scholarly journals Effects of Alvelestat, an Oral Neutrophil Elastase Inhibitor, on Elevated Elastase and Collagen Turnover Biomarkers in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1815-1815
Author(s):  
Annie Im ◽  
Jacqueline Parkin ◽  
Noa G. Holtzman ◽  
William Moore ◽  
Lauren M. Curtis ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Neutrophil Elastase ◽  
Bronchiolitis Obliterans ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
Bronchiolitis Obliterans Syndrome ◽  
Collagen Turnover ◽  
Elastase Activity

Abstract Introduction Bronchiolitis Obliterans Syndrome (BOS) is a rare but devastating complication of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and is associated with a high morbidity and mortality. There is a dearth of treatment options for BOS and new strategies are needed. Airway neutrophilia is a hallmark of BOS, even in the absence of infection, and neutrophil elastase (NE) is an enzyme that has been implicated in the pathogenesis of BOS. We are conducting a phase 1b study of an oral NE inhibitor, alvelestat, in patients with BOS after HCT . Biomarkers, including the elastin breakdown peptides desmosine/isodesmosine (DES/IDES), and stimulated neutrophil elastase assess direct effect on NE activity. Neo-epitope by-products of collagen type 3 and 6 synthesis (PRO-C3 and PRO-C6) and degradation (C3M and C6M) are measured as biomarkers of fibrosis/tissue modelling Methods Patients age ≥18 years with BOS and chronic GVHD after HCT were recruited to the National Cancer Institute protocol (NCT02669251). This phase 1 study had 2 parts: 8-week intra-patient dose escalation period, followed by a continuation period that allowed for up to 6 months of treatment. Alvelestat was given orally starting at 60mg twice daily, increased every 2 weeks to 120mg twice daily, 180mg twice daily, and finally 240mg twice daily. Peripheral blood samples were collected at baseline and at the end of each dose-escalation stage. Plasma DES/IDES was measured by isotopic dilution liquid chromatography-tandem mass spectrometry (Huang et al Thorax 2012;67:502-508). Ex vivo zymosan stimulated neutrophil elastase activity was measured by ProteaseTag® immunoassay (ProAxsis Ltd, Northern Ireland). PRO-C3, PRO-C6, C3M and C6M were measured by competitive ELISA. (Nordic Biosciences, Denmark). Results are presented as Mean and Standard Error Mean (SEM). Results Between 2016 and 2018, 7 patients were enrolled (3 men and 4 women). Median FEV 1 after bronchodilator at time of enrollment was 44% predicted (range 38-74). All 7 patients were able to tolerate dose escalation of alvelestat up to the maximum dose 240mg twice daily. Preliminary clinical results were previously presented. DES/IDES was elevated at baseline (mean 0.464 (SEM 0.0508) ng/ml, with 6 of 7 subjects above the Upper Limit of Normal (ULN, 0.280 ng/ml)). Levels progressively declined during the dose escalation period to 0.380 (SEM 0.0419) ng/ml by week 8, representing a mean within subject % change from baseline (CFB) of -16.2% (SEM 6.794, Figure 1a) Ex vivo zymosan stimulated elastase activity also showed progressive decrease over the dose escalation period, with some subjects demonstrating 100% suppression (Figure 1b). Collagen synthesis as measured by PRO-C3 and PRO-C6 was increased above ULN at baseline and declined with alvelestat treatment (Figure 1c and 1d). There was no consistent change in collagen degradation biomarkers (C3M, C6M) There was consistency of a suppressive effect on biomarkers of elastase activity and collagen turnover in 6 of 7 treated patients, all of whom had improved or stable lung disease (ranging from change in FEV1 % predicted at end of treatment from +9% to -6%). Conclusion NE can damage lung tissue due to elastin breakdown, pro-inflammatory and pro-fibrotic effects (Sallenave J-M, J Leuk Biol 2015;98:137-139). This is the first evidence of elevated elastase activity as detected by elastin breakdown in patients with BOS and chronic GVHD. Treatment with the selective NE inhibitor, alvelestat was associated with progressive reduction of plasma desmosine levels over 8 weeks of within-subject dose escalation and reduction stimulated neutrophil elastase activity. The consistent suppression of elastase and of collagen synthesis/turnover biomarkers following alvelestat treatment is encouraging for its potential to impact progressive lung fibrosis in BOS and chronic GVHD. Disclosures Parkin: Mereo BioPharma Group: Current Employment. Moore: Mereo BioPharma Group: Current Employment. Pavletic: Center for Cancer Research: Research Funding; National Cancer Institute: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Actelion: Research Funding; Eli Lilly: Research Funding; Pharmacyclics: Research Funding; Kadmon: Research Funding.

scholarly journals Phase 1 Study of Alvelestat, an Oral Neutrophil Elastase Inhibitor, in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Annie Im ◽  
Noa G. Holtzman ◽  
Lauren M. Curtis ◽  
Laura Parsons-Wandell ◽  
Jeannette Nashed ◽  
...  
Keyword(s):  
Steady State ◽  
Dose Escalation ◽  
Bronchiolitis Obliterans ◽  
Hematopoietic Cell Transplantation ◽  
Phase 1 ◽  
Chronic Gvhd ◽  
Study Drug ◽  
Bronchiolitis Obliterans Syndrome ◽  
Phase 1 Study ◽  
Grade 3

Introduction Bronchiolitis Obliterans Syndrome (BOS) is a rare but devastating complication of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and is associated with a high morbidity and mortality. There is a dearth of treatment options for BOS and new strategies are needed. Airway neutrophilia is a hallmark of BOS, even in the absence of infection, and neutrophil elastase (NE) is an enzyme that has been implicated in the pathogenesis of BOS. We conducted a phase 1 study of an oral NE inhibitor, alvelestat, in patients with BOS after HCT. Methods Patients age ≥18 years with BOS and chronic GVHD after HCT were recruited to the National Cancer Institute protocol (NCT02669251). Patients had stable systemic immunosuppression and FEV1 ≥30% on pulmonary function tests (PFTs). This phase 1 study had 2 parts: 8-week intra-patient dose escalation period, followed by a continuation period that allowed for up to 6 months of treatment. Alvelestat was given orally starting at 60mg twice daily (the dose previously used in patients with chronic lung disease) and increased every 2 weeks as tolerated to 120mg twice daily, 180mg twice daily, and finally 240mg twice daily. Patients continued this dose until completion of the continuation phase, or occurrence of unacceptable toxicity, dose interruption >28 days, or progression of GVHD or BOS. Primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities. Secondary objectives included determining pharmacokinetics, markers of NE activity, and markers of inflammation in blood and sputum. PFTs and chronic GVHD evaluations were performed at baseline, 4 weeks and 8 weeks during the dose escalation period, and at 3 months and 6 months during the continuation period. Results Between 2016 and 2018, 7 patients were enrolled (3 men and 4 women). Median FEV1 after bronchodilator at time of enrollment was 44% (range 38-74). All 7 patients were able to tolerate dose escalation of alvelestat up to the maximum dose 240mg twice daily; MTD was not reached. The most common adverse events (AEs) that were possibly related to study treatment were all grade 2, and included increased creatinine (3 patients), ALT or AST elevation (3 patients), and upper respiratory infection (3 patients). The only grade 3 AEs that were possibly related to study drug were gastroenteritis and vomiting requiring hospitalization in 1 patient and pneumonia in 1 patient. Three patients completed the study with 8 weeks + 6 months of treatment. Four patients required dose interruptions, and only 1 of those required dose reduction for grade 3 gastroenteritis (resulting in dehydration and elevated creatinine). Four patients discontinued treatment prior to end of study: 2 patients had dose interruption of >28 days due to adverse events, 1 patient had a decline in FEV1 after pneumonia, and treatment was stopped in 1 patient due to investigator discretion. The median duration of treatment was 6.4 months. Based on NIH chronic GVHD consensus criteria, 6 patients had unchanged disease and 1 patient had progressive disease (decline in FEV1 after pneumonia). Although patients did not achieve the 10% improvement in FEV1 required for an organ response, 2 patients had improvement of 9% in FEV1 and 4 patients had improvement in the Lee chronic GVHD symptom scale lung score. Preliminary pharmacokinetic analyses of the 7 patients showed a linear dose-dependent increase in each exposure metric (steady-state trough and steady-state peak), despite some inter-patient variability. Bronchoalveolar lavage fluid and induced sputum samples are being analyzed for NE activity. Conclusion In this phase 1 study of the oral NE inhibitor, alvelestat, in patients with BOS after HCT, MTD was not reached and the study drug was well tolerated. Six patients had stable disease, while 1 patient had progression in the setting of pneumonia. Two patients notably had improvement in FEV1 of 9%, and 4 patients experienced improvement in symptoms. We have demonstrated that NE inhibition is well tolerated and shows a signal of stabilizing disease in patients with advanced BOS. Further study of the clinical efficacy of alvelestat in BOS after HCT is warranted, especially at an earlier stage of disease and longer duration of drug administration. Disclosures No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation From Combined Haploidentical Family Members and Unrelated Cord Blood (CB) Can Benefit High Risk Patients Lacking HLA-Identical Donors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3378-3378 ◽  
Author(s):  
Elizabeth Shima Rich ◽  
Andrew Artz ◽  
Theodore Karrison ◽  
Lucy A Godley ◽  
Olatoyosi Odenike ◽  
...  
Keyword(s):  
High Risk ◽  
Cord Blood ◽  
Median Time ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Blood Transplantation

Abstract Abstract 3378 Poster Board III-266 Introduction: Haploidentical-cord blood transplantation is a promising approach for patients (pts) who lack HLA donors and may improve rates of early engraftment while allowing long term cord blood reconstitution with low rates of GVHD. We enrolled 29 pts (17 AML/MDS, 4 ALL, 3 CML, 4 NHL/HL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 40 years (range, 4-67), and median weight was 75 kg (range, 14-125). Twenty-two (76%) pts had active disease at time of transplant; 6 had prior autologous transplants. 14 pts were Caucasian; 15 were other race or ethnicity. The haploidentical donor was the mother in 4; father in 3; child in 10; sibling in 10; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.51 × 106/kg (range, 1.25-10.95); CD3+ cells were 1.0 × 104/kg (range, 0.3-3.7). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 2 pts; 5/6 in 18 pts; 4/6 in 9 pts. Median cord total nucleated cells equaled 1.93 × 107/kg (range, 1.07-9.36); CD34+ cells were 0.08 × 106/kg (range, 0.03-0.75). The conditioning regimen for 18 pts was fludarabine (Flu) (30 mg/m2 on d-7 through -3), melphalan (Mel) (70 mg/m2 on d -3 and -2), and Thymoglobulin (rATG) (1.5 mg/kg on d-7, -5, -3, -1). Eleven pts received Flu, thiotepa (5 mg/kg on d -7 and -6), total-body irradiation (TBI) (12 Gy lateral opposed fields in 2 Gy fractions BID on d-3 through -1), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Engraftment: Two pts died early (sepsis, CVA). Three other pts failed to engraft with either haploidentical or CB and died of infection on d36, 43, and 63. One of these had anti-donor HLA antibodies. 24 pts engrafted with a median time to ANC >500/mL of 10 days (range, 9-31) and median time to sustained platelets >20,000/mL of 20 days (range, 15-63). In the majority of pts, early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. However, 3 pts had persistent hematopoiesis associated with only the haploidentical donor, while a fourth pt engrafted with only CB on day 31. Late graft failure and death from sepsis occurred in one of the patients with haploidentical engraftment. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0-100) on d14; 76% (range, 0-95) on d30; 6% (range, 0-87) on d100. Median unfractionated cord chimerism was <5% (range, 0-100) on d14; 20% (range, 0-100) on d30; 85% (range, 0-100) on d100. In the CD3+ compartment, median haploidentical chimerism was 95% (range, 0-100) on d14; 86% (range, 0-95) on d30; 6% (range, 0-79) on d100. Median CD3+ cord chimerism was 5% (range, 0-100) on d14; 26% (range, 0-100) on d30; 90% (range, 1-100) on d100. Toxicities and outcome: Other fatal toxicities included VOD (1), EBV-associated PTLD (1), ARDS (1), cardiac arrest (1), intractable seizures (1). Two patients developed TTP and later died of complications related to sepsis. Five pts relapsed of whom 4 have died. Acute GVHD (aGVHD) grade II occurred in 3 pts, one of whom developed the only case of chronic GVHD after failing to continue prograf. No aGVHD grade III-IV was seen. Twelve pts are currently alive; 11 are without disease. The median follow up for survivors is 186 days (range, 16-642). Estimated one year survival is 26% (95%CI, 6-46), and PFS is 19% (1-36). Conclusions: Combined haploidentical and CB transplantation results in early haploidentical engraftment followed by durable CB predominance in a majority of pts. The median times to neutrophil engraftment are considerably shorter - and the range narrower - than with other methods of cord blood transplantation. Early haploidentical engraftment failed in four patients; cord blood engraftment also failed in three of these pts and in three others. Rates of acute and particularly of chronic GVHD are low. Durable remissions can be achieved even in high risk pts regardless of age or remission status at the time of transplant. Disclosures: Rich: Genzyme: Research Funding. Odenike:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. van Besien:Genzyme: Research Funding.

The Role of In Vivo T-Cell Depletion On Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation From HLA-Identical Siblings in Patients with Follicular Lymphoma: An European Blood and Marrow Transplantation Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3375-3375
Author(s):  
Julio Delgado ◽  
Carme Canals ◽  
Michel Attal ◽  
Kirsty Thomson ◽  
Antonio Campos ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Alkylating Agent ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Off Label ◽  
Reduced Intensity

Abstract Abstract 3375 Poster Board III-263 Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (Allo-HCT) has become a feasible and effective therapeutic approach for younger patients with relapsed or refractory follicular lymphoma (FL). However, there is still much debate regarding the most appropriate conditioning regimen or whether the use of in vivo T-cell depletion (TCD) is beneficial or not for these patients. We analyzed the outcome of 164 patients with advanced FL reported to the EBMT from 1999 to 2007, who underwent RIC Allo-HCT conditioned with fludarabine plus an alkylating agent. Donors were HLA-matched siblings in all cases. Patients receiving transplants from alternative donors or conditioned with other agents were specifically excluded. The alkylating agent was melfalan in 48% of cases, busulfan in 32% and cyclophosphamide in 20%. Forty-six patients (28%) received anti-thymocyte globulin (ATG), 41 (25%) received alemtuzumab and 77 (47%) did not receive TCD in vivo. Median age at transplantation was 50 (range 29-64) years, and patients receiving alemtuzumab were significantly younger [45 (33-63)] than those receiving ATG [52 (29-64)] or no TCD [50 (32-64)], P = 0.05. There were no other differences among groups in terms of disease stage or presence of bulky masses at diagnosis, interval from diagnosis to HCT, number of prior therapies, or disease status at HCT. Engraftment was observed in 161 (98%) patients, with no significant differences among groups. Median follow-up was 43 (1–110) months for survivors. At three years, non-relapse mortality (NRM), relapse rate (RR), progression-free survival (PFS) and overall survival (OS) were 17% (95% CI 12-24%), 23% (17-31%), 60% (52-68%) and 75% (67-82%), respectively, for the entire cohort. The incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher for patients not receiving any TCD (31%) compared to TCD patients (18%), P = 0.05, and the incidence of chronic GVHD at one year was also significantly higher for the former compared to the latter group (68% vs. 25%, P < 0.001). There were no significant differences in NRM among groups, but there was a trend towards a higher RR in patients receiving alemtuzumab (40%) or ATG (24%) compared to patients receiving no TCD (16%) (P = 0.15), which translated into a trend towards a significantly shorter 3-year PFS for the alemtuzumab group (42% vs. 69%; P = 0.18). However, there were no differences in the 3-year OS among groups, which was 77% for patients receiving alemtuzumab, 73% for those receiving ATG and 77% for patients not receiving any TCD. In conclusion, results with RIC Allo-HCT from HLA-identical siblings were very promising for patients with advanced FL. Both alemtuzumab and ATG were effective in reducing acute and chronic GVHD, but had no significant impact on NRM. There was a trend towards a shorter PFS for patients receiving alemtuzumab, which did not translate into a significantly different OS. Disclosures: Delgado: Bayer Schering Pharma: Consultancy, Research Funding; Genzyme: Research Funding. Off Label Use: The use of alemtuzumab as a T-cell depleting agent in the context of hematopoietic transplantation is considered off-label.

Dose Dependent Enhancement Of Neutrophil Recovery By Infusion Of Notch Ligand Ex Vivo Expanded Cord Blood Progenitors: Results Of a Multi-Center Phase I Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 297-297 ◽  
Author(s):  
Colleen Delaney ◽  
Filippo Milano ◽  
Ian Nicoud ◽  
Shelly Heimfeld ◽  
Chatchada Karanes ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Ex Vivo ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Neutrophil Recovery ◽  
Cd34 Cells ◽  
Primary Graft Failure

Abstract Introduction There is a strong clinical need to overcome the increased early non relapse mortality (NRM) associated with delayed neutrophil recovery following cord blood transplant (CBT). Therefore we established a methodology using Notch ligand (Delta1) as a strategy for increasing the absolute number of marrow repopulating CB hematopoietic stem/progenitor cells (HSPC). We previously reported preliminary results of the first 10 patients in 2010 demonstrating the ability of Notch-expanded CB HSPC to provide rapid myeloid recovery post-CBT.1 Herein we present the updated results on 23 patients accrued to this trial aimed at assessment of efficacy as well as the feasibility of overnight shipment of the expanded cell product to three outside institutions. Methods Between July 2006 and March 2013, 23 patients with hematologic malignancies were enrolled in this prospective multi-center Phase I trial coordinated by the Fred Hutchinson Cancer Research Center in which one CB unit was ex vivo expanded prior to infusion. Conditioning consisted of Fludarabine (75mg/m2), Cyclophosphamide (120mg/kg) and TBI (13.2 Gy) over 8 days. On day 0, the unmanipulated CB unit was infused first followed 4 hours later by infusion of the freshly harvested expanded CB cells. Graft versus host disease (GVHD) prophylaxis consisted of cyclosporine and MMF beginning on day -3. All CB grafts were 4-6/6 HLA-matched (A/B antigen level, DRB1 allele level) to the recipient. Engraftment, NRM, relapse and GVHD were calculated using cumulative incidence rates to accommodate competing risks. Overall survival was analyzed using Kaplan-Meier estimates. Results Patient diagnosis was AML (n=16), ALL (n=5) and biphenotypic leukemia (n=2). Nine patients (39%) were ≥CR2 and 5 were MRD+ at the time of transplant. Median age was 28 years (range, 4-43) and weight 70 kg (range, 16-91) with a median follow-up of 614 days (range, 271-2443). 22 patients received the expanded graft with one product not meeting release criteria. The cell doses infused were significantly higher in the expanded CB graft: 2.7 (1.5-6.3) vs 6.9 (0.4-27.6) x107 TNC/kg, p<0.0008; 0.15 (0.02-0.57) vs 7.7 (0.62-49.5) x106 CD34/kg, p<0.0001. HLA-matching and ABO incompatibility of the expanded and unmanipulated products were similar. The incidence of neutrophil recovery was 95% (95% CI, 71-100) at a median of 13 days (range, 6-41 days) among the 22 patients receiving expanded CB cells which is significantly faster than that observed in 40 recipients of two unmanipulated units otherwise treated identically at a median time of 25 days (range, 14 to 45; p<0.0001). The incidence of platelet recovery (>20 x 10^9/L) was 77% (CI 95%: 53- 89) by day 100 at a median of 38 days (range, 19 – 134). There was one case of primary graft failure. Importantly, rate of neutrophil recovery correlated with CD34+ cell dose/kg with 8 out of 11 patients receiving greater than 8x106 CD34+cells/kg achieved an ANC ≥ 500/µl within 10 days. 21 patients were evaluable for in vivo persistence of the expanded cells. Ten (48%) demonstrated in vivo persistence beyond one month post infusion. The expanded cell graft was persistent at day 180 in 7 patients, and in those that survived to one year, dominance of the expanded cell graft persisted in one patient. The incidences of grade II-IV and III-IV acute GVHD was 77% (95% CI, 53-89) and 18% (95% CI, 5-36%), respectively; mild chronic GVHD was observed in 4 patients and severe chronic GVHD in one. Probability of OS was 62% (95% CI, 37-79%) at 4 years. Notably, the cumulative incidence of NRM at day 100 was 8% (95% CI, 14-24%) and at 4 years was 32% (95% CI, 8-40%). Nine patients died at a median time of 216 days (range, 31-1578 days) with respiratory failure/infection the most common cause (n=6). There were two relapses at day 156 and 365 post-transplant, with one death due to relapse. Secondary malignancy and primary graft failure were the other 2 causes of death. Conclusions Infusion of Notch-expanded CB progenitors is safe and effective, significantly reducing the time to neutrophil recovery and risks of NRM during the first 100 days. An advantage for infusion of higher numbers of CD34+ cells/kg further demonstrates the need to develop methods that reproducibly provide even greater expansion of repopulating cells than currently achieved to improve efficacy and potentially cost effectiveness. 1. Delaney C, et al, Nat Med. 2010 Feb;16(2):232-6. Disclosures: Delaney: Novartis: DSMB, DSMB Other; Biolife: Membership on an entity’s Board of Directors or advisory committees; medac: Research Funding. Wagner:Novartis: Research Funding; cord use: Membership on an entity’s Board of Directors or advisory committees.

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