scholarly journals Treatment of Steroid Resistant Grade II to IV Acute GVHD by Infusion of Mesenchymal Stroma Cells Expanded with Human Plasma and Platelet Lysate – a Phase I/II Study

2012 ◽  
Vol 18 (2) ◽  
pp. S265 ◽  
Author(s):  
L.C.J. Boome ◽  
C.M. Mansilla Puerta ◽  
C.A. Lindemans ◽  
I.C.M. Slaper ◽  
H. Rozenmuller ◽  
...  
Keyword(s):  
Phase I ◽  
Human Plasma ◽  
Acute Gvhd ◽  
Platelet Lysate ◽  
Steroid Resistant ◽  
Grade Ii ◽  
Mesenchymal Stroma ◽  
Mesenchymal Stroma Cells

scholarly journals Treatment of Steroid Resistant Grade II to IV Acute GVHD by Infusion of Mesenchymal Stroma Cells Expanded with Platelet Lysate - a Phase I/II Study

2013 ◽  
Vol 19 (2) ◽  
pp. S144
Author(s):  
Liane te Boome ◽  
Cristina Mansilla ◽  
Caroline Lindemans ◽  
Lotte van der Wagen ◽  
Marloes Cuijpers ◽  
...  
Keyword(s):  
Phase I ◽  
Acute Gvhd ◽  
Platelet Lysate ◽  
Steroid Resistant ◽  
Grade Ii ◽  
Mesenchymal Stroma ◽  
Mesenchymal Stroma Cells

Treatment of Steroid Resistant Grade II to IV Acute Gvhd by Infusion of Mesenchymal Stroma Cells Expanded with Human Plasma and Platelet Lysate - a Phase I/II Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 736-736
Author(s):  
Liane CJ te Boome ◽  
Cristina M Mansilla ◽  
Caroline A Lindemans ◽  
Lotte E Van der Wagen ◽  
Marloes Cuijpers ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Human Plasma ◽  
Calf Serum ◽  
Platelet Lysate ◽  
Steroid Resistant ◽  
Grade Ii ◽  
Mesenchymal Stroma ◽  
Mesenchymal Stroma Cells ◽  
Steroid Refractory

Abstract Abstract 736 Introduction Despite multiple improvements in the last decade in the field of HSCT, acute graft versus host disease (aGVHD) remains a life-threatening complication and reduces substantially efficacy of HSCT. In particular, the outcome of patients with severe steroid-resistant aGVHD is very poor. Therefore, it remains important to search for new therapeutic strategies for the treatment of aGVHD. Objective Feasibility of the generation and efficacy of mesenchymal stroma cells (MSCs) generated with fetal calf serum (FCS) has been suggested recently. However, FCS is a putative source of prions and virus transmission. Therefore, the feasibility of the generation of MSCs expanded with human plasma and platelet lysate (hPPL) was tested as well as the feasibility and safety of the application of hPPL-MSCs in patients with steroid-refractory aGVHD. Furthermore multiple immunological changes after infusion of MSC were characterized, in vitro. However, truly active mechanisms in human are poorly understood as well as whether infusion of MSC selectively impairs GVHD-inducing immune cells or also anti-virus and anti-leukemia reactive T-cells. Therefore, phenotypical and functional changes in immunological cell types and cytokine levels were investigated. Method In an open-label, non-randomized prospective phase I/II study MSCs were extracted from the bone marrow of healthy volunteers, expanded with hPPL, and stored. Patients with steroid-refractory aGVHD grade II to IV were treated with hPPL-MSC. 50 patients were included and received up to four infusions. Response rate, transplantation-related deaths, and other adverse events were assessed for up to 12 months after the last infusion of the cells. In addition, a comprehensive phenotypical and functional analysis was performed with PBMCs and serum isolated from all patients before, during, and after infusion of MSC. Results Between January 2009 and July 2012, 50 patients were included, 2 patients dropped out, 5 patients are so far incompletely documented. Thus 43 patients were so far available for analysis, 6 children and 37 adults. Median age was 51,5 years (1.3–65.9). Organs involved in aGVHD were the skin (56%), the gastro-intestinal tract (86%) and the liver (33%). Overall grade was II for 11 (26%), III for 28 (65%), and IV for 3 (7%) patients. Mean number of infusion were 3 (1–4). No severe side effects were observed. Median follow-up was 4.06 months (range 0.43–12). Complete overall response was observed in 24 patients (56%) after a median of 53 days (range 3–116 days). The overall survival was significantly better in responders when compared to non-responders (p <0.001). Most patients who relapsed with GVHD of the gut were again sensitive to steroids, except one patient who then responded well to a second cycle of MSCs. Immunological monitoring suggests that anti-viral and anti-leukemia reactive T-cells are well preserved in all patients who responded to MSC treatment. In addition, we identified biomarkers which associate even 2 weeks after MSC infusion with a complete resolution of GVHD, which occurred usually after months. Conclusion Generation and infusion of hPPL-MSCs in steroid-resistant aGVHD grade II- IV is feasible, safe and appears to be effective. In addition, also patients who initially responded to hPPL-MSCs but develop later a relapse of aGVHD during tapering or cessation of immunosuppressive drugs become again sensitive to the treatment with steroids. Infusion of MSC did not impair anti-virus and anti-leukemia reactive T-cells. Identified biomarkers predict very early a usually late clinical resolution of GVHD, thus might be useful to early guide clinical decisions. Disclosures: No relevant conflicts of interest to declare.

Treatment of Steroid Resistant Grade II to IV Acute Gvhd by Infusion of Mesenchymal Stroma Cells Expanded with Human Plasma and Platelet Lysate - a Phase I/II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3046-3046
Author(s):  
Liane CJ te Boome ◽  
Caroline A Lindemans ◽  
Ineke Slaper-Cortenbach ◽  
Henk Rozemuller ◽  
Eefke J Petersen ◽  
...  
Keyword(s):  
Phase I ◽  
Human Plasma ◽  
Conflicts Of Interest ◽  
Platelet Lysate ◽  
Hematopoietic Stem ◽  
Steroid Resistant ◽  
Grade Ii ◽  
Mesenchymal Stroma ◽  
Mesenchymal Stroma Cells ◽  
Steroid Refractory

Abstract Abstract 3046 Introduction For numerous malignant and non-malignant hematological diseases allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy. However, a major complication is the acute graft versus host disease (aGVHD), which is life-threatening and substantially reduces efficacy of HSCT. In particular, the outcome for patients with severe steroid-resistant aGVHD is very poor. Therefore, it remains important to search for new therapeutic strategies for the treatment of aGVHD. Objective Feasibility of the generation mesenchymal stroma cells (MSCs) expanded with human plasma and platelet lysate (hPPL) was tested as well as the feasibility and safety of the application of MSCs in patients with steroid-refractory extensive aGVHD. Method In an open-label, non-randomized prospective phase I/II study MSCs were extracted from the bone marrow of healthy volunteers, expanded with human plasma and platelet lysate (hPPL), and stored. Patients with steroid-refractory extensive aGVHD were treated with ∼2×106/kg MSC. Response rate, transplantation-related deaths, and other adverse events were assessed for up to 12 months after the last infusion of the cells. Results Between January 2009 and December 2010, 18 patients were treated, 5 children and 13 adults, median age was 32.5 years (range 1.3–65.9). Organ involvement of the aGVHD was 67% skin, 83% gastro-intestinal and 28% liver. Overall grade was II for 4 (22%), III for 13 (72%), and IV for 1(6%) patients. 1 patient received one infusion, all other patients received two or more infusions. No patient had side-effects during or immediately after infusions of the MSC. Median follow-up was 5.5 months (range 0.33–12). Complete overall response was observed in 11 (61%) patients after a median of 65 days (range 10–184 days). The overall survival was significant better (p <0.001) compared to non-responders. Of the 11 patients who reached a CR, 8 relapsed median 59 days (1–244) after reaching CR. Three children with subsequently limited cGVHD, allo immune lung and auto-immune cytopenia and 5 adults with all relapse GVHD of the gut, median 98 days (35–302 days). However, GVHD of the gut was then sensitive for the treatment with steroids. Overall, 7 patients died, 4 due to progression of aGVHD, 1 patient due to abdominal bleeding and 2 due to sepsis. Conclusion Generation and infusion of MSCs in steroid-resistant aGVHD grade II- IV is a feasible, safe and very effective. In addition, also patients who initially responded to MSCs but develop later a relapse of aGVHD during tapering or cessation of immunosuppressive drugs become again sensitive to the treatment with steroids. Disclosures: No relevant conflicts of interest to declare.

Treatment of steroid resistant grade II to IV acute GVHD by infusion of mesenchymal stromal cells expanded with platelet lysate - a phase I/II study

Cytotherapy ◽  
2014 ◽  
Vol 16 (4) ◽  
pp. S13 ◽  
Author(s):  
L. van der Wagen ◽  
L. te Boome ◽  
C. Mansilla ◽  
C. Lindemans ◽  
M. Cuijpers ◽  
...  
Keyword(s):  
Phase I ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Acute Gvhd ◽  
Platelet Lysate ◽  
Steroid Resistant ◽  
Grade Ii

scholarly journals Results from an Expanded Access Program of Anti-CD3/CD7 Immunotoxin Combination (T-Guard®) for the Treatment of Steroid-Refractory Acute Gvhd

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4553-4553 ◽  
Author(s):  
Lenneke F J Groningen ◽  
Christoph Groth ◽  
Manita E J Bremmers ◽  
Eric G Hooren ◽  
Ypke V J M van Oosterhout ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Acute Gvhd ◽  
Expanded Access ◽  
Plasma Citrulline ◽  
Recent Phase ◽  
Grade Ii ◽  
Third Line ◽  
To Receive ◽  
Access Program

Background More effective therapies for treating steroid-refractory acute GVHD (SR-aGVHD) are urgently needed. In our recent phase I/II study, we showed that anti-CD3/anti-CD7 immunotoxin (IT) therapy T-Guard was both safe and well tolerated, and yielded both a high rate of CR and high 6-month OS in high-risk patients (Groth et al. BBMT 2019). Following this study, patients with SR-aGVHD were offered T-Guard via an expanded access treatment program (EAP). Objectives We evaluated patients' outcome after receiving T-Guard for SR-aGVHD. In addition, we examined the relationship between plasma citrulline levels (a biomarker of enterocyte mass) and the response to T-Guard in a subset of patients with SR-aGVHD of the gut, combining 16 patients from the phase I/II trial and 9 patients in the EAP group. Methods An EAP was started after completion of the phase I/II trial. This program was approved by the local ethics committee and the Health and Youth Care Inspectorate of the Dutch government. Adult patients with grade II-IV SR-aGVHD were eligible to receive T-Guard as their second- or third-line treatment for aGVHD. Patients with an uncontrolled infection, signs of moderate-severe chronic GVHD, and/or severe renal impairment were not eligible to receive T-Guard. Eligible patients received four 4-hour i.v. infusions of 4 mg/m2 T-Guard delivered at 48-hour intervals. In addition, plasma citrulline levels were measured at baseline and every 7 days after the start of T-Guard therapy using HPLC with mass spectrometry. A plasma citrulline level <10 µmol/L was considered to indicate severe GI-GVHD. Results From Jan. 2017 through Dec. 2018, 12 patients (8 male, 4 female; median age: 54 yr, range: 20-70 yr) who had received an allogeneic stem cell transplantation for myeloid or lymphoid malignancy were treated with T-Guard. T-Guard was given as the second-line therapy to 10 patients; the remaining 2 patients received T-Guard as the third-line therapy after receiving ruxolitinib (N=1) or cyclosporin-UVB (N=1). The median time between aGVHD onset and the start of T-Guard therapy was 7 days (range: 3-55 days). SR-aGVHD was classified as grade II, III, or IV in 1, 7, and 4 patients, respectively. Nine patients (75%) had GI involvement, and the skin and liver were involved in 6 and 2 cases, respectively. All 12 patients were classified as high-risk in accordance with MacMillan et al. (BJH 2012), and the median albumin level at baseline was 23 g/L (range: 13-32 g/L). By treatment day 28, 9 patients (75%) had achieved a clinical response, with 5 achieving complete remission. After a median follow-up of 16 months, 7 patients were alive; the 6-month and 1-year OS rate was 75% and 58%, respectively, which was significantly higher than historical controls; Figure 1. The cause of death in the other five patients was refractory aGVHD (N=3), relapse AML (N=1), and GVHD after undergoing a second stem cell transplantation for relapse AML (N=1). No significant infusion-related reactions were recorded. As expected, the overall rate of infection was high, but was comparable to other cohorts; 1 and 2 patients developed an EBV or CMV infection, respectively, but these were manageable. The most common potentially treatment-related adverse events were transient worsening of hypoalbuminemia and thrombocytopenia. One patient developed grade 2 vascular leak syndrome, but this was easily managed. One patient developed severe thrombotic microangiopathy with renal insufficiency, but several contributing factors other than the use of T-Guard were present in this patient, including calcineurin toxicity, severe GI-GVHD, and CMV disease. Our preliminary analysis of citrulline levels in 16 patients with GI-GVHD showed that mean baseline levels were extremely low (4.3 µmol/L; range: 2.9-17.9 µmol/L); 28 days after the start of T-guard, citrulline levels had increased significantly in the 9 patients who achieved complete remission; Figure 2. Conclusion Consistent with our recent phase I/II trial, our expanded access program in which 12 patients with high-risk SR-aGVHD received T-guard confirms that this treatment is safe and significantly improves patient outcome. A multicenter phase III study is planned to start in 2019 (BMT-CTN 1802). Disclosures Hooren: Xenikos BV: Employment. van Oosterhout:Xenikos BV: Employment.

The Addition Of Interleukin-6 Inhibition To Standard Gvhd Prophylaxis Prevents Acute Gvhd: Interim Results Of a Phase I/II Clinical Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 908-908 ◽  
Author(s):  
Glen A Kennedy ◽  
Antiopi Varelias ◽  
Slavica Vuckovic ◽  
Ping Zhang ◽  
Kelli PA MacDonald ◽  
...  
Keyword(s):  
Phase I ◽  
Interleukin 6 ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Off Label Use ◽  
Control Cohort ◽  
Off Label ◽  
Gvhd Prophylaxis ◽  
Matched Sibling ◽  
Grade Ii

Abstract We and others have demonstrated the dysregulation of interleukin-6 (IL-6) early after experimental bone marrow transplantation (BMT) and protection from acute GVHD following the administration of an anti-IL-6 receptor (IL-6R) antibody. In these models, where GVHD prophylaxis is not administered, systemic IL-6, IFNγ and TNF levels peak 7 days after BMT before returning to baseline by the third week. We have determined cytokine dysregulation in a large clinical cohort of allogeneic stem cell transplant (SCT) recipients conditioned with myeloablative Cy/TBI (12 Gy, n = 25) or reduced intensity Flu/Mel (120mg/m2, n = 25) receiving standard GVHD prophylaxis with cyclosporine and MTX (d 1 at 15mg/m2, d 3, 6, 11 at 10mg/m2). IL-6 levels rose from pre-transplant levels of 6.4 ± 0.7 pg/ml to a peak of 58.8 ± 8.8 pg/ml at day 7 (P < 0.0001) with a fall at day 14 to 39.0 ± 12.5 pg/ml (P < 0.0001) and return to baseline by day 30 (6.2 ± 0.9 pg/ml), consistent with the preclinical data. IL-6 dysregulation was not different in recipients of matched sibling or unrelated donor grafts but was proportional to the intensity of conditioning (day 7 levels after Cy/TBI vs. Flu/Mel: 83.3 ± 12.2 pg/ml vs. 31.0 ± 10.1 pg/ml, P< 0.0001). In contrast to preclinical mouse data, no systemic increases were seen in any other cytokine including IFNγ, TNF, IL-17, IL-4, IL-13 and IL-10. We thus initiated a phase I/II study whereby a human neutralizing monoclonal antibody (mAb) against the IL-6R was administered on day -1 to patients receiving Cy/TBI or Flu/Mel conditioned allogeneic SCT from HLA (10/10)–matched sibling or unrelated donors with standard cyclosporine/MTX GVHD prophylaxis. There was no T cell depletion. The primary endpoint was the incidence of grade II-IV acute GVHD and the study has achieved its planned enrollment (n = 48). There was no toxicity attributable to IL-6R antibody administration. Pharmacokinetic analysis confirmed high levels of IL-6R Ab at day 3 (mean 64.7 ug/ml) which persisted in all patients 3 weeks after BMT (mean = 9.8 ug/ml) and remained above the level of detection (0.1ug/ml) in 75% of patients at day 30 (mean = 1.9 ug/ml). IL-6 levels were dramatically increased (relative to baseline) in patients receiving antibody due to the inability to excrete the inactive IL-6 – soluble IL-6R antibody complex (peak IL-6 levels at day 7 = 773.6 ± 207.9 pg/ml; P < 0.0001) and remained increased at day 30 (60.9 ± 24.4 pg/ml; P < 0.0001), returning to baseline by day 60 (9.5 ± 1.7 pg/ml), consistent with antibody clearance. Soluble IL-6R levels also rose over the first month of SCT and levels at day 30 correlated with residual antibody levels (r2 = 0.72, P = 0.02). Neutrophil (> 0.5x109/L) and platelet (> 20x109/L) recovery was normal relative to a matched untreated control cohort at a median of 16 and 18 days respectively. Donor chimerism and immune reconstitution (conventional T, regulatory T and B cells) was equivalent at day 30 in recipients of IL-6R inhibition versus the control cohort. In contrast, changes in innate immunity were seen in patients receiving IL-6R inhibition with increases in plasmacytoid DC (P = 0.002), CD1c+ conventional DC (P = 0.04) NKT cells (P =0.03) and marked reductions in inflammatory (CD14+CD16+) monocytes (P < 0.0001). Transcriptional profiling of T cell subsets is underway. With 36 patients evaluable (beyond day 100, median follow up of 297 days), the incidence of grade II-IV GVHD is 11.1% in recipients of IL-6R inhibition versus 39.6% in the matched (n = 53) control cohort (P = 0.004). The incidence of grade III/IV acute GVHD is 5.6% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.045). Protection from grade II-IV acute GVHD was noted in patients receiving both Cy/TBI (7.7% vs. 40.7%, P=0.045) and Flu/Mel conditioning (13.0% vs. 38.5%, P = 0.044). Rates of CMV reactivation were very low in the IL-6R neutralized patients (16.7% vs. 35.8% in controls, P = 0.04), likely due to the prevention of acute GVHD and its’ consequent therapy. At one year, the relapse incidence and disease free survival in patients receiving IL-6R inhibition versus the control cohort is 21.2% vs. 30.0% (P = 0.28) and 73.1% vs. 62.4% (P = 0.14) respectively. IL-6 is thus the principal inflammatory cytokine dysregulated after clinical allogeneic SCT and its inhibition appears to offer profound protection from acute GVHD despite robust immune reconstitution, without compromise of the GVL effect. Disclosures: Off Label Use: The use of Tocilizumab to prevent GVHD is experimental and an off label use.

A Phase I/II Trial Evaluating the Use of a Histone Deacetylase Inhibitor Panobinostat (LBH589) in Addition to Glucocorticoids in Patients with Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1167-1167 ◽  
Author(s):  
Lia Perez ◽  
Teresa Field ◽  
Marcie L Riches ◽  
Hugo F Fernandez ◽  
Frederick L Locke ◽  
...  
Keyword(s):  
Phase I ◽  
Graft Versus Host Disease ◽  
Histone Deacetylase Inhibitor ◽  
Acute Gvhd ◽  
Response Rate ◽  
Liver Stage ◽  
Graft Versus Host ◽  
Deacetylase Inhibitor ◽  
Grade Ii ◽  
Stage 1

Abstract Graft-versus-host disease (GVHD) remains the principal obstacle to successful outcomes in allogeneic hematopoietic stem cell transplant (HCT). Glucocorticoids are the current standard initial treatment for acute GVHD with variable complete responses rates (30% to 60%). New immunosuppressive strategies are required to improve survival and to decrease immunosuppressive toxicities. Vorinostast, a histone deacetylase inhibitor (HDACi), have shown efficacy for acute GVHD prevention in MRD HCT. Panobinostat is a potent inhibitor of deacetylases and HSP90 belonging to a structurally novel class of the cinnamic hydroxamic acid class and is one of most potent pan-HDACi. This protocol tested the safety and efficacy of Panobinostat (LBH589) as initial adjunct treatment for acute GVHD, administered within 72 hours of the first high dose glucocorticoid (methylprednisolone 0.8 mg/Kg/day IV or equivalent PO for 14 days and then taper per MD discretion). We have enrolled 19 subjects, median age 53 years (range, 34-76), male (n=12)/female (n=7), white(n=14)/hispanic(n=5); with diagnosis of CLL (n=2), MDS (n=2), Myeloma (n=1), Follicular NHL (n=1), CML(n=1), Myelofibrois (n=3), AML (n=5), MDS/CMML (n=3) or ALL(n=1). Conditioning regimens included Busulfan(BU)/fludarabine(FLU) AUC 5300 (n=10) or AUC 3500 (n=3), FLU/Melphalan (n=4) or Pentostatin/BU (n=2); and GVHD prophylaxis for MUD 8/8 (n=11) or MRD (n=5) HCT with TAC/MTX (n=6), TAC/rapamycin(n=7), TAC/MMF(n=3) and for mismatched transplants with either TAC/RAPA/ATG (n=2) or TAC/MTX/ATG (n=1). Median day of acute GVHD (n=16) onset was day + 37 post HCT (26 -109 days) with overall grade GVHD II (n=13) or III (n=6); and median day of acute symptoms in overlap GVHD patients (n=3) was day + 712 (528-981). All Patients were treated with voriconazole (n=15) or micafungin (n=4) for fungal prophylaxis. For the first four patients Panobinostat was administered intravenously (IV) weekly x 4 at 2.5MG/M2 (n=3) or 5MG/M2 IV (n=1) with all 4 achieving either CR (n=3) or PR (n=1) GVHD responses by day +15 of Panobinostat. Due to manufacturer discontinuation of IV formulation, the protocol was amended to use PO Panobinostat. Using 10mg PO TIW 3 doses q week x 4 weeks, we treated 2 subjects which were both discontinued from study drug due to presumed GHVD progression within 7 days of Panobinostat (after 3-4 doses). First subject had grade II GVHD (skin stage 3, gut stage 1 and liver stage 0) that progress in gut and skin; second subject with grade II GVHD (skin stage 3, gut stage 1, liver stage 1) with LFTs worsening ultimately evolving into VOD. Due to safety concerns next subjects were treated with 5 mg PO TIW 3 doses q week x 4 weeks, dose that was determined to be the maximal tolerated dose (MTD) after 6 patients completed therapy in phase I. Currently we are enrolling in phase II portion (n=7). GVHD response rate among MTD treated was complete in 85% (n=11), partial in 7.6% (n=1) or progressive in 7.6% (n=1) by day +36 after Panobinostat with majority achieving responses by day +21. Chronic GVHD at day +365 in evaluable patients (n=6) was none (n=3) or mild (n=3) and steroid was discontinued at a median of 3 months (3-6). Hematological toxicities in evaluable patients (n=13) were mild with worsening of prior thrombocytopenia (n=7/10), anemia (n=3/10) and leukopenia (n=3/10) and returned to baseline within 1-2 weeks; LFTs deterioration (n=1) within 1 week of Panobinostat in a GVHD stages 3 liver/3 skin patient; pericarditis/cardiogenic shock CTCAE 5 of unclear etiology (n=1); worsening thyroid function (n=1) and hypercholesterolemia (n=1). Preliminary correlative studies in MTD treated patients showed that CD4 and CD8 numbers remained stable during treatment. T regulatory cells numbers decreased at day +8 after Panobinostat and recovered by days +15 and +29 of treatment. Level of T regs inducing cytokines (TGFB and IL-10) increased, possibly contributing to an immune-modulatory environment. There is evidence of an increased in acetylation of histone 3 in CD4, CD8 and monocytes subsets over time. We are encouraged with tolerability of level -1 Panobinostat dose and the high GVHD response rate of 85% which may compare favorably to the historical GVHD response rate. These results suggest a potential role for Panobinostat as a tool to improve success of glucocorticoids for acute GVHD treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phase I Study of Cord Blood Transplantation with Intra-Bone Marrow Injection of Mesenchymal Stem Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2004-2004
Author(s):  
Tatsunori Goto ◽  
Makoto Murata ◽  
Tetsuya Nishida ◽  
Seitaro Terakura ◽  
Sonoko Kamoshita ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Median Number ◽  
Blood Transplantation ◽  
Cell Counts ◽  
Otsuka Pharmaceutical ◽  
Grade Ii

Background: Delayed hematological recovery, graft failure, and acute graft-versus-host disease (GVHD) remain major problems in cord blood transplantation (CBT). Mesenchymal stem cells (MSCs) are known to support bone marrow (BM) stroma and promote hematopoiesis. Additionally, MSCs possess immunomodulatory properties and are used clinically for the treatment of acute GVHD. Therefore, the use of MSCs to enhance engraftment and prevent GVHD after allogeneic hematopoietic cell transplantation has been explored. Recent clinical trials have shown the safety and feasibility of CBT with intravenous co-transplantation of MSCs in pediatric patients (pts), but not in adults, who are at greater risk of graft failure. Previous preclinical study showed that direct intra-BM injection of MSCs enhanced the engraftment of CB cells more than intravenous injection. Based on these backgrounds, to develop a new strategy not only to enhance engraftment but also to prevent GVHD, we designed a first phase I clinical trial to evaluate the safety of CBT combined with intra-BM injection of MSCs (MSC-CBT) for adults (UMIN-CTR, number 000024291). Methods: This study was a single arm, non-randomized, open-label, single-center, phase I trial. Adult pts with hematological disorders were eligible for this study. The target sample size was 5. MSCs were expanded from BM mononuclear cells harvested from healthy adult donors who were patient's spouse or relative within the fourth degree of relationship. The target dose of MSCs infused was 0.5×106 cells/kg of patient body weight. On the day of CBT, MSCs were injected into the intra-BM of the patient 4 hours before the infusion of a single CB unit. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint of this study was toxicity related to intra-BM injection of MSCs within 14 days after transplantation. Hematopoietic recoveries, clinical outcomes, lymphocyte subsets, and cytokine/chemokine levels were compared with controls (n=6) who received CBT without MSC during same time period in our institute. Results: Between February 2017 and June 2018, 6 pts were enrolled, but one did not meet the criteria for release of MSCs due to insufficient cell counts. Among 5 eligible pts, the median age was 47 years (range, 24-70 years). Four pts (80%) were male. Two pts (40%) had AML in 1st or 2nd CR, 2 (40%) had MDS-EB-2, and one (20%) had malignant lymphoma in 1st remission. The median number of cryopreserved TNCs and CD34+ cells in a CB unit was 2.6 × 107/kg (range, 1.9-4.3 × 107/kg) and 1.0 × 105/kg (range, 0.7-1.2 × 105/kg), respectively. No pts had donor-specific HLA antibodies. All pts received myeloablative conditioning regimen. There was no significant difference between pts and controls in these characteristics. The median number of MSCs was 1.4 × 106/kg (range, 0.3-1.8 × 106/kg). No adverse events related to intra-BM injection of MSCs were observed. All pts achieved neutrophils ≥0.5 × 109/L, reticulocytes ≥1%, platelets ≥20 × 109/L , and platelets ≥50 × 109/L recoveries, with median time to recoveries of 21 (range, 17-27), 35 (range, 29-39), 38 (range, 29-48), and 52 (range, 42-57) days after transplantation, respectively. There was no difference in hematopoietic recoveries compared to controls. Grade II-IV acute GVHD developed in 3 controls (50%); however, there was no grade II-IV acute GVHD in MSC-CBT pts (Fig. 1). No pts developed chronic GVHD in both groups. At 1 year after transplantation, 2 controls developed relapse and 1 died for relapse, whereas all MSC-CBT pts survived without relapse. T and NK cell counts at 28 days after transplantation in MSC-CBT pts had tendencies to be higher compared to controls, with median cell counts of 166 (range, 21-351) vs. 25 (range, 3-120) cells/μL (P=0.09) and 107 (range, 78-168) vs. 61 (range, 11-117) cells/μL (P=0.06), respectively (Fig. 2). There were tendencies to decrease in IFN-γ, IL-21, IL-1α, IL-2, and IL-4 levels within 28 days after transplantation in MSC-CBT pts compared to controls (Fig. 3). Conclusions: The present study shows the safety of CBT combined with intra-BM injection of MSCs. Our findings also suggest that co-transplantation of MSCs may prevent GVHD, accompanied by decrease in some inflammatory cytokines, whereas may enhance immune reconstitutions. Further analysis is required to confirm the efficacy of co-transplantation of MSCs. Disclosures Goto: JCR Pharmaceuticals Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Murata:Chugai Pharmaceutical Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria; GSK Co., Ltd.: Consultancy; MSD Co., Ltd.: Honoraria. Nishida:Amgen Astellas BioPharma K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MSD K.K.: Consultancy, Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Terakura:Sumitomo Dainippon Pharma: Honoraria; Novartis: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Yakult Honsha, Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Amgen Astellas BioPharma K.K.: Honoraria. Ishikawa:Bristol-Myers Squibb: Honoraria; Celgene Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Abbvie GK.: Honoraria. Matsushita:CSL: Consultancy, Honoraria; Bioverative: Research Funding; Novo Nordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; KM biologists: Consultancy, Honoraria, Research Funding; uniQure: Consultancy, Honoraria. Kiyoi:Bristol-Myers Squibb: Research Funding; FUJIFILM Corporation: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding.

scholarly journals T-Cell Depleted HLA-Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (haplo-HSCT) Followed By Donor Lymphocyte Infusion with T Cells Transduced with the Inducible Caspase 9 (iC9) Suicide Gene in Children with Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4683-4683 ◽  
Author(s):  
Barbarella Lucarelli ◽  
Alice Bertaina ◽  
Pietro Merli ◽  
Concetta Quintarelli ◽  
Daniela Pende ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Median Time ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Suicide Gene ◽  
Grade Ii

Abstract Background: Haplo-HSCT after depletion of α/β T and B cells is a suitable and effective option for those children with acute leukemia (AL) who need an allograft and lacking an immediately available HLA-identical donor. With this approach, recipients can benefit immediately after transplantation from the anti-leukemia effect mediated by donor natural killer (NK) and γd T cells, which can also protect against infections. A further improvement of the results achievable with this platform could achieved with a faster adaptive T-cell immunity recovery, which play a key role to augment the graft-versus-leukemia effect and the capacity to fight infections. In light of these considerations, we designed a phase I/II trial aimed at testing the safety and efficacy of post-transplant infusion of donor-derived T cells transduced with the new iC9 suicide gene (BPX-501) in children with either malignant or non-malignant disorders (NCT02065869). Remarkably, after the activation and transduction with the retroviral iC9 construct, BPX501 cells switch the phenotype towards a preferential CD45RO pattern. Patients and methods: The phase I portion of the trial consisted of a classical 3+3 design with 3 cohorts, receiving escalating doses of BPX-501 cells of 2.5x105, 5x105, and 1x106 cells/kg, respectively. Patients included in the phase II portion were planned to receive the recommended dose identified during the phase I part of the study.Enrollment of patients started in December 2014; so far, 25 patients with AL in morphological complete remission (CR) have been enrolled. Twenty patients had acute lymphoblastic leukemia (ALL) and 5 acute myeloid leukemia (AML). Details on patient, donor and transplant characteristics are reported in table 1. All patients transplanted in CR1 had either poor cytogenetic/molecular characteristics or high levels of minimal residual disease at the end of induction therapy, both factors predicting a high relapse rate. All patients were given a fully myeloablative conditioning regimen (table 1). Before haplo-HSCT, children received rabbit anti-thymocyte globulin (ATG NEOVII, 12 mg/Kg over 3 days, from day -4 to day -2) to prevent both graft-versus-host disease (GvHD) and graft failure, and Rituximab (200 mg/ m2 on day -1) to prevent EBV-related lymphoproliferative disorders. No post-transplantation GvHD prophylaxis was administered. Results: All patients engrafted and no secondary graft failure was recorded. Median time to neutrophil and platelet recovery was 18 days (range 10-22) and 11 days (range 9-13), respectively. Once documented the engraftment of donor cells, BPX-501 T lymphocytes were infused at a median time of 17 days (range 13-52) after the allograft. Two patients were enrolled in the phase I portion of the study; one each received 2.5x105 and 1x106 cells/kg. The remaining 23 children were treated in the phase II, where the recommended dose was 1x106 cells/kg. However, since we did not observe any acute GvHD requiring the infusion of the dimerizing agent (Rimiducid/AP1903) activating iC9 gene in the first 15 children receiving 1x106 cells/kg, we decided to emend the protocol to further increase the BPX501 cell dose infused to 2 and 4x106 cells/kg. Thus, the last 6 patients were enrolled in these 2 last dose levels (3 patients each). Six and 3 patients developed grade II-IV acute and chronic GvHD, respectively. In one child, given 4x106 cells/kg, we infused rimiducid for steroid-resistant grade II skin acute GvHD, with complete resolution of the disease in 24 hours. The cumulative incidence of grade II-III acute and chronic GvHD are shown in figure 1A and B, respectively. Median follow-up of these 25 children is 8 months (range 1-19 months). One of them died due to chronic GvHD-associated bronchiolitis obliterans and one child with ALL transplanted in CR2 relapsed; the cumulative incidence of non-relapse mortality and leukemia recurrence are shown in figure 1C. The probability of disease-free survival at 15 months is 87% (figure 1D). Once infused, BPX501 cells expanded and persisted over time in both peripheral blood and bone marrow. Conclusion: Overall, these data indicate that the infusion of BPX-501 cells in children with AL given selectively manipulated haplo-HSCT results in low non-relapse mortality and chronic GvHD. Although the median observation time is still limited, the cumulative incidence of disease recurrence is promising. Table 1 Table 1. Figure 1 Figure 1. Disclosures Stanson: Bellicum pharmaceuticals: Employment. Moseley:Bellicum Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.

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