically, anti-thymocyte globulin has been used in this setting with prior reports demonstrating that even when patients respond, long-term survival occurs in only 5% of patients (Arai et al, 2012). Unfortunately, no therapy has been shown to improve outcomes for this high-risk group. Pentostatin, a potent adenosine deaminase inhibitor, was previously tested in a phase 1/ 2 study in steroid-refractory aGVHD and demonstrated an overall survival (OS) of 25% with a median follow-up of < 3 months (m). We performed a retrospective review of patients receiving pentostatin for steroid-refractory aGVHD with the goal of characterizing long-term outcomes. Methods: All patients transplanted at MD Anderson Cancer Center from January, 2006 to December, 2014 who received at least one dose of pentostatin for steroid-refractory aGVHD were included in this analysis. Pentostatin was dosed at 1.5 mg/m2 on days 1-3 and repeated every two weeks as indicated. Patients who received the drug as GVHD prophylaxis, upfront therapy, beyond third-line, for classic chronic GVHD or following relapse were excluded. Primary endpoints included day 28 response and OS. Results: A total of 60 patients received pentostatin as second (n=22) or third line (n=38) treatment for steroid-refractory aGVHD. The median age was 52 years (range, 2-70). First dose of pentostatin was administered at a median 69 days post-transplant (27-595) with a median of 3 doses provided (range, 1-9). A majority of patients had steroid-refractory lower GI (78%) and/or liver (43%) GVHD. Baseline characteristics described in table 1. The median time from initiation of steroids to pentostatin was 15 days (range, 4-172). OS at 18 m after pentostatin initiation was 21%, with median follow-up of 19 m (range, 7-77).A total of 22 (37%) patients died before day 28 and were considered non-responders. Day 28 response rate was 33% with 20 patients achieving a complete (n=11) or partial response (n=9). Pentostatin administration <10 days following initiation of steroid was the only predictor for day 28 response (HR 2.2, 95% CI 1.2-4.3, p=0.02). The median survival was 25 and 341 days in non-responders and responders, respectively. Landmark analysis starting on day 29 after pentostatin is shown in figure 1. Predictors for OS on multivariate analysis at 18 m included: day 28 complete/partial response (CR/PR) as a time dependent variable (HR 0.3, 95% CI 0.1-0.7, p=0.005), liver GVHD (HR 2.2, 95% CI 1.2-4.1, p=0.007), and age >60 (HR 1.9, 95% CI 0.99-3.6, p=0.05). Within our analysis, patients destined for early mortality within 30 days of pentostatin exhibited all these features: liver GVHD, receipt of pentostatin >100 days from transplant, and age >60, with an OS of 35% at 30 days compared to 72% in the absence of these features (p=0.001). Conclusions: Patients with steroid refractory aGVHD have dismal outcomes. However, long-term survival does occur, especially when additional therapy is administered promptly. Novel strategies to identify patients who are destined to fail upfront therapies are likely to improve outcomes. We identified that earlier dosing of pentostatin after recognition of steroid refractoriness improved response rates. Further, patients without liver GVHD and who were ≤60 had better OS, identifying those who will benefit most from this therapy. Conversely, pentostatin should be avoided in patients >60 with liver GVHD as these patients had extremely high mortality with two-thirds dying by day 30. Table 1. Baseline characteristics at pentostatin initiation. Variable Patients (N=60) Preparative Regimen Intensity  Non-myeloablative (%) 22 (37)  Ablative (%) 38 (63) Overall GVHD Grade  2 (%) 11 (18)  3 (%) 21 (35)  4 (%) 28 (47) Skin GVHD Stage  0 (%) 48 (80)  1 (%) 4 (7)  2 (%) 5 (8)  3 (%) 3 (5) Lower GI GVHD Stage  0 (%) 12 (20)  1 (%) 10 (17)  2 (%) 6 (10)  3 (%) 11 (18)  4 (%) 20 (33)  Unknown (%) 1 (2) Liver GVHD Stage  0 (%) 33 (55)  1 (%) 4 (7)  2 (%) 9 (15)  3 (%) 6 (10)  4 (%) 7 (11)  Unknown (%) 1 (2) Number of GVHD sites  1 (%) 40 (67)  2 (%) 15 (25)  ≥3 (%) 5 (8) Day 28 Response  CR (%) 11 (18)  PR (%) 9 (15)  No Response (%) 11 (18)  GVHD Progression (%) 5 (9)  Died by Day 28 (%) 22 (37)  Progression of Malignancy (%) 2 (3) Figure 1. OS, starting at day 29, stratified by response. Figure 1. OS, starting at day 29, stratified by response. Disclosures Alousi: Therakos, Inc: Research Funding.

scholarly journals Extended CCR5 Blockade in Graft-Versus-Host Disease Prophylaxis – a Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2491-2491 ◽  
Author(s):  
Ran Reshef ◽  
James K. Mangan ◽  
Selina M. Luger ◽  
Alison Wakoff Loren ◽  
Elizabeth O. Hexner ◽  
...  
Keyword(s):  
Phase Ii ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Phase Ii Study ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Ccr5 Blockade

Abstract Background: Blocking lymphocyte trafficking after allogeneic stem cell transplantation (alloSCT) may prevent graft-versus-host disease (GvHD) without interfering with graft-versus-tumor (GvT) activity. We previously reported that brief (up to day+30) CCR5 blockade using maraviroc (MVC, Pfizer) after reduced-intensity conditioned (RIC) alloSCT resulted in a low incidence of acute GvHD and absence of early liver and gut GvHD, although delayed GvHD still occurred. We designed a phase II study to test the hypothesis that extended administration of MVC would be feasible, safe and provide protection against late-onset GvHD without impairing immune reconstitution or GvT responses. Patients and Methods: In April 2013 we initiated a 37-patient (pt) phase II study to test an extended course of MVC in recipients of RIC alloSCT from unrelated donors. Pts receive fludarabine 120 mg/m2 and busulfan i.v. 6.4 mg/kg followed by peripheral blood stem cells. MVC 300 mg b.i.d. is orally administered from day -3 to day +90 in addition to standard prophylaxis with tacrolimus and methotrexate. The primary endpoint is the cumulative incidence of grade 2-4 acute GvHD by day 180. As of July 2014 we enrolled 20 pts at high risk for transplant-related toxicity by virtue of age (median=64, range 55–72), donor source (matched unrelated 80%, single-antigen mismatch unrelated 20%) or comorbidities (comorbidity index: low 15%, intermediate 35%, high 50%). Underlying diseases were AML (16), MDS, MPD, ALL and CTCL (1 each). Feasibility and Safety: The median follow-up on surviving patients is 5.7 months. The 3-month course of MVC was well tolerated with no increased toxicity; two pts did not complete their treatment due to early disease relapse and one patient discontinued therapy due to a skin reaction with eosinophilia where the histological features favored a drug reaction and the attribution to MVC was possible. Postural hypotension, a known dose-dependent toxicity, was observed in one pt who completed the course with a 50% dose reduction. Engraftment and Immune Reconstitution: The median time to ANC>500/μL was 12 d (range 10-21) and platelets>20k/μL was 14 d (range 9-28). The median whole blood and T-cell donor chimerism levels at day 100 were 95% (range 12–100%) and 80% (range 23–94%) respectively, which are similar to historical rates. Median CD4 counts on day 30 were 341 (range 206-424). Only 3/16 evaluable pts had Ig levels<500 mg/dL in the first 100 days. GvHD: Sixteen pts are evaluable with > 3 mo of follow-up. The day-180 cumulative incidence rates (± s.e.) of grade 2-4 and grade 3-4 acute GvHD are 25 ± 11% and 6 ± 6% respectively (Fig. 1). Of patients who developed acute GvHD in the first 180 days, there have been no cases of liver GvHD, 2 cases of stage 1 steroid-responsive gut GvHD and 1 case of severe diarrhea with combined features of GvHD and leukemic infiltrates in the gut. These results are comparable to the GvHD rates in our phase I/II MVC study (grade 2-4: 23.6% and grade 3-4: 5.9%), which included related and unrelated donor transplants. These results also compare favorably with a 45% day-180 acute GvHD rate seen in similar patients treated with our standard GvHD prophylaxis alone. Notably, there has been no treatment-related mortality. Five patients have relapsed at a median of 2.6 months post-transplant (range 0.93 – 3.5), which is similar to our historical rates after RIC alloSCT. PD analysis: We developed a phosphoflow assay to assess in real-time the activity of MVC in fresh blood samples. The assay quantifies the activation of CCR5 by measuring the phosphorylation of C-terminal serine residues as a result of CCL4 stimulation. In 15 evaluable patients, we observed diminished pCCR5 levels with CCL4 stimulation on day 0 as compared to day -6 (Fig. 2). In summary, our preliminary results support the feasibility, safety and protective activity of the CCR5 antagonist MVC against acute GvHD, with preferential activity against visceral GvHD. Continued pt enrollment and follow-up are ongoing. Updated safety, efficacy and PD results will be presented. A multi-center study (BMT-CTN 1203) will be initiated later this year to further clarify the role of this novel strategy in improving the outcome of alloHSCT. Fig 1. Cumulative Incidence of Acute GvHD Fig 1. Cumulative Incidence of Acute GvHD Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Disclosures Reshef: Pfizer: Research Funding. Off Label Use: Maraviroc for graft-versus-host disease prophylaxis.

scholarly journals Cyclosporine or Cyclosporine Plus Methylprednisolone for Prophylaxis of Graft-Versus-Host Disease: A Prospective, Randomized Trial

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3880-3887 ◽  
Author(s):  
H. Joachim Deeg ◽  
Danyu Lin ◽  
Wendy Leisenring ◽  
Michael Boeckh ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Single Agent ◽  
Incidence Rates ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

scholarly journals Cyclosporine or Cyclosporine Plus Methylprednisolone for Prophylaxis of Graft-Versus-Host Disease: A Prospective, Randomized Trial

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3880-3887 ◽  
Author(s):  
H. Joachim Deeg ◽  
Danyu Lin ◽  
Wendy Leisenring ◽  
Michael Boeckh ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Single Agent ◽  
Incidence Rates ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Abstract Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 415-419 ◽  
Author(s):  
Mary E. D. Flowers ◽  
Pablo M. Parker ◽  
Laura J. Johnston ◽  
Alice V. B. Matos ◽  
Barry Storer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Long Term Follow Up

Abstract In a previous multicenter phase III trial comparing peripheral blood stem cell transplantation (PBSCT) to bone marrow transplantation (BMT) from HLA-matched related donors, we found no statistically significant difference in the cumulative incidence of clinical extensive chronic graft-versus-host disease (GVHD) in the 2 groups. We have analyzed the results in more detail to determine whether the clinical characteristics of chronic GVHD after PBSCT might be distinct from those that occur after BMT. Clinical extensive chronic GVHD developed in 39 of 63 recipients of PBSCs and in 32 of 63 BM recipients who were alive and free of malignancy at day 100 after the transplantation. No significant differences were found in the time and type of onset of clinical extensive chronic GVHD or in the frequency of complications associated with severe morbidity. Involvement of skin and female genital tract was more frequent in PBSC recipients than in BM recipients. The cumulative incidence of chronic GVHD at 3 years was similar in the 2 groups, but the number of successive treatments needed to control chronic GVHD was higher after PBSCT than after BMT (P = .03), and the duration of glucocorticoid treatment was longer after PBSCT compared to BMT (P = .03). These results suggest that chronic GVHD after PBSCT may be more protracted and less responsive to current treatment than chronic GVHD after BMT. Assessment of the overall benefits of PBSCT compared to BMT will require continued long-term follow up of morbidity associated with chronic GVHD.

Early Intervention with Mesenchymal Stromal Cells for Refractory Grade III-IV Graft Versus Host Disease In Children Results In Excellent Long Term Outcome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2336-2336
Author(s):  
Lynne Margaret Ball ◽  
Maria E. Bernardo ◽  
Jaap Jan Zwaginga ◽  
Maarten van Tol ◽  
Angela Cometa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Term Survival ◽  
Long Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Abstract Abstract 2336 Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with severe, steroid-refractory, acute graft-versus-host disease (aGVHD). However, long term comprehensive follow up data on pediatric patients is limited. We analyzed the outcome of 37 children receiving MSC for steroid-refractory aGvHD in two centers between January 2005 and December 2009 (characteristics see Table 1). A median of 2 infusions (range 1–13) were administered, with a median cell dose of 2×106/kg (range 0.9–3.0). MSC were from 3rd party HLA-mismatched donors (n=31), haploidentical relative (n=3) or both (n=3). (see Table 2) Fifteen children had either no (n=6) or partial (n=9) response to MSC. In this group, transplantation-related mortality (TRM) was 60%. Complete response (CR) was observed in 22 children, TRM being 14%. (p=0.005). Among the 28 patients with hematological malignancies, 5 relapsed, three with CR and two with PR. With a median follow-up of 2.3 years (range 7 months–4.7 years), overall survival was 62% with 87% versus 27% in patients who did or did not achieve CR after MSC respectively (p value <0.001). MSC after 2009 given at the time of steroid failure (median 8 days range 4 to 24) compared to pre 2009 (median 24 days range 5 to 85) (Maan-Whitney U = 65.5 two tailed p= 0.002) reduced fatal infections and was associated with a trend to better overall survival at 2 years post MSC infusion (p = 0.07). Although infections were evident at the time of immune suppression and mortality was high in NR/PR, response to MSC allows for reduction and eventual discontinuation of pharmacological immune suppression. Long term survival in responders is associated with eventual immune recovery, no late infections and persistent remission status. Treatment of steroid refractory aGVHD should aim to induce rapid stable control and early reduction of steroids to reduce TRM from viral reactivations. We conclude that MSC are ideal candidates for this purpose. Our results show that children responding to MSC treatment for severe steroid refractory GvHD have an excellent long term survival. Legend: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; jMML = juvenile myelomonocytic leukemia; HLH = hemophagocytic lymphohistiocytosis; MSD = matched sibling donor; (m) MUD (mis) Matched unrelated donor; PBSC = peripheral blood stem cells; TBI = total body irradiation; CSA = Cyclosporine A; MTX = short course methrotrexate; ATG = anti-thymocyte globulin; HSCT = hematopoietic stem cell transplantation; DLI = donor lymphocyte infusion; GvHD = graft versus host disease; M=Male; F=Female. Disclosures: No relevant conflicts of interest to declare.

Cannabidiol - An Innovative Strategy For Graft Versus Host Disease Prevention

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3299-3299 ◽  
Author(s):  
Moshe Yeshurun ◽  
Ofer Shpilberg ◽  
Corina Herscovici ◽  
Juliet Dreyer ◽  
Anat Peck ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
End Points ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade 3

Abstract Introduction Acute graft-versus-host disease (aGVHD) is a major life-threatening complication following allogeneic stem cell transplantation (alloSCT), affecting 35%-70% of recipients despite standard prophylaxis regimens. Thus, developing innovative strategies to prevent and treat GVHD is a major unmet need. Cannabidiol (CBD), a safe and non-psychotropic ingredient of marijuana, has been shown to exhibit potent immune-modulatory and anti-inflammatory properties in animal models of various inflammatory diseases. We hypothesized that administration of CBD during alloSCT may significantly decrease GVHD incidence. Methods We conducted a phase I/II trial. All patients were given standard GVHD prophylaxis consisting of cyclosporine and a short course of methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3 and +6). The investigational agent, CBD (STI Pharmaceuticals, Essex, UK), was orally administered at a dosage of 150 mg twice daily from starting of conditioning up to day +30. Primary end points were safety and cumulative incidence of grade 2-4 and grade 3-4 aGVHD by day +100. The secondary end points were cumulative incidence of chronic and chronic extensive GVHD, non-relapse mortality (NRM), relapse incidence, and overall survival (OS). Results Between 9/2012 and 6/2013, 30 consecutive unselected adult patients undergoing alloSCT were enrolled (median age=52, range, 22-71 years). Median follow-up was 4.8 months (range, 1-10.3). Base line diseases were acute leukemia (n=21, 70%), myelodysplastic syndrome (n=2, 7%), lymphoma (n=5, 17%), aplastic anemia (n=1, 3%), and multiple myeloma (n=1, 3%). 73% were in CR/PR at transplantation. The majority of patients were given a myeloablative preparative regimen (n=22, 73%). The donor was either an HLA identical sibling (n=16) or 10/10 matched unrelated donor (n=12) or 1 antigen mismatched unrelated donor (n=2). All patients were given G-CSF mobilized peripheral blood stem cell grafts. There were no documented grade 3-4 toxicities attributed to CBD. There were no cases of graft rejection. In all, 2 patients developed aGVHD by day 100 (grade 2, n=1 and grade 3, n=1) and one patient developed late onset aGVHD (grade 4, n=1). The cumulative incidences of grade 2-4 aGVHD and grade 3-4 aGVHD by day +100 were 8.4% and 4.5%, respectively. Five patients developed chronic GVHD, 4 had limited disease and one extensive disease. There were 4 deaths because of sepsis (n=1), cardiac arrhythmia (n=1), grade 4 aGVHD (n=1) and relapse (n=1). Cumulative incidences of NRM at 3 and 6 months were both 6.9% and incidences of relapse were both 10.7%. OS at 3 and 6 months were both 90%. Conclusion These data suggest that the combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of GVHD. Nevertheless, a well designed prospective controlled study comparing this novel approach with standard GVHD prophylaxis is warranted. Follow-up data on safety, efficacy, and on additional subjects will be presented. Disclosures: No relevant conflicts of interest to declare.

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