scholarly journals Safety and Efficacy of Aru-1801 in Patients with Sickle Cell Disease: Early Results from the Phase 1/2 Momentum Study of a Modified Gamma Globin Gene Therapy and Reduced Intensity Conditioning

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3970-3970
Author(s):  
Michael Grimley ◽  
Monika Asnani ◽  
Archana Shrestha ◽  
Sydney Felker ◽  
Carolyn Lutzko ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Research Funding ◽  
Drug Product ◽  
Phase 1 ◽  
Cell Disease ◽  
Reduced Intensity Conditioning ◽  
Renal Hyperfiltration ◽  
F Cells ◽  
Reduced Intensity

Abstract Introduction: Sickle cell disease (SCD) is a genetic red blood cell (RBC) disorder that causes chronic hemolytic anemia, progressive organ damage, and life-threatening acute complications such as painful vaso-occlusive crises. Allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning remains the only curative therapy for SCD but has several limitations including low donor availability and conditioning-related toxicity. Genetic modification of autologous hematopoietic system cells (HSCs) with reduced-intensity conditioning (RIC) using a high-potency drug product may address these limitations. ARU-1801 is a gene therapy that uses a modified γ-globin lentiviral vector to produce HbF G16D within autologous CD34+ HSCs. Preclinical studies in SCD mice have shown the G16D mutation enables γ-globin G16D to bind α-globin with higher affinity; lentiviral transfer of γ-globin G16D resulted in 1.5-2x more HbF per vector copy number (VCN) compared to analogous wild-type γ-globin vector. Early studies also suggested HbF G16D may be more potent for anti-sickling than HbF, lowering reticulocyte counts in SCD mice to a greater extent at similar protein levels. We hypothesize ARU-1801 with RIC could lessen toxicities and resource utilization relative to myeloablative approaches, allowing expanded access to gene therapy for a broader group of SCD patients. Updated data from patients in the ongoing Phase 1/2 study (NCT02186418) including laboratory and clinical markers of efficacy are presented here. Methods: Adults (18-45 years old) with severe SCD (defined by recurrent vaso-occlusive events [VOE] and acute chest syndrome) were screened for eligibility. Prior to ARU-1801 drug product (DP) infusion, all patients received a single IV dose of RIC melphalan (140 mg/m 2). Endpoints included measures of safety, engraftment, VCN, hemoglobin sub-fractions, and SCD-related outcomes. Patients were weaned off transfusions 3-6 months after DP infusion. Levels of anti-sickling globins (including HbF G16D) are presented as proportions of non-transfused total hemoglobin. Results: As of 28 July 2021, four patients (mean, 26 [19-35] years old) have been treated with ARU-1801 gene therapy for SCD with three patients followed for ≥12 months post-transplant. Transient neutropenia and thrombocytopenia were the predominant adverse events, lasting a median seven days each. There have been no other serious adverse events related to chemotherapy or ARU-1801 to date. At 36 months post-transplant, Patient 1 has shown stable HbF expression (27%) and 64% F-cells. Patient 2 has maintained 14% HbF and 37% F-cells at 36 months despite lower engraftment of ARU-1801 due to renal hyperfiltration (eGFR = 200 mL/min/1.73 m 2) at time of conditioning, which resulted in lower melphalan exposure. Both patients saw marked improvements in SCD manifestations, including 93% and 85% fewer annualized VOEs, respectively, in the two years after receiving ARU-1801 gene therapy compared to two years prior. Patient 3 received ARU-1801 manufactured with several process modifications (including improvements of HSC collection timing and lentiviral production) and has maintained 36% HbF at month 15 with pancellular distribution (96% F-cells). To date, Patient 3 has had no VOEs since ARU-1801 administration, representing 100% reduction from baseline. Conclusion: Amelioration of SCD phenotype and engraftment of ARU-1801 gene-modified HSCs is possible with a single RIC dose of melphalan, as demonstrated in three patients. The first patient shows 27% HbF expression at three years, and 93% reduction in VOEs. The second patient had lower HSC engraftment due to below-target melphalan exposure (likely caused by renal hyperfiltration), with 14% HbF and 5% HbA2 at three years. Nonetheless, an 85% reduction in VOEs in Patient 2 demonstrates significant clinical benefit. Dose-adjusted melphalan has the potential to improve engraftment in SCD patients with renal hyperfiltration. Following manufacturing process improvements, the third patient has shown the highest HbF (36%) at one year, the highest F-cells (96%), and no VOEs since receiving ARU-1801. ARU-1801, with RIC melphalan conditioning, is a promising alternative to myeloablative transplants for achieving durable responses with a favorable safety profile in patients with severe SCD. Longer follow-up and additional patients will be presented. Figure 1 Figure 1. Disclosures Asnani: Avicanna Ltd.: Research Funding; Aruvant Sciences: Research Funding. Lutzko: Aruvant Sciences: Patents & Royalties: preclinical vector development. Quinn: Forma Therapeutics: Consultancy; Emmaus Medical: Research Funding; Novo Nordisk: Consultancy; Aruvant: Research Funding. Lo: Aruvant Sciences: Current Employment. Little: Aruvant Sciences: Current Employment. Dong: Aruvant Sciences: Current Employment. Malik: Aruvant Sciences: Consultancy; Forma Therapeutics: Consultancy; Aruvant Sciences: Patents & Royalties; CSL Behring: Patents & Royalties. OffLabel Disclosure: Plerixafor was used for stem cell mobilization. Melphalan was used as chemotherapy conditioning prior to autologous transplant with ARU-1801

scholarly journals Early Results from a Phase 1/2 Study of Aru-1801 Gene Therapy for Sickle Cell Disease (SCD): Manufacturing Process Enhancements Improve Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Michael Grimley ◽  
Monika Asnani ◽  
Archana Shrestha ◽  
Sydney Felker ◽  
Carolyn Lutzko ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Safety Profile ◽  
Manufacturing Process ◽  
Research Funding ◽  
Phase 1 ◽  
Reduced Intensity Conditioning ◽  
F Cells ◽  
Favorable Safety ◽  
Reduced Intensity

Introduction: ARU-1801 is a gene therapy consisting of autologous CD34+ hematopoietic stem cells and progenitors (HSCPs) transduced with a lentiviral vector (LV) encoding a modified γ-globinG16D gene. Preclinical studies in SCD mice have shown that g-globinG16D binds α-globin with higher affinity; hence, the g-globinG16D LV produces 1.5-2x more HbF/vector copy number (VCN) than a g-globin LV. Preliminary studies also show greater reduction in reticulocytes in SCD mice expressing HbFG16D compared to those expressing the same level of HbF, suggesting that HbFG16D may have a more potent anti-sickling effect than HbF. We hypothesized a high potency anti-sickling globin would allow ARU-1801 to be effective with reduced intensity conditioning (RIC). RIC would result in lower toxicities and resource utilization compared to myeloablative approaches, allowing access of gene therapy to a broader group of SCD patients. We previously reported early data from patient 1 (P1) and 2 (P2) in the ongoing Phase 1/2 study (NCT02186418), who were treated with drug product (DP) from the initial ARU-1801 manufacturing process (Process I). We now present the long-term data on these patients and early data from P3, the first patient treated with our new manufacturing process (Process II). Methods: Adults with severe SCD, as defined by recurrent vaso-occlusive events (VOE) and acute chest syndrome deemed eligible were enrolled. Manufacturing process improvements in Process II included optimized timing of HSCP collection after plerixafor mobilization, LV production and improved HSCP transduction. Prior to DP infusion, all patients received a single dose of IV melphalan (140 mg/m2 BSA) and were weaned off transfusions 3-6 months after DP infusion. Patients were monitored for safety, engraftment, VCN, anti-sickling Hb (ASG) expression, and hematological and clinical manifestations of SCD. Levels of ASG (including HbFG16D) are presented as fractions of endogenous Hb. Results: As of 28 July 2020, data from 3 patients treated with ARU-1801 are available. P1 (34yr old) has HbSβ0- and P2 (24yr old) has HbSβ+ thalassemia (2-3% HbA). Both have 30 months (mo) post-transplant (PT) follow up. P3 (19yr old) has HbSS genotype with 6 mo PT follow up. ARU-1801 demonstrated a favorable safety profile with no treatment-related adverse events to date. Time to neutrophil engraftment (ANC ≥500) was 9, 7, and 7 days PT, and time to platelet recovery (Plt >50,000) was 12, 7, and 6 days PT, in P1, P2, and P3, respectively. Figure 1 shows HSPC dose, conditioning exposure and gene transfer; Figure 2 shows ASG over time. Using Process I, P1 has shown stable expression of 20% HbFG16D, 31% ASG and 31%à64% F-cells over 2.5 years, despite a low DP VCN of 0.2 and low HSPC dose of 1.4 x106 cell/kg. P2 received a higher cell dose of 7.1 x106 cell/kg with a DP VCN of 0.47 but had below target melphalan exposure, likely due to rapid clearance from hyperfiltration (GFR= 200 mL/min/1.73m2). Despite lower engraftment and HbFG16D level, P2 maintains stable total ASG of 22% at 30 mo due to a compensatory increase in HbF. Using Process II, P3 received DP of 6.8 x106 cells/kg with a VCN of 1.0, and demonstrated an engrafted VCN of 0.74, 71% F-cells and 91% F-reticulocytes at 6 mo. As P3 is being weaned off transfusions, HbFG16D is progressively rising, showing the selective advantage to HbFG16D-containing RBCs. P1 and P2 have maintained improvements in VOEs, no VOE in P3 so far (data will be presented). Conclusion: We show that engraftment of ARU-1801 and amelioration of disease is possible with RIC using IV melphalan, with persistent stable ASG expression and meaningful improvement in VOEs in P1 and P2. P1 shows stable HbFG16D and high ASG despite low, albeit stable VCN. P2 had lower HSCP engraftment, which we hypothesize was due to below target melphalan exposure. Nevertheless, significant clinical benefit was observed in P2 due to stable ASG of 22% at mo 30. It is likely that the presence of this amount of HbFG16D has provided enough ASG to prevent sickling/ineffective erythropoiesis, resulting in the preferential survival of HbF+HbFG16D-expressing RBC. Process II DP in P3 resulted in 2-4X higher engraftment of transduced HSCPs at 6 mo. Additional process enhancements are under development for future treated patients. ARU-1801, administered with RIC, holds significant promise for achieving durable responses with a favorable safety profile in patients with severe SCD. Disclosures Asnani: Aruvant Sciences: Research Funding; Avicanna Ltd.: Research Funding. Lutzko:Aruvant Sciences: Patents & Royalties: pre-clinical vector development. Lo:Aruvant Sciences: Current Employment. Little:Aruvant Sciences: Current Employment. McIntosh:Aruvant: Current Employment, Current equity holder in private company. Malik:Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy; Aruvant Sciences, CSL Behring: Patents & Royalties. OffLabel Disclosure: Plerixafor - stem cell mobiliziation Melphalan - chemotherapy conditioning pre autologous transplant with ARU-1801

Correction of Sickle Cell Anemia with γ-Globin Gene Delivered by Lentivirus Vector in the Setting of Myeloablative or Reduced Intensity Conditioning, and Establishing Critical Determinants for Successful Gene Therapy for Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2354-2354
Author(s):  
Ajay Perumbeti ◽  
Tomoyasu Higashimoto ◽  
Fabrizia Urbinati ◽  
Kristy Lauderback ◽  
Anastacia Loberg ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Lentivirus Vector ◽  
Reduced Intensity Conditioning ◽  
F Cells ◽  
Transplant Model ◽  
Reduced Intensity

Abstract While genetic delivery of recombinant anti-sickling β-globin genes have been shown to correct murine sickle cell anemia (SCA), correction of SCA by delivery of a natural hemoglobin, fetal hemoglobin (HbF), the proportion of genetically modified hematopoietic stem cells (HSC), or amount of HbF necessary to correct the disease is unknown. We designed a lentivirus vector carrying γ-globin exons with β-globin regulatory elements and non-coding sequences, GbG. First, GbG or mock transduced Berkeley sickle HSC were transplanted using a myeloablative (lethal irradiation) transplant model, to acheive full donor chimerism. GbG mice showed high HbF expression (HbF 41 ± 5% measured by HPLC) that was sustained in primary (6 mo) and secondary (7.5 mo) transplant recipients, and resulted in effective correction of hematological and functional RBC parameters, and reduction of inflammation that results from sickle cell disease. We found significantly reduced irreversibly sickled cells (2.3 ± 0.7% in GbG versus 10.2 ± 0.3% in mock mice; p<0.001), minimal sickling of RBC when exposed to graded hypoxia using tonometry, improved RBC deformability (performed by ektacytometry), and a four-fold increase in RBC half-life (by in vivo biotin labeling) in the GbG group of mice. There was correction of anemia, and reduction in hemolysis (measured by LDH levels), reticulocytes, and leukocytosis (Table 1). This was accompanied by a dramatic improvement in chronic organ damage that is seen in untransplanted Berkeley/mock group of mice: there was a significant reduction in spleen weights and normalization of splenic follicular architecture, correction in bone marrow myeloid:erythroid ratios, and a notable absence of kidney infarction and atrophy, and liver infarction and extramedullary hematopoiesis that was observed in mock mice. Untransplanted Berkeley and mock mice showed shortened survival consistent with a severe SCA phenotype. Genetic correction with GbG improved survival to 100% compared to a 20% survival in the mock transplanted. Notably, in our proof-of principle studies, comparable functional sickle RBC correction was also seen in the Townes knock-in sickle mice (Wu et al, Blood 2006) transduced with GbG. Myeloablative conditioning in this setting allowed non-competitive repopulation of donor genetically modified HSC, resulting in high HbF and correction of disease. However, myeloablation in SCA is associated with peri-transplant mortality and long-term effects, and may not be necessary for achieving correction of phenotype. To address this, we used a unique reduced-intensity conditioning transplant model. We transplanted GbG-modified Berkeley HSC into sub-lethally irradiated Berkeley mice. In this model, when HbF was <10%, there was a small and variable improvement in hematological and functional sickle RBC parameters. However, when HbF was γ10%, there was consistent long-term correction in RBC sickling, deformability, RBC survival, and improvement in hematological parameters for 10–11 months (Table 1). Impressively, when HbF was γ10%, there was a significant reduction in splenomegaly, absence of liver and kidney pathology, and a dramatically improved overall survival of the mice, comparable to that seen in the myeloablative model. Comparison of the proportion of F-cells (HbF containing RBC) and HbF/F-cell to the assays showing correction of SCA revealed that >30% HbF/F-cell and >60% F-cells consistently corrected SCA. The mean HSC transduction (assessed by secondary HbF+ CFU-S at 6 months post transplant) was 50% and 30% in the myeloablative and reduced intensity transplant models, respectively, with 1–3 GbG copies/ cell. Furthermore, three GbG mice showed correction of SCA with 20% HSC transduction, a clinically achievable goal. Taken together, this study is the first demonstration of correction of SCA with gene therapy using γ-globin, and defines critical determinants for effective gene therapy of this disease. Mouse Model Hb (g/dl) RBC 106/ul) Reticulocyte (%) WBC (K/ul) *p<0.05; ** p<0.001 Mock Myeloablative 7.6±0.7 5.8±0.4 40.0±3.0 29.7±1.4 GbG Myeloablative 10±0.8* 9.4±0.8** 15.8±3.2** 10.6±3.1** GbG, HbF ≥ 10% Reduced intensity 9.3±0.6* 8.1±0.5** 21.2±1.9** 13.4±1.1**

Results of a Two-Arm Phase II Clinical Trial Using Post-Transplantation Cyclophosphamide for Prevention of Graft-Versus-Host Disease in Haploidentical and Mismatched Unrelated Donors Hematopoietic Stem-Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 152-152 ◽  
Author(s):  
Sameh Gaballa ◽  
Isabell Ge ◽  
Riad O. El Fakih ◽  
Jonathan E. Brammer ◽  
Sa A. Wang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Equity Ownership ◽  
Reduced Intensity

Abstract Allogeneic stem cell transplantation offers curative therapy for many patients (pts) with high-risk hematologic malignancies. Donor availability remains a major limitation for many pts. The introduction of high-dose post-transplant cyclophosphamide (PTCy) has significantly improved the outcomes of pts undergoing haploidentical (HAPLO) stem cell transplants. The choice between a HAPLO or a one-antigen HLA mismatched unrelated donor (9/10 MUD) for pts lacking an HLA-matched donor remains unclear. Methods: We conducted a prospective non-randomized phase 2 clinical trial with two parallel arms, HAPLO (n=60) and 9/10 MUD (n=46) transplants, for pts with advanced hematologic malignancies or aplastic anemia who lacked an HLA-matched unrelated donor type at 10 loci (HLA-A, -B, -C, -DRB1, and -DQB1) using a MEL-based reduced-intensity conditioning regimen. The regimen included a single intravenous dose of MEL 140 mg/m2 (day -7), thiotepa 5 mg/kg (day -6), and four daily IV doses of fludarabine 40 mg/m2 (day -5 to day -2) (FM140). Thiotepa was intermittently available and was replaced by total body irradiation at a dose of 2 Gy on day -1. Pts >55 years (yr) old or with significant comorbidities received a lower MEL dose (100 mg/m2) (FM100). All pts with CD20-positive lymphoma received rituximab (375 mg/m2) on days -13, -6, +1 and +8. GVHD prophylaxis consisted of PTCy 50 mg/kg on day +3 and +4, and tacrolimus and mycophenolate for 6 and 3 months (mo), respectively. The stem cell source was unmodified bone marrow for both arms. Results: Patient characteristics are shown in Table 1. The median follow-up duration was 24 mo in the HAPLO arm and 29 mo in the 9/10 MUD arm. The cumulative incidence (CI) of neutrophil (ANC) recovery at day 45 was 95% and 98% in the HAPLO and 9/10 MUD arm, respectively. The median time to ANC recovery was 18 days in both arms; the median time to platelet recovery was 25 days in the HAPLO arm and 28 days in the 9/10 MUD arm. Primary graft failure developed in two pts in the HAPLO arm (one due to anti-donor HLA antibodies) and one patient in the 9/10 MUD arm. One pt in both arms developed mixed donor chimerism at day 100; otherwise, all pts in both arms achieved full (>95%) donor chimerism. Bone marrow was the graft source in all pts except 2 in the HAPLO arm and 8 in the 9/10 MUD arm who received a peripheral blood graft. The 1-yr overall and progression free survival were 70% and 60%, respectively, in the HAPLO arm (Fig. 1A) and 60% and 47%, respectively, in the 9/10 MUD arm (Fig. 1B). Day 100 CI of grade II-IV aGVHD and III-IV aGVHD were 28% and 3%, respectively, in the HAPLO arm versus 33% and 13%, respectively, in the 9/10 MUD arm; the 2-yr CI of chronic extensive GVHD was 13% and 14% in the two groups, respectively. The 1-yr CI of non-relapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, while the 1-yr relapse rate was 19% and 25% in the two groups, respectively. Conclusions: This study establishes PTCy, tacrolimus, and mycophenolate as an effective regimen for GVHD prevention in mismatched transplantation using both haploidentical and mismatched unrelated donor sources. Melphalan-based reduced-intensity conditioning is an effective regimen for a broad range of hematologic malignancies. Prospective randomized studies comparing haploidentical and unrelated donor sources are needed. Table 1. HAPLO (n=60) 9/10 MUD (n=46) Median Age, years (Range) 45 (20-63) 51 (20-64) Sex (M/F) 29/31 23/23 KPS ³90 53 (88%) 40 (87%) <90 7 (12%) 6 (13%) HCT-CI 0-3 50 (83%) 38 (83%) >3 10 (17%) 8 (17%) Disease Risk Index* Very high 5 (8%) 3 (7%) High 18 (30%) 15 (33%) Intermediate 29 (48%) 12 (26%) Low 8 (13%) 12 (26%) NA 0 4 (9%)** Conditioning Regimen FM100 20 (33) 18 (39%) FM140 40 (67%) 28 (61%) Diagnosis AML/MDS 33 (55%) 18 (39%) ALL 7 (11%) 5 (11%) Lymphoma 10 (17%) 13 (28%) Others 10 (17%) 10 (22%) Disease Stage Acute Leukemia CR1/CR2 24 (66%) 9 (56%) CR3 or higher/ CRpx 6 (17%) 5 (31%) Active disease 6 (17%) 2 (13%) Lymphoma CR 3 (30%) 8 (62%) PR 5 (50%) 3 (23%) Chemoresistant 2 (20%) 2 (15%) *Disease Risk Index by Armand et al; xCRp: Complete Remission with incomplete count recovery; **Patients had aplastic anemia. Figure 1. Figure 1. Disclosures Brammer: Celgene: Research Funding. Lee:Ziopharm: Equity Ownership; Cyto-Sen: Equity Ownership; Intrexon: Equity Ownership. Rezvani:Pharmacyclics: Research Funding. Alousi:Therakos, Inc: Research Funding.

Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

2022 ◽  
Author(s):  
Farid Boulad ◽  
Aurelio Maggio ◽  
Xiuyan Wang ◽  
Paolo Moi ◽  
Santina Acuto ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase 1 ◽  
Globin Gene ◽  
Reduced Intensity Conditioning ◽  
Phase 1 Trial ◽  
Reduced Intensity

Validation of BCL11A As Therapeutic Target in Sickle Cell Disease: Results from the Adult Cohort of a Pilot/Feasibility Gene Therapy Trial Inducing Sustained Expression of Fetal Hemoglobin Using Post-Transcriptional Gene Silencing

Blood ◽  
2019 ◽  
Vol 134 (Supplement_2) ◽  
pp. LBA-5-LBA-5 ◽  
Author(s):  
Erica B. Esrick ◽  
Maureen Achebe ◽  
Myriam Armant ◽  
Pablo Bartolucci ◽  
Marioara Felicia Ciuculescu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Research Funding ◽  
Lentiviral Vector ◽  
Cell Disease ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
F Cells ◽  
Post Infusion

BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at the gamma (γ)-globin locus (Sankaran et al., Science, 2008), and thus it represents an appealing therapeutic target for sickle cell disease (SCD). BCH-BB694 is a lentiviral vector (LVV) encoding a shRNA targeting BCL11A embedded in a microRNA scaffold (shmiR) allowing erythroid-specific knockdown to induce γ-globin expression and concomitantly and coordinately repress β-sickle globin expression (Brendel et al. JCI, 2016). In a pilot and feasibility gene therapy study we are evaluating the safety of infusion of BCH-BB694-transduced autologous CD34+ cells in patients with severe SCD. The study is an IND enabled and IRB approved open label, non-randomized, single center trial (NCT 03282656). We report here data from the full adult cohort which has completed enrollment with > 6 months of follow up in all patients. The adult cohort included three patients >/= 18 years old. Autologous CD34+ cells were collected by plerixafor mobilization and then transduced ex vivo with the BCH-BB694 shmiR lentiviral vector. Cell doses and vector copy number (VCN) are shown in the Table. After testing and release, gene modified cells were infused into subjects who had received busulfan conditioning. There were no Grade 3 or 4 AEs associated with mobilization, collection or infusion. All three adults (age 21-26 years old) demonstrated neutrophil engraftment on day +22 with adverse events consistent with busulfan conditioning. These patients are now 7, 9, and 17 months post infusion. One subject resumed red cell transfusions at 3 months due to pre-existing moyamoya using a pre-defined conservative trigger value of 40% sickle Hb in whole blood and will be detailed separately. There have been no adverse events related to the gene therapy product. VCN has been stable in bone marrow (BM) and peripheral blood (PB) in all cell lineages during the length of the study, with the latest time point studied at 15 months (BCL002) and ranged from 0.45-2.85 copies per cell in erythroid progenitor cells. BCL11A protein levels evaluated by immunoblot in subject BCL002 at 30 days (PB) and 6 months (BM) post-infusion showed highly effective and selective knockdown of BCL11A in erythroid progenitors with no reduction in BCL11A expression in B lymphoid cells. The number of HbF-containing cells (F cells) was assessed by flow cytometry and the kinetics of F cell production was remarkably similar in all subjects. The two untransfused subjects (BCL002 and BCL004) produced 70% F-cells in PB at 3 and 5 months, which has remained stable until the last point assayed (15 months and 7.5 months, respectively) (table). Calculated average HbF per F cell was >10pg in all subjects (table) and quantitative single cell HbF flow analysis showed the majority of F cells had >4pg F/cell, a level that is believed to prevent sickling under physiological oxygen saturation (Rakotoson et al., ASH 2017). In both untransfused subjects, total Hb remained stable with evidence of reduced hemolysis by reticulocyte count (slightly elevated) and LDH (normal in one subject, slightly elevated in the other). At the 3-month timepoint before re-starting transfusions, the subject with moyamoya (BCL003) had a pre-transfusion Hb of 11 g/dL with 76% of non-transfused cells containing on average 17pg F/F cell. For all subjects, we estimated the fraction of RBCs containing significant Hb sickle polymers and the amount of polymer in each sickled RBC at physiologic oxygen tension (where 50% of monomeric hemoglobin was oxygen saturated, or the P50) (Di Caprio et al. PNAS 2019, in press). The results for all 3 subjects in this adult cohort showed fewer RBCs with significant Hb polymer than two hydroxyurea-responsive treated comparators and significantly less Hb polymer per sickled RBC than a third highly responsive hydroxyurea-treated comparator. In conclusion, these data demonstrate successful and sustained engraftment in three adult patients treated with LVV-delivered shmiR technology targeting BCL11A. Early results suggest an acceptable safety profile, validation of BCL11A as effective target for HbF induction in humans with high numbers of F cells in circulation containing high levels of HbF per F cell, and mitigation of cellular pathology of SCD. Disclosures Achebe: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Bartolucci:Novartis: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Heeney:AstraZeneca: Research Funding; Micelle Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Research Funding; Ironwood / Cyclerion: Research Funding; Vertex / Crisper Therapeutics: Other: Data Safety Monitoring Board. Higgins:Sanofi: Consultancy, Research Funding. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Wood:Sanofi: Consultancy, Research Funding. Williams:Alerion Biosciences: Other: Co-founder; Novartis: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder, Patents & Royalties: Potential for future royalty/milestone income, X-SCID., Research Funding; bluebird bio: Patents & Royalties: Licensed certain IP relevant to hemoglobinopathies to bluebird bio. Received payment in the past bluebird bio through a BCH institutional licensing agreement and there is a potential for future royalty/milestone income from this agreement., Research Funding.

Stem cell transplantation after reduced-intensity conditioning for sickle cell disease

2013 ◽  
Vol 90 (4) ◽  
pp. 308-312 ◽  
Author(s):  
Susanne Matthes-Martin ◽  
Anita Lawitschka ◽  
Gerhard Fritsch ◽  
Thomas Lion ◽  
Brigitte Grimm ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Sickle Cell ◽  
Cell Disease ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Allogeneic Stem Cell Transplantation for MDS Patients More Than 70 Years of Age: a Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party (CMWP) of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4390-4390
Author(s):  
Silke Heidenreich ◽  
Dimitris Ziagkos ◽  
Anja van Biezen ◽  
Jürgen Finke ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Reduced Intensity Conditioning ◽  
Advisory Committees ◽  
Remission Status ◽  
Unrelated Donors ◽  
Karnofsky Index ◽  
Reduced Intensity

Abstract Introduction Myelodysplastic syndromes (MDS) are diagnosed at median age of 70 years. Allogeneic stem cell transplantation (HSCT) is the only curative treatment option, but with an increasing age, morbidity escalates. Treatment guidelines suggest HSCT for intermediate-II and high risk constellations up to the age of 65, and reduced intensity conditioning (RIC) regimens are commonly used up to 70 years of age. However, increasing life expectancy, availability of RIC regimens and good Karnofsky performance status (KPS) of MDS patients more than 70 years of age, has led to an increased use of HSCT. We performed a retrospective analysis to investigate results after HSCT for those patients and influence of KPS on outcome. Patients and methods We analyzed data of 345 patients in the EMBT database older than 70 years with MDS/sAML. The disease status at transplantation was available in 233 patients and most of the them were in more advanced stage of the disease: RA/RARS,RCMD (n=25) , RAEB (n=68) and RAEB-T/secondary acute leukemia (sAL, n=140). Donor were: related (n=88) and unrelated (n=257). Cytogenetic data were available only in 73 patients and classified as good (58), intermediate (6), poor (5) and very poor (4). Median follow up was 29.7 months. Median age at transplantation was 72 years (70-79 years) with 249 male and 96 female patients. KPS was defined in 300 cases, being 90-100% in 61% and 80% or less in 39%. Stem cell source was peripheral blood (94%) or bone marrow (6%). The intensity of the conditioning regimen was mainly reduced intensity (78%) rather than myeloablative (22%). Negative or positive CMV sero-status of the patient were seen in 35% and 65%, respectively. Results The number of HSCT for MDS patients of 70 years or more has increased over time. While 2000-2004 only 19 patients received transplantation, the following 3-year periods included 28 (2005-2007), 97 (2008-2010) and 200 (2011-2013) patients, respectively. The estimated 3-year OS was 33% (27-39%). A significant better 3 year OS in the univariate analysis was seen for Karnofsky (90-100%) vs 80% or less (41 vs 23%, p=0.008) and for CMV negative sero-status (46% vs 27%, p> <0.001) while disease status, remission status, intensity of the conditioning regimen, and donor source did not influence OS significantly. The cumulative incidence of relapse at 3 years was 40% (95% CI: 32-48) and significantly lower with unrelated than related donors (24% vs 43%, p =0.004). There was only a trend for a lower incidence of relapse after myeloablative conditioning in comparison to RIC (22% vs 31%, p=0.09), while remission status, T-cell depletion or disease stage did not influence the risk of relapse. The cumulative incidence of non-relapse mortality at 1 year was 36% (95% CI: 30-42) and significantly influenced by CMV sero-negativity of the recipient (22% vs 38%, p=0.02) and by Karnofsky index 90-100% (29% vs 34% and at 2 years: 32% vs 46%, p=0.01). A trend for lower NRM was seen for related donors (24% vs 35%, p=0.07) and after reduced intensity conditioning (29% vs 41%, p=0.09). No impact on NRM was seen for disease and remission status. In a multivariate analysis (MVA) significant factor for improved OS was Karnofsky index of 90-100% (HR 0.65: 95% CI: 0.48-0.88, p=0.001) and for worse survival CMV sero-positivity (HR 1.61; 95% CI: 1.15-2.21, p<0.001). For relapse the only significant factor was the use of unrelated donors (HR 0.50; 95% CI: 0.32-0.80, p=0.004). Significant factors for NRM in the MVA were Karnofsky index 90-100% (HR 0.63; 95% CI: 0.42-0.96, p=0.03), CMV sero-positivity of the recipient (HR 1.76; 95% CI: 1.12-2.76, p=0.001) and unrelated donors (HR 1.67; 95% CI: 0.16-2.76, p=0.04). Conclusion HSCT from related or unrelated donor after myeloablative or dose reduced intensity conditioning for advanced MDS patients 70-years and more is a curative treatment option with a 3-year OS of 33%. Good performance, determined by KPS, and sero-negativity for CMV in the patient increase the 3 year estimated overall survival to 41 and 46%, respectively. Disclosures Platzbecker: Boehringer: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Einsele:Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tischer:Sanofi-Aventis: Other: advisory board. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Glass:Roche, MSD, Takeda, Riemser, Ctilifesciences: Honoraria, Research Funding. Sill:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. de Witte:Novartis: Research Funding.

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