Outcomes for Initial Patient Cohorts with up to 33 Months of Follow-up in the Hgb-206 Phase 1 Trial

Abstract Background Sickle cell disease (SCD) is a progressively debilitating genetic disease causing significant morbidity and early mortality for which a universal curative therapy is lacking. Expression of an anti-sickling β-globin via gene transfer into hematopoietic stem cells (HSCs) may reduce or eliminate SCD symptoms. LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin in adults with severe SCD is being evaluated in the ongoing multi-center Phase 1 study HGB-206 (NCT02140554). The first 7 patients (Group A) received DP from bone marrow harvested (BMH) HSCs and demonstrated stable but sub-optimal gene therapy-derived hemoglobin (HbAT87Q). The protocol was amended to include pre-harvest transfusions, increased target busulfan levels and a refined DP manufacturing process (Group B). The study is now enrolling patients in Group C, treated under modified protocol and including DP manufactured from plerixafor-mobilized HSCs. Data from patients in fully enrolled Groups A and B are shown here. Methods Patients ≥18 years old with severe SCD, as previously described, were enrolled. CD34+ cells from BMH were transduced with the BB305 LVV to produce LentiGlobin DP. Following myeloablative busulfan conditioning, patients were infused with DP. Group A patients received DP from the original manufacturing process. One Group B patient (1313) received DPs from a combination of original and refined manufacturing processes, while the other (1312) was entirely from the refined process. Adverse events (AEs), engraftment, vector copy number (VCN) in peripheral blood (PB), Hb fractions, and hemolysis markers were monitored. Results Nine patients (7 Group A, 2 Group B) with severe SCD (median age 26 [min - max: 18 - 42] years) were treated with LentiGlobin gene therapy. DP characteristics are shown in Table 1 and were improved in Group B patients, with higher VCNs, cell doses and % transduced cells compared to Group A. As of May 15, 2018, all Group A patients had completed ≥2 years follow-up and enrolled in a long-term follow-up study. Median follow-up was 24.2 (min - max: 22.8 - 32.9) months in Group A; 14.3 and 8.5 months for Group B patients 1313 and 1312. All patients engrafted. The toxicity profile was consistent with myeloablative conditioning. Serious AEs were reported in 8 patients; vaso-occlusive pain (n=5) was most common. No grade ≥3 DP-related AEs and importantly, no evidence of graft failure, veno-occlusive liver disease, replication competent lentivirus or clonal dominance were observed. All patients demonstrate stable PB VCN and HbAT87Q levels over prolonged follow-up. In Group A, PB VCN and HbAT87Q levels were modest, with a median of 0.1 c/dg and 0.8 g/dL at last visit, respectively (Table 1). Unsupported total Hb in 6/7 patients (1 patient is on transfusions) ranged from 7.1 - 11.4 g/dL. Total bilirubin and lactate dehydrogenase (LDH) at last visit vs. baseline decreased by a median of 46% (n=7) and 24% (n=6), respectively, while reticulocyte count increased by a median of 8% (n=7). With modest HbAT87Q production the annualized vaso-occlusive events (VOEs) rate decreased 17 - 100% compared to the 2-years pre-DP infusion (n=6; Figure 1). PB VCN and HbAT87Q in Group B patients were improved (Table 1). Total Hb at last visit was 11.0 g/dL in patient 1313 (29% HbAT87Q). In patient 1312, who received DP entirely from refined manufacturing, total Hb was 12.8 g/dL, with HbAT87Q contributing 56%. Total bilirubin and LDH normalized in both Group B patients, reticulocyte count decreased in patient 1312 (Table 1). Changes in VOE rates will be presented. Summary In the initial HGB-206 cohorts (Groups A and B), the safety profile of LentiGlobin gene therapy observed to date, is consistent with myeloablative busulfan conditioning. While HbAT87Q levels in Group A are sub-optimal, they are stable through ≥2 years of follow-up and most patients show a decrease in VOEs, suggesting that even modest HbAT87Q production may improve the clinical status of patients with SCD. Patients in Group B had improved DP characteristics, increased PB VCN and HbAT87Q levels with normalization of Hb in 1 patient and normalization of LDH and total bilirubin in both. Improvements in DP manufacturing correlate with increased levels of therapeutic HbAT87Q and could lead to significant clinical benefit. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancilio: Research Funding; Pfizer: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kwiatkowski:bluebird bio: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Novartis: Research Funding. Mapara:Incyte: Consultancy. Schmidt:German Cancer Research Center: Employment; bluebird bio: Consultancy; GeneWerk GmbH: Employment. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Walters:bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director; Sangamo Therapeutics: Consultancy. Thompson:La Jolla Pharmaceutical: Research Funding; Biomarin: Research Funding; Novartis: Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Baxalta/Shire: Research Funding.

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Exploring the Drivers of Potential Clinical Benefit in Initial Patients Treated in the Hgb-206 Study of Lentiglobin for Sickle Cell Disease (SCD) Gene Therapy

Blood ◽

10.1182/blood-2019-128814 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2061-2061 ◽

Cited By ~ 2

Author(s):

Mark C. Walters ◽

John F. Tisdale ◽

Janet L. Kwiatkowski ◽

Lakshmanan Krishnamurti ◽

Markus Y. Mapara ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Benefit ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Group A ◽

Equity Ownership ◽

Grade 3 ◽

Group B

Background LentiGlobin for SCD gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti-sickling substitution (T87Q). Its safety and efficacy are being studied in the ongoing multi-center Phase 1/2 HGB-206 trial (NCT02140554). Initial patients received LentiGlobin drug product (DP) using bone marrow-harvested (BMH) CD34+ HSCs transduced with the BB305 LVV under original manufacturing. All patients had successful engraftment but levels of gene therapy-derived hemoglobin (HbAT87Q) were lower than expected. Despite this, hemolysis markers and the annualized rate of vaso-occlusive crisis (VOCs) plus acute chest syndrome (ACS) were reduced post-infusion. Here, we provide an update on these patients and explore factors that may contribute to the clinical benefit. Data on patients treated more recently are presented separately. Methods Adults with SCD-related complications (previously described) were enrolled in HGB-206. All patients received myeloablative busulfan conditioning before DP infusion. The initial group (Group A; N=7) was treated with DP from BMH HSCs using the original LentiGlobin manufacturing process. The protocol was amended, and 2 patients were subsequently treated in Group B with DP from BMH HSCs. Patient 1 had DP made with original and refined manufacturing processes and patient 2 had DP made only with the refined process. Patients were followed for 2 years in HGB-206 and offered participation in the LTF-303 study for long-term follow-up. Adverse events (AEs), Hb fractions, and additional laboratory and clinical parameters were monitored. Results As of 7 March 2019, the median follow-up post-DP infusion was 35.8 (min-max: 29.8-44.5) months in Group A; it was 17.2 and 20.2 months for Group B patients 1 and 2. There was full hematological recovery with no graft failure. The safety profile of LentiGlobin post-DP infusion was consistent with myeloablative busulfan conditioning and underlying SCD. No cases of Grade ≥ 3 DP-related AEs, veno-occlusive liver disease, vector-mediated replication competent lentivirus or clonal dominance were observed. Three years after LentiGlobin gene therapy, one Group A patient developed myelodysplastic syndrome, reported as unlikely related to LentiGlobin. The patient subsequently received an HLA-haploidentical donor transplant. The annualized rate of VOCs plus ACS from LentiGlobin infusion to last follow-up was reduced by a median of 89 (min-max 10-100) % compared to that in the 2-year interval before enrollment in the 8 patients who had a history of VOC and/or ACS. One Group A patient who had a stroke pre-DP infusion has not had any red blood cell (RBC) transfusions through ~3 years post-DP infusion and no stroke recurrence. Median HbAT87Q levels were 1.0 (min-max 0.7-2.8) g/dL for Group A and 3.4 g/dL for Group B patient 1 at last visit and were stable for up to 3.5 years follow-up (Figure 1A). In several patients, HbF levels increased post-LentiGlobin treatment, peaking at ~2-6 months, and remaining higher at last visit compared to 1-month post-DP infusion. At last visit, the median HbF level was 0.6 (min-max 0.1-1.8) g/dL for all Group A and 0.8 g/dL for Group B patient 1 (Figures 1B and 2). In these patients, the median fraction of anti-sickling Hb (HbAT87Q + HbF + HbA2) was 22.9 (min-max 14.2-29.8) % and 39.4%, respectively. Patient 2 in Group B, who had DP made entirely using refined manufacturing process, had no HbF but produced high levels of HbAT87Q (7.5 g/dL) that contributed to 53.7% of total Hb. Summary In the HGB-206 Group A patients, the modest expression of gene therapy-derived HbAT87Q is accompanied by an induction of HbF. Elevated HbF levels have been shown to be associated with reduced severity of SCD. The resulting 14-30% of anti-sickling Hb observed in Group A patients, while not likely to be curative, showed clinical benefit as suggested by a reduction in the annualized rate of VOC plus ACS. Further, Group A and B patients have maintained HbAT87Q production, demonstrating the durability of gene therapy-derived β-globin gene expression. There have been no Grade ≥ 3 DP-related AEs in LentiGlobin-treated patients with up to 3.5 years of follow-up. Longer follow-up will help determine whether the initial induction of HbF, as is common after myeloablation, will be sustained and continue to contribute to therapeutic anti-sickling Hb levels. Disclosures Walters: Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy. Kwiatkowski:Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Terumo: Research Funding; Novartis: Research Funding. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller:bluebird bio, Inc.: Employment, Equity Ownership. Pierciey:bluebird bio, Inc.: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Kanter:Rockpointe: Honoraria; GLG: Consultancy; Guidepoint Global: Consultancy; Novartis: Consultancy, Honoraria; Imara: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Medscape: Honoraria; Peerview: Honoraria; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; Jeffries: Consultancy; Cowen: Consultancy. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding.

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Current Results of Lentiglobin Gene Therapy in Patients with Severe Sickle Cell Disease Treated Under a Refined Protocol in the Phase 1 Hgb-206 Study

Blood ◽

10.1182/blood-2018-99-113480 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1026-1026 ◽

Cited By ~ 11

Author(s):

John F. Tisdale ◽

Julie Kanter ◽

Markus Y. Mapara ◽

Janet L. Kwiatkowski ◽

Lakshmanan Krishnamurti ◽

...

Keyword(s):

Gene Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership ◽

Grade 3

Abstract Background β-globin gene transfer has the potential for substantial clinical benefit in patients with sickle cell disease (SCD). LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin gene therapy is being evaluated in the ongoing Phase 1 HGB-206 study (NCT02140554). Results in the initial 7 patients treated with LentiGlobin DP from steady state bone marrow harvested (BMH) HSCs using original DP manufacturing process (Group A) demonstrated stable HbAT87Q production in all patients, but at levels below the anticipated target. The protocol was thus amended to include pre-harvest RBC transfusions, optimize myeloablation by targeting higher busulfan levels, and use a refined DP manufacturing process (Group B); additionally, HSC collection by plerixafor mobilization/apheresis was instituted (Group C). Data from patients in Group C, treated under the modified protocol with DPs manufactured from plerixafor-mobilized HSCs using the refined process, are reported here. Results in patients in Groups A and B are reported separately. Methods Patients with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Patients in Group C received ≥2 months of transfusions to reach Hb of 10 - 12 g/dL and <30% HbS before HSC collection. Patients received 240 μg/kg of plerixafor 4 - 6 hours before HSCs were collected by apheresis and CD34+ cells were transduced with the BB305 LVV at a central facility. Following myeloablative conditioning with busulfan, the DP was infused, and patients were monitored for adverse events (AEs), engraftment, peripheral blood (PB) vector copy number (VCN), HbAT87Q expression, and HbS levels. Summary statistics are presented as median (min - max). Results As of 15 May 2018, 11 Group C patients (age 25 [18 - 35] years) had undergone mobilization/apheresis, 9 patients had DP manufactured (median 1 cycle of mobilization [1 - 3]) and 6 patients had been treated. Cell dose, DP VCN and % transduced cells in the 6 treated patients were: 7.1 (3 - 8) x 106 CD34+ cells/kg, 4.0 (2.8 - 5.6) copies/diploid genome (c/dg) and 81 (78 - 88) % transduced cells. The median follow-up was 3.0 (1.2 - 6.0) months. Patients achieved neutrophil engraftment at a median of 19 (18 - 20) days. Platelet engraftment was achieved at a median of 28 (12 - 64) days in 4 patients; platelet engraftment was pending in 2 patients. Two of 11 patients experienced 4 grade ≥3 AEs associated with plerixafor mobilization/HSC collection: 1 had vaso-occlusive pain and hypomagnesaemia, and the other had vaso-occlusive pain and non-cardiac chest pain. The toxicity profile from DP infusion to last follow-up in the 6 treated patients was consistent with myeloablative conditioning. Febrile neutropenia (n=5) and stomatitis (n=4) were the most common non-hematologic grade ≥3 AEs. Serious AEs were reported in 3 patients post-DP infusion: splenic hematoma, non-cardiac chest pain and mucosal inflammation. To date, there have been no DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. In the 6 treated patients, PB VCN at last visit ranged from 1.4 - 2.9 c/dg. In the 3 patients with 3 months follow-up, total Hb levels were 11.7 g/dL, 9.8 g/dL and 9.2 g/dL, and HbAT87Q levels were 4.7 g/dL, 3.2 g/dL and 3.5 g/dL. One additional patient with 6 months follow-up was off transfusions and had total Hb of 14.2 g/dL, of which 62% (8.8 g/dL) was vector-derived HbAT87Q and 36% (5.1 g/dL) was HbS. All 4 patients had HbAT87Q (median 39%) levels higher than or equal to HbS (median 31%) at the 3-month visit. Summary HGB-206 protocol changes and refined DP manufacturing have improved the LentiGlobin DP characteristics resulting in significantly improved outcomes. In addition, the HbAT87Q expression is comparable to, or exceeds, HbS levels as early as 3 months post DP infusion. These data support the feasibility of plerixafor-mediated CD34+ cell collection in patients with severe SCD and the efficacy of gene therapy. The safety profile of LentiGlobin gene therapy remains consistent with single-agent busulfan conditioning. Additional data and longer follow-up will determine the clinical effect of increased HbAT87Q/HbS ratios. Disclosures Kanter: Global Blood Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees. Mapara:Incyte: Consultancy. Kwiatkowski:Novartis: Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:Amgen: Research Funding; Celgene: Research Funding; Baxalta/Shire: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding; Biomarin: Research Funding; La Jolla Pharmaceutical: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

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Results from the Completed Hgb-205 Trial of Lentiglobin for β-Thalassemia and Lentiglobin for Sickle Cell Disease Gene Therapy

Blood ◽

10.1182/blood-2019-127393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3358-3358 ◽

Cited By ~ 3

Author(s):

Elisa Magrin ◽

Michaela Semeraro ◽

Alessandra Magnani ◽

Hervé Puy ◽

Annarita Miccio ◽

...

Keyword(s):

Gene Therapy ◽

Board Of Directors ◽

Research Funding ◽

Weighted Average ◽

Employment Equity ◽

Advisory Committees ◽

Long Term Follow Up ◽

Equity Ownership

Background LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding human β-globin with a T87Q substitution. This substitution confers anti-sickling properties to the gene therapy-derived hemoglobin (HbAT87Q) and allows for its quantification in transduced HSCs. The proof of concept for LentiGlobin gene therapy in patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) was established in the recently completed HGB-205 study (NCT02151526). Herein, we provide the safety and efficacy outcomes and long-term follow-up data for all 7 treated patients, 4 with TDT and 3 with SCD. Methods Patients 5−35 years old with TDT (≥ 100 mL/kg of packed red blood cells [pRBCs]/year) or severe SCD (e.g., ≥ 2 acute chest syndromes [ACS] or ≥ 2 vaso-occlusive crises in the preceding year or the year before regular transfusions) were enrolled. CD34+ HSCs were obtained by mobilization and apheresis in patients with TDT or by bone marrow harvest in patients with SCD. Following collection, cells were transduced with the BB305 LVV. Patients underwent busulfan myeloablative conditioning and were infused with transduced cells. Patients were monitored for engraftment, adverse events (AEs), HbAT87Q levels, and other hematologic and clinical parameters. After 2 years in HGB-205, patients transitioned into the long-term follow-up study, LTF-303 (NCT02633943). Summary statistics are shown as median (min-max). Results As of June 2019, patients with TDT (n=4) and SCD (n=3) had a median follow-up of 49.6 (40.5-60.6) and 28.5 (25.5-52.5) months, respectively. Table 1 shows patient and drug product characteristics and several key efficacy outcomes. All patients achieved HSC engraftment. LentiGlobin safety profile was consistent with busulfan myeloablative conditioning and, in case of SCD, with the underlying disease state. The most common non-hematologic Grade ≥ 3 AEs post-LentiGlobin gene therapy (≥ 2 patients) for patients with TDT were stomatitis (n=4) and increased aspartate aminotransferase (n=2), and for patients with SCD were ACS (n=2) and vaso-occlusive pain (n=2). In all 4 patients with TDT, total Hb and HbAT87Q levels remained generally stable up to 5 years post-LentiGlobin infusion. Three of 4 patients achieved transfusion independence (TI; defined as weighted average Hb ≥ 9g/dL without pRBC transfusions for ≥ 12 months), for an ongoing duration of 56.3 (38.2-57.6) months. Weighted average total Hb during TI was 11.4 (10.5-13.0) g/dL. One patient has been off transfusions for 37.5 months and had total Hb of 7.7 g/dL, which was below the ≥ 9 g/dL requirement to meet the protocol definition of TI. At last visit, HbAT87Q levels in these 4 patients ranged from 6.2-11.2 g/dL, which contributed 73.8-86.8% of the total Hb. The first patient treated with LentiGlobin for SCD experienced one vaso-occlusive pain episode, which developed at 30 months after LentiGlobin gene therapy following a case of acute gastroenteritis with fever and dehydration. The second SCD patient had 2 serious AEs (SAEs) of ACS approximately 6 and 8 months after LentiGlobin gene therapy. The patient resumed chronic pRBC transfusions and hydroxyurea treatment and subsequently experienced 2 SAEs of vaso-occlusive pain; no additional SAEs of vaso-occlusive pain or ACS were reported during the last 16 months of follow-up after LentiGlobin infusion. The third SCD patient had no episodes of vaso-occlusive pain or ACS during 25.5 months of follow-up post-LentiGlobin gene therapy as of the data cut-off. Two patients with SCD who have been off chronic pRBC transfusions, showed improvement in hemolysis markers post-LentiGlobin treatment and stabilization of HbAT87Q expression at approximately 6 months post-LentiGlobin infusion. Total Hb levels for patients with SCD at last visit were 13.0 g/dL (patient 1), 9.4 g/dL (patient 2), and 9.8 g/dL (patient 3), with corresponding HbAT87Q contributions of 47.9%, 7.9%, and 25.8%, respectively. Summary With up to 5 years of follow-up, treatment with LentiGlobin gene therapy was well tolerated and resulted in improvement in hematologic parameters and disease-related symptoms. Further results from the completed study will be presented. Disclosures Hermine: Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding. Brousse:bluebird bio, Inc: Consultancy; AddMedica: Consultancy. El Nemer:Hemanext: Other: Other. 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; 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; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees. Asmal:bluebird bio, Inc: Employment, Equity Ownership. Whitney:bluebird bio, Inc: Employment, Equity Ownership. Gayron:bluebird bio, Inc: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Cavazzana:SmartImmune: Other: Founder.

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Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽

10.1182/blood.v120.21.801.801 ◽

2012 ◽

Vol 120 (21) ◽

pp. 801-801 ◽

Cited By ~ 21

Author(s):

Francisco Cervantes ◽

Jean-Jacques Kiladjian ◽

Dietger Niederwieser ◽

Andres Sirulnik ◽

Viktoriya Stalbovskaya ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Extension Phase ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA)

Blood ◽

10.1182/blood.v126.23.679.679 ◽

2015 ◽

Vol 126 (23) ◽

pp. 679-679 ◽

Cited By ~ 32

Author(s):

Giovanni Martinelli ◽

Hervé Dombret ◽

Patrice Chevallier ◽

Oliver G. Ottmann ◽

Nicola Goekbuget ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Pcr Amplification ◽

Employment Equity ◽

Advisory Committees ◽

T315i Mutation ◽

Equity Ownership ◽

Grade 3

Abstract Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity. Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57). We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI. Methods. Eligible adult pts (≥18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib. All pts had to have >5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2. Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter). The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints. Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10-5. Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation). 53% of pts were men. Median (range) age was 55 (23-78) years (≥65 years, 27%). Ten pts (22%) had a BCR-ABL gene with T315I mutation. All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy. 38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT. Efficacy outcomes for key endpoints are shown in the table. 16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1. The patient who never received 2+ generation TKI did not respond to treatment. 12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response. Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response. Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response). One patient died in CR post alloHSCT. Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months). Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%). Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator. Three pts discontinued because of AEs. Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2). 21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption. Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity. AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab. Table 1. Table 1. Disclosures Martinelli: Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Bayer: Equity Ownership; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Erytech: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Gilead Sciences: Consultancy; Sanofi: Equity Ownership; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Fielding:Amgen: Consultancy, Honoraria. Sterling:Amgen: Employment, Equity Ownership. Benjamin:Amgen: Employment, Equity Ownership. Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding.

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Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽

10.1182/blood.v128.22.2000.2000 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2000-2000

Author(s):

Hagop Kantarjian ◽

Pierre Fenaux ◽

Mikkael A. Sekeres ◽

Jeffrey Szer ◽

Uwe Platzbecker ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Controlled Study ◽

Bleeding Events ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P<0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P<0.001). Peripheral blast count increases >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML, and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data. Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group. Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival. Disclosures Kantarjian: Amgen Inc.: Research Funding. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

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Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.1176.1176 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1176-1176 ◽

Cited By ~ 19

Author(s):

Julie Kanter ◽

Mark C. Walters ◽

Matthew M. Hsieh ◽

Lakshmanan Krishnamurti ◽

Janet Kwiatkowski ◽

...

Keyword(s):

Gene Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Globin Gene ◽

Advisory Committees ◽

Cell Dose ◽

Cd34 Cells ◽

Equity Ownership

Abstract β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms and long-term complications of severe sickle cell disease (SCD). LentiGlobin Drug Product (DP) is a gene therapy product containing autologous CD34+ cells transduced with the BB305 lentiviral vector. BB305 encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed in fetal hemoglobin (γ-globin). In two ongoing studies, subjects with transfusion-dependent β-thalassemia (Studies HGB-204 and HGB-205) or SCD (Study HGB-205) receiving LentiGlobin DP have demonstrated sustained expression of 3-9 g/dL therapeutic hemoglobin (HbAT87Q) and have shown marked improvements in clinical symptoms 1 year post-treatment. Study HGB-206 is a multi-center, Phase 1/2 safety and efficacy study of LentiGlobin DP in adults with severe SCD. We previously (ASH 2015) presented results from 2 subjects, who had 3 and 6 months of follow-up after LentiGlobin treatment. We now present data from 7 treated subjects, 4 of whom have ≥6 months of follow-up data. Subjects (≥18 years of age) with severe SCD (history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were screened for eligibility. Following bone marrow harvest (BMH), CD34+ cells were transduced with the BB305 vector. Subjects underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. Safety assessments include adverse events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL). After infusion, subjects are monitored for hematologic engraftment, vector copy number (VCN), HbAT87Q expression, and other laboratory and clinical parameters. As of July 2016, 7 subjects with severe SCD (median age: 26 years, range 18-42 years) have received LentiGlobin DP in this study. All subjects successfully underwent BMH, with a median of 2 harvests required (range 1-4). Fifteen Grade 3 AEs in 5 subjects were attributed to BMH: pain (n=10), anemia (n=3) and VOC (n=2); all resolved with standard measures. Table 1 summarizes cell harvest, DP characteristics, and lab results. The median LentiGlobin DP cell dose was 2.1x10e6 CD34+ cells/kg (range 1.6-5.1) and DP VCN was 0.6 (0.3-1.3) copies/diploid genome. Median post-infusion follow-up as of July 2016 is 7.1 months (3.7-12.7 months). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 22 days (17-29 days). The toxicity profile observed from start of conditioning to latest follow-up was consistent with myeloablative conditioning with single-agent busulfan. To date, there have been no DP-related ≥Grade 3 AEs or serious AEs, and no evidence of clonal dominance or RCL. The BB305 vector remains detectable at low levels in the peripheral blood of all subjects infused, with median VCN 0.08 (0.05-0.13, n=7) at last measurement. All subjects express HbAT87Q, with a median of 0.4g/dL (0.1-1.0 g/dL, n=7) at 3 months; most subjects demonstrated modest increases over time, and the 2 subjects with the longest follow-up expressed 0.31 and 1.2 g/dL HbAT87Q at 9 months. All 4 subjects with ≥6 months of follow-up experienced multiple VOCs in the 2 years prior to study entry (2-27.5 VOCs annually). Since LentiGlobin DP infusion, 3 of these 4 subjects have had fewer VOCs, although this trend may be confounded by the short follow-up, the effects of transplant conditioning, and/or post-transplant RBC transfusions. The decrease in VCN between DP and peripheral cells contrasts with previous reports of successful LentiGlobin gene therapy in ongoing studies HGB-204 and HGB-205. The relatively low in vivo VCN in this study appears to result in the lower HbAT87Q expression seen to date. We are exploring multiple hypotheses as to the etiology of the VCN drop between DP and peripheral blood, including the adverse impact of sickle marrow pathology on HSCs, the adequacy of myeloablation, and the magnitude of the transduced cell dose. We will provide an update on study data and ongoing efforts to increase in vivo VCN in patients with SCD, such as increasing the transduced cell dose through alternate HSC procurement methods or enhancing the DP VCN through manufacturing improvements. Disclosures Kanter: Novartis: Consultancy. Walters:Bayer HealthCare: Honoraria; AllCells, Inc./LeukoLab: Other: Medical Director ; ViaCord Processing Laboratory: Other: Medical Director ; Leerink Partners, LLC: Consultancy; Kiadis Pharma: Honoraria; bluebirdBio, Inc: Honoraria. Kwiatkowski:Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy; Sideris Pharmaceuticals: Consultancy; Apopharma: Research Funding; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Kuypers:Children's Hospital Oakland Research Institute: Employment; bluebird bio: Consultancy. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Eli Lily: Research Funding.

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Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy

Blood ◽

10.1182/blood-2018-99-117210 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2883-2883

Author(s):

Matthew S. Davids ◽

Andrew W. Roberts ◽

William G. Wierda ◽

Kathryn Humphrey ◽

Debbie J Alter ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progressive Disease ◽

Response Rate ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Mantle Cell ◽

Equity Ownership

Abstract Introduction: Venetoclax is a selective, oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway. The dose-escalation phase 1 study of venetoclax in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) enrolled 106 patients from June 2011, and the overall response rate across the entire NHL cohort was 44%. The highest response rate (75%) was seen in the 28 patients with mantle cell lymphoma (MCL) (Davids et al., J Clin Oncol. 2017). Here, we report longer-term outcomes for those patients, now with a median of 27 months (range: 0.2 - 59) follow up. Methods: Venetoclax was administered in dose cohorts ranging from a maximum dose of 300-1200 mg and continued until progressive disease (PD) or unacceptable toxicity; intra-patient dose escalation was allowed. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and responses were assessed using 2007 Cheson IWG response criteria, utilizing CT scans beginning at week 6. The data cut off for this analysis was June 4th, 2018. Results: For the 28 patients with MCL, the median age was 72 years (range: 35 - 85). They had received a median of 3 (range: 1 - 7) prior treatments; 5 patients received prior PI3K inhibitor (but no prior ibrutinib). The median time from the preceding treatment to start of venetoclax was 13 months (range: 2 - 148). The median dose of venetoclax was 400 mg/day; 25/28 received at least 400mg/day. Median time on study drug was 11 months (range: 0.2 - 59). Three patients have been on therapy for over 4 years. The overall response rate was 75%, with 6 (21%) patients achieving complete remission (CR) and 15 (54%) partial response (PR). The median duration of response was 16 months (95% CI: 4, 30) and median progression free survival was 11 months (95% CI: 5, 21) for all patients (Figure). The 2 year PFS estimate was 30% (95% CI: 14%, 47%) for all patients, 83% (95% CI: 27%, 97%) for patients who achieved CR and 14% (95% CI: 2%, 37%) for patients who achieved PR. One patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last protocol defined follow-up (24 months after coming off study). Three patients developed progressive disease after receiving venetoclax for more than two years of therapy (time to progression: 31, 33, and 33 months). Two patients with CR continue on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy. The most common (≥25% of patients with MCL) all grade treatment emergent AEs were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%) and upper respiratory infection (25%). The most common (≥10% of patients with MCL) grade 3/4 AEs were neutropenia (14%), anemia (14%), pneumonia (11%), and thrombocytopenia (11%). Biochemical tumor lysis syndrome (TLS), without accompanying clinical features, was reported in one patient considered high risk for TLS. Specific interventions were not required, and the patient continued on study drug. Conclusions: Venetoclax monotherapy leads to durable remission in a meaningful proportion of patients with pretreated MCL. Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including a Phase 3 randomized study with ibrutinib (SYMPATICO, NCT03112174). Disclosures Davids: Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Alter:AbbVie, Inc: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Buss:Abbvie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Seymour:Janssen: Honoraria, Research Funding; Celgene: Consultancy; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding.

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