Bayer HealthCare Pharmaceuticals Research Articles

Ensuring commercial readiness in the cellular cancer immunotherapy space

David McCall, Editor, Cell & Gene Therapy Insights, talks to three experts from Gamida Cell’s leadership team – Julian Adams PhD, CEO, Michele Korfin PhD, COO & CCO & Ronit Simantov MD, CMO & CSOJulian Adams joined Gamida Cell’s leadership team as CEO in November 2017, bringing more than 35 years of drug discovery and development experience to his role. Prior to his CEO appointment, Julian served as President and Chief Scientific Officer at Clal Biotechnology Industries (CBI), where he oversaw the Boston office, evaluating investment opportunities and supporting portfolio companies, including Gamida Cell. Before joining CBI, he served as president of research and development at Infinity Pharmaceuticals and as senior vice president of drug discovery and development at Millennium Pharmaceuticals, now part of Takeda Oncology. At Millennium, he played a key role in the discovery of Velcade (bortezomib), a therapy widely used for treatment of multiple myeloma. He was also instrumental at developing an oral inhibitor of phosphoinositide 3-kinase (PI3K), also known as duvelisib. In 2018, the FDA approved COPIKTRA (duvelisib, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Earlier in his career, while at Boehringer Ingelheim, he was credited with discovering Viramune (nevirapine) for HIV. He has also worked in research and development leadership roles at LeukoSite and at ProScript. Julian serves as Chairman at Elicio Therapeutics since 2017. He also serves on the Stand Up to Cancer Scientific Advisory Committee, AACR Council of Scientific Advisors, and MGH Center for Cancer Research Scientific Advisory Board.Julian has won several awards for his drug development efforts throughout his career, holds more than 40 patents from the United States Patent and Trademark Office and has authored more than 100 papers and book chapters in peer-reviewed journals. Julian holds a BSc from McGill University and a Ph.D. from the Massachusetts Institute of Technology. He also holds a ScD, honoris causa, from McGill University.Michele Korfin joined Gamida Cell’s leadership team as Chief Operating and Chief Commercial Officer in July 2020. Prior to Gamida Cell, Michele served as Chief Operating Officer at TYME Technologies. From 2016–2018, she was Vice President of Market Access at Kite Pharma, where she oversaw market access strategy, including payer relations, reimbursement and government affairs for YESCARTA®, the first approved CAR-T therapy in lymphoma. She also worked closely with the manufacturing and supply chain teams at Kite to prepare for FDA approval and commercialization. Before joining Kite, Michele spent more than a decade at Celgene in a variety of key strategic and operational roles, including in commercial leadership and oversight of the global development programs for REVLIMID®, a foundation therapy for multiple myeloma and MDS del 5Q. She also led the Celgene oncology sales force of over 120 representatives who were responsible for $650 million in revenue for ABRAXANE®, which is now a standard of care in pancreatic cancer. Michele has also held positions at Merck & Co. as a manufacturing scientist, Bain & Company as a consultant and Schering-Plough in sales and marketing. Michele holds an MBA from Harvard Business School and a BSc in pharmacy from Rutgers University. She is also on the Board of Trustees of BioNJ, the organization that represents the biotechnology industry for New Jersey.Ronit Simantov joined Gamida Cell’s leadership team as Chief Medical Officer in July 2017, bringing more than 20 years of experience in hematology and oncology research, development, registration and product launch. Prior to joining Gamida Cell, Ronit served as Head of Oncology Global Medical Affairs at Pfizer, where she was responsible for multiple programs including Sutent® (sunitinib), Inlyta ® (axitinib), Ibrance® (palbociclib), Bosulif® (bosutinib) and Xalkori ® (crizotinib). Ronit previously led phase 1-3 studies as Vice President of Clinical Research at OSI Pharmaceuticals. She also served as Chief Medical Officer at CuraGen Corporation (acquired by Celldex), where she led development of small molecules and antibody-drug conjugates. At Bayer HealthCare Pharmaceuticals, Ronit led the phase 3 study of Nexavar® (sorafenib) resulting in the first approval of a tyrosine kinase inhibitor in renal cell carcinoma. Prior to joining industry, Ronit spent seven years on the academic faculty at Weill Medical College of Cornell University, where she directed the fellowship program and conducted angiogenesis and vascular biology research. She has authored over 40 peer-reviewed manuscripts.Ronit holds an MD from New York University School of Medicine and a BSc. from Johns Hopkins University. She completed a residency in internal medicine at New York Hospital Cornell Medical Center, and a fellowship in hematology and oncology at Weill Cornell Medicine.

524-P: CME Activity Series Highlights Changes in Clinicians’ Knowledge and Competence about Novel Approaches to Reduce DKD Progression

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, significantly impacting morbidity and mortality. Novel approaches to target DKD progression are needed, and non-steroidal mineralocorticoid receptor antagonists (MRAs) have recently emerged as a viable option, however, clinicians may not be aware of them. Based on this gap, CMHC organized 4 accredited virtual symposia from 2020 to 2021 to educate multi-disciplinary clinicians and assess knowledge/competence changes using pre-/post assessment questions. The activities took place between Oct. 2020 - Oct 2021 with the participation of 829 healthcare professionals (MD/DO, PAs, RNs, NPs, PharmDs) representing specialties that treat high-risk diabetes patients. A Chi-Square test was used to analyze the percentage of correct responses and determine statistical significance (p <0.05) . A significant increase in knowledge regarding the pathophysiology of DKD and emerging non-steroidal MRAs in DKD was observed (43% and 34% relative increase in knowledge compared to baseline, p <0.0001) . Additionally, a significant increase in competency regarding identifying patients at-risk for DKD progression and management of DKD patients was demonstrated (37% relative increased to baseline, p<0.0001) . At post-activity evaluation, 99.7% indicated that information via these activities is useful for their practice. Furthermore, the majority of participants indicated that they intended to change their practice based on information received, including monitoring clinical trial advances with non-steroidal MRAs, evaluating the risk of potential hyperkalemia with DKD treatments, and screen for risk of DKD progression. It is evident from the outcomes of these educational activities that they led to significant improvement in knowledge and competence related to novel DKD treatment options and commitment to change among learners. Disclosure S.Karandrea: None. N.Agarwal: None. A.Jamrogiewicz: None. Funding Bayer HealthCare Pharmaceuticals (24656) Bayer HealthCare Pharmaceuticals (66351473) Bayer HealthCare Pharmaceuticals (25319) Bayer HealthCare Pharmaceuticals (67463661)

Finerenone: Reducing Progressive Kidney Dysfunction and Secondary Cardiovascular Complications in Patients With Chronic Kidney Disease Associated With Type 2 Diabetes

Heart failure (HF) in patients with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM) presents complexities because current treatment options are limited for those individuals with CKD and T2DM. Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist (MRA), has been approved by the United States Food and Drug Administration and received priority review for a fast-track application in 2021. 1 Finerenone [package insert]. Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ2021 Google Scholar ,2 Center for Drug Evaluation and ResearchFDA approves drug for chronic kidney disease. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-diseaseDate accessed: March 9, 2022 Google Scholar The drug has demonstrated a reduced risk of ongoing decline in kidney function in adults with CKD and T2DM among those with end-stage kidney disease, nonfatal myocardial infarction (MI), cardiovascular (CV)-related death, and HF requiring hospitalization (HHF). Finerenone has exhibited significantly lower incidences of composite end point CV-related death and total (first and recurrent) HF events in the overall population compared with the placebo, including an 18% lower risk of CV death or first HHF and a 30% lower rate of total HHF. Robin E. Beacom, MSN, FNP-C, is a clinical instructor in the College of Nursing and Health Sciences at the University of Louisiana in Lafayette, LA. James K. Blankenship, MSN, FNP-C, is a clinical pharmacology instructor at the College of Nursing and Health Sciences at the University of Louisiana. Deedra H. Harrington, DNP, ACNP-BC, is an associate professor in the College of Nursing and Health Sciences at the University of Louisiana. Mr. Blankenship can be reached at [email protected] In compliance with standard ethical guidelines, the authors all report no financial relationship that would pose a conflict of interest. The authors do not present any off-label or non–Food and Drug Administration–approved recommendations for treatment.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint.

Comparison of early diabetic retinopathy staging in asymptomatic patients between autonomous AI-based screening and human-graded ultra-widefield colour fundus images

Learning ObjectivesUpon completion of this activity, participants will:Compare diabetic retinopathy (DR) severity scores of ophthalmologically asymptomatic people with diabetes between outputs from an artificial intelligence (AI)-based system and human-graded ultra-widefield (UWF) color fundus imaging, according to a clinical study.Compare manual 7F-mask gradings vs UWF full-field gradings and describe the correlation with patient characteristics, according to a clinical study.Describe clinical implications of the comparison between the DR severity scores of ophthalmologically asymptomatic people with diabetes outputs using outputs from an AI-based system and human-graded UWF color fundus imaging, according to a clinical study.Accreditation StatementsIn support of improving patient care, this activity has been planned and implemented by Medscape, LLC and Springer Nature. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/eye; (4) view/print certificate.Credit hours1.0Release date:Expiration date:Post-test link:https://www.medscape.org/eye/posttest964708Authors/Editors disclosure informationS.S. has disclosed the following relevant financial relationships: Served as consultant or advisor for Allergan, Inc.; Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Heidelberg Pharma GmbH; Novartis Pharmaceuticals Corporation; Optos; Roche; Served as a speaker or a member of a speakers bureau for Allergan, Inc.; Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos; Roche; Received research funding from Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; Optos; Is employed by or has an executive role as Data Monitoring Chair for Phase 2 study sponsored by Bayer HealthCare Pharmaceuticals; Scientific Committee Member of EyeBio Steering Committee for FOCUS sponsored by Novo Nordisk. Other: Trustee member for Macular Society Scientific/Research Advisory Committee Member for Sight UK, Retina UK, Macular Society.Journal CME author disclosure informationLaurie Barclay has disclosed no relevant financial relationships.

Duration of Objective Responses for Patients with Indolent Non-Hodgkin Lymphoma Discontinuing Treatment before Progression: Analysis from the Phase III Chronos-3 Trial Comparing Copanlisib Plus Rituximab with Placebo Plus Rituximab

Duration of Objective Responses for Patients with Indolent Non-Hodgkin Lymphoma Discontinuing Treatment before Progression: Analysis from the Phase III Chronos-3 Trial Comparing Copanlisib Plus Rituximab with Placebo Plus Rituximab

Analysis of Factors Associated with Conversion to CR in Patients with Large B-Cell Lymphoma Achieving Day 30 PR after CAR T-Cell Therapy

Analysis of Factors Associated with Conversion to CR in Patients with Large B-Cell Lymphoma Achieving Day 30 PR after CAR T-Cell Therapy

The Addition of Rituximab to Cyclophosphamide, Doxorubicine, Vincristine and Prednisone (CHOP) Prolongs Overall Survival in Previously Untreated Mantle Cell Lymphoma: A Long Term Pooled Trials Analysis

The Addition of Rituximab to Cyclophosphamide, Doxorubicine, Vincristine and Prednisone (CHOP) Prolongs Overall Survival in Previously Untreated Mantle Cell Lymphoma: A Long Term Pooled Trials Analysis

Mismatch in Sirpα, a Regulatory Protein in Innate Immunity, Is Associated with Outcomes of Allogeneic Stem Cell Transplantation for Lymphoid Malignancies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with hematologic malignancies. It is conventionally believed that alloreactivity is initiated by T-cells recognizing the non-self HLA molecules on the graft. Cells from the innate immune system, such as macrophages and monocytes, are induced by nonspecific “danger” molecules released from damaged tissue. Recent studies revealed that the innate immune system could distinguish the non-self graft and subsequently prime the adaptive immune system to advance the allorecognition process. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on macrophages and myeloid cells. The interaction between SIRPα and its ubiquitously expressed ligand, CD47, suppresses the macrophages phagocytic function. It has been demonstrated that recipient's monocytes detect polymorphism in SIRPα, and mismatches of SIRPα between donor and recipient can regulate the allorecognition response in the murine model. Our group has recently investigated the role of SIRPα variant mismatch in recipients of allo-HSCT from an HLA-matched related donor for treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We found that donor/recipient SIRPα mismatch was commonly detected in 39% of transplant pairs, and the presence of the mismatch was significantly associated with an increase rate of chronic graft-versus-host disease (cGvHD) and a lower rate of early relapse. We hypothesized that comparable effects could be occurring in recipients of allo-HSCT for treatment of lymphoid malignancies. We tested our hypothesis in a cohort of patients who received an allo-HSCT from an HLA matched-related donor at our institution between January 2008 and December 2018 for the treatment of lymphoid malignancies. Only patients who received a peripheral blood stem cell graft and tacrolimus/methotrexate for GvHD prophylaxis were eligible for the study. A total of 313 patients met the eligibility criteria including 310 (99%) who engrafted and 3 (1%) who died early before engraftment. The risk of early death was not associated with SIRPα mismatch variant. Only patients who engrafted (N=310) were included in subsequent analyses. Among these, 42% (N=130) of donor/recipient pairs were SIRPα mismatched. The majority of patients were treated for acute lymphoblastic leukemia (N=115, 37%) or non-Hodgkin's lymphoma (NHL) (N=114, 37%), followed by chronic lymphoblastic leukemia (N=59, 19%), and Hodgkin's lymphoma (N=22, 7%). Most (N=259, 84%) of patients had chemo-sensitive disease. The median age at transplant was 51 (range: 18-72) years, and 64% of patients were female. The median age of donors was 50 (range: 18-79) years and 53% were male. Conditioning regimens were myeloablative in 52% of cases. Outcomes were evaluated accounting for competing risks. The median follow-up in surviving patients was 74 (range: 3-124) months. A total of 99, 84, 108, and 51 patients experienced grade 2-4 acute GvHD, cGvHD requiring systemic immunosuppressive therapy, disease progression, and non-relapse mortality (NRM), respectively. Multivariate analyses showed that SIRPα mismatch was associated with a significantly higher rate (hazard ratio [HR]=1.9, P=.005) of cGvHD requiring systemic immunosuppressive therapy, and a lower rate (HR=.5, P=.004) of disease progression. Notably, the increased rate of cGVHD was consistent across the 4 lymphoid malignancies evaluated, yet the lower rate of relapse was observed in all diagnoses except NHL. There was no significant impact of SIRPα mismatch on grade 2-4 acute GvHD (HR=1.2, P=.3) or on NRM (HR=0.7, P=.3). Consistent with our preceding study in the AML/MDS cohort, the mismatch in SIRPα, a regulatory protein in innate immunity, is associated with a higher rate of cGvHD and relapse protection in patients who underwent allo-HSCT for lymphoid malignancies. The results of this study could be clinically important in donor selection and provide insight into the underlying role of innate immunity in allo-HSCT. DisclosuresShpall: Adaptimmune: Consultancy; Takeda: Patents & Royalties; Novartis: Consultancy; Magenta: Honoraria; Navan: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Consultancy; Axio: Consultancy; Affimed: Patents & Royalties; Novartis: Honoraria.

Allogeneic and Autologous Hematopoietic Transplants Can be Safely Performed after COVID-19 Infections

We are in the midst of a pandemic with the COVID-19 virus, a pathogen with potential severe manifestations. A major clinical question is whether it is safe to undergo hematopoietic stem cell transplantation (HSCT) shortly after COVID-19 infection. A total of 21 patients received HSCT following a diagnosis of COVID-19 infection at our institution between 7/30/2020 and 4/14/2021. The majority (n=13, 62%) received an allogeneic (ALLO) HSCT from an HLA-matched related (n=5), -matched unrelated (n=6), or haploidentical (n=2) donor. The remaining 8 patients received autologous (AUTO) HSCT. Among ALLO-HSCT recipients, 4 (31%), 5 (38%), 3 (23%), and 1 (8%) patients had grade 1, 2, 3, and 4, manifestations respectively, scored according to the WHO COVID-19 infection severity grading system. Among AUTO-HSCT recipients, 5 (62%), 1 (12%), and 2 (25%) patients had grade 0, 1, and 2 manifestations, respectively. All patients had resolution of COVID-19 symptoms before HSCT. In recipients of ALLO-SCT, the median time from diagnosis of the COVID infection to HSCT was 134 (range: 55-311) days. Median age of recipients was 53 (range: 17-71) years and the majority (69%) of patients were male. Only one patient was <18 years old, and 38% were >60 years. Patients received ALLO-HSCT for treatment of acute myeloid leukemia or myelodysplastic syndrome (n=7, 54%), acute lymphoblastic leukemia (n=2, 15%), chronic lymphoblastic leukemia (n=2, 15%), and Hodgkin's (n=1, 8%) or non-Hodgkin's lymphoma (n=1, 15%). Most (62%) patients were not in remission at the time of HSCT. The median hematopoietic cell transplant-co-morbidity index (HCT-CI) score was 3 (range 0-6); one patient had a history of diabetes and another of hypertension before HSCT. Conditioning regimen was myeloablative in 61%, and stem cell source was peripheral blood (PB) in 92% of transplants. Median time to neutrophils engraftment was 15 (range: 10-20) days. With a median follow-up of 3.5 (range: 0.4-8) months since ALLO-HSCT, two patients died and another two experienced progression of the underlying malignancy. Three patients were diagnosed with grade 2 and none with grade 3 or 4 acute graft-versus-host disease (GvHD). The deaths occurred among patients with COVID-19 infection grade 2 and 3. The primary cause of death was attributed to alveolar hemorrhage/pneumonitis (no organism identified) and acute GvHD, respectively. Overall survival was 89% (95% confidence interval [CI]:43-98) and 76% (95% CI 33-93) at 3 and 6 months, respectively. In recipients of AUTO-HSCT, the median time from diagnosis of the COVID-19 infection to HSCT was 55 (range: 20-157) days. Median age of recipients was 55 (range: 34-75) years, and the majority (62%) of patients were male. One (12%) patient was >60 years. Patients received AUTO-HSCT for treatment of Hodgkin's (n=1, 15%) or non-Hodgkin's (n=4, 50%) lymphoma, or multiple myeloma (n=3, 37%). Six (75%) patients were in remission at the time of HSCT. The median HCT-CI score was 2 (range 0-6). None of the patients had a history of diabetes or hypertension before transplant. Conditioning regimen was myeloablative and stem cell source was PB for all patients. Median time to neutrophils engraftment was 10 (range: 9-13) days. With a median follow-up of 4 (range: 0.8-9) months since AUTO-HSCT, one patient with grade 1 COVID infection died as a result of a candida/cytomegalovirus infection, and none of the patients experienced progression of the underlying malignancy. Overall survival was 100% and 75% (95% CI 13-96) at 3 and 6 months respectively. After HSCT, one ALLO and two AUTO asymptomatic patients had a positive nasal swab COVID-19 PCR assay possibly due to delayed shedding of the virus. None of the 21 patients developed active COVID infections post-transplant. In conclusion, allogeneic and autologous hematopoietic transplantation can be performed in patients after COVID-19 infection. Two of 13 allogeneic and one of 8 autologous recipients experienced non-relapse mortality, none directly related to COVID-19 infection. Patients recovering from COVID-19 infection should be considered eligible for hematopoietic transplantation as clinically indicated. DisclosuresShpall: Magenta: Honoraria; Affimed: Patents & Royalties; Novartis: Honoraria; Navan: Consultancy; Magenta: Consultancy; Axio: Consultancy; Adaptimmune: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Novartis: Consultancy; Takeda: Patents & Royalties. Chemaly: Other: Other: Compensation: I am a consultant and advisor on companies who are developing new agents such as Merck, Ansun, and Janssen.

Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial, a Mantle Cell Lymphoma Network Study

Impact of Maintenance Arm on Prognostic Value of MRD after Induction Treatment in MCL R2 Elderly Trial, a Mantle Cell Lymphoma Network Study

Modified Risk-Stratified Sequential Treatment in B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD) after Solid Organ Transplantation (SOT): The Prospective Multicenter Phase II PTLD-2 Trial

Modified Risk-Stratified Sequential Treatment in B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD) after Solid Organ Transplantation (SOT): The Prospective Multicenter Phase II PTLD-2 Trial

Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study

Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study

Assessment of Healthcare Resource Utilization and Costs in Patients with Relapsed or Refractory Follicular Lymphoma Undergoing CAR-T Cell Therapy with Tisagenlecleucel: Results from the Elara Study

Assessment of Healthcare Resource Utilization and Costs in Patients with Relapsed or Refractory Follicular Lymphoma Undergoing CAR-T Cell Therapy with Tisagenlecleucel: Results from the Elara Study

An EZH2 Gene Expression Signature Is Predictive of Differential Efficacy of Chemotherapy Irrespective of EZH2 Mutation Status in Patients with Follicular Lymphoma Treated within the Gallium Trial

An EZH2 Gene Expression Signature Is Predictive of Differential Efficacy of Chemotherapy Irrespective of EZH2 Mutation Status in Patients with Follicular Lymphoma Treated within the Gallium Trial

Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial

Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial

Efficacy Comparison of Tisagenlecleucel Versus Standard of Care in Patients with Relapsed or Refractory Follicular Lymphoma

Efficacy Comparison of Tisagenlecleucel Versus Standard of Care in Patients with Relapsed or Refractory Follicular Lymphoma

Optimizing Myeloablative Fractionated Busulfan, Fludarabine and Thiotepa Regimen: Results of Two Parallel Cohorts in a Phase 2 Prospective Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan (Bu) over a longer period (fractionated (f)-Bu) with fludarabine (Flu) than the standard four-day regimen. (Popat et al Lancet Haematology 2018). We added thiotepa (Thio) to this f-Bu/Flu regimen in patients with haploidentical (haplo) donors to promote engraftment and to reduce relapse. With encouraging results, Thio was then added in matched unrelated (MUD) and sibling (MSD) donor recipients also. However, the optimal doses of Thio and Bu were undefined. To further optimize the regimen, we tested two different f-Bu/Flu/Thio regimens in parallel prospective cohorts: (a) higher dose Bu with lower dose Thio, and (b) lower dose Bu with a higher dose Thio. Patients were enrolled on these cohorts based on age and co-morbidity index (HCT-CI). Herein, we report on the safety and preliminary efficacy of these regimens (NCT02861417).Methods: Patients <60 years with HCT-CI <3, or >60 years with HCT-CI <2 received IV f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min with Thio 2.5 mg/kg (Bu20K/Thio2.5; Cohort 1). Patients <60 years with an HCT-CI >3, or >60 years with HCT-CI >2, or >70 years irrespective of HCT-CI received f-BU to target AUC of 16,000 with Thio 5mg/kg (Bu16K/Thio5; Cohort 2). In both cohorts, the first two doses of Bu (80 mg/m2 IV each) were given as outpatient on days -20 and -13. The last four Bu doses were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. Thio was given on day -7. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4, tacrolimus and MMF.Results: 66 patients were enrolled - 25 in cohort 1 and 41 in cohort 2, with a median age 60 years (range, 22-69) vs 62 years (range, 30-74), respectively (P=0.14). Diagnoses were AML/MDS (64% vs 54%), CML/MPD (24% vs 22%), ALL (12% vs 22%) and 1 myeloma; P=0.24. Most had intermediate disease risk index (80% vs 73%, P=0.57); median HCT-CI was 1 (range, 0-6) vs 3 (range, 0-9); P<0.0001. Donor was haplo (60% vs 19%), MUD (24% vs 54%) or MSD (16% vs 27%); P=0.002; BM graft was used in 56% vs 27%; p=0.02, respectively, in cohorts 1 and 2. The median follow-up among survivors was 18.7 months.Primary graft failure occurred in 1 patient in cohort 1 and none in cohort 2. The median time to neutrophil engraftment was 17.5 days (range, 14-26) vs 18 days (range, 12-26); P=0.12, respectively; platelet engraftment > 20K was 30 days in both groups; P=0.75. Median donor chimerism at day 30 was 100% in both groups. The incidence of acute GVHD grade III-IV was 4% vs 5%; P=0.88 at day 100; extensive chronic GVHD at 1 year was 13% vs 10%; P=0.83. At 1-year overall survival was 72% vs 78%; P=0.95; relapse was 12% each; non-relapse mortality was 20% vs 17%; P=0.97 [Table 1, Fig 1]. Common grade >3 toxicities were neutropenic fever (64% vs 42%; P=0.13), bacterial infection (44% vs 34%; P=0.45), nausea (12% vs 2%; P=0.15), mucositis (8% vs 5%; P=0.63), pneumonitis (12% vs 7%; P=0.67), hemorrhagic cystitis (8% vs 5%) and sinusoidal obstructive syndrome (8% vs 2.4%).Conclusion: In this population of older patients and/or high co-morbidities, both myeloablative regimens with f-Bu/Flu with thiotepa and PTCy were well tolerated and led to low NRM, low risk of relapse and encouraging survival. Although both regimens led to similar outcomes, the f-Bu/Flu/Thio regimen with Bu16K and thiotepa 5 mg/kg dose may be preferred as this was used in patients who were older and/or had high co-morbidities. [Display omitted] DisclosuresPopat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Caribou: Other: Scientific Advisory Board; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Bayer: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding; Biolline: Research Funding. Shpall: Affimed: Patents & Royalties; Adaptimmune: Consultancy; Novartis: Consultancy; Magenta: Consultancy; Magenta: Honoraria; Axio: Consultancy; Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria.

Incidence and Outcomes of Toxoplasma Reactivation in Patients with Hematologic Diseases after Allogeneic Hematopoietic Stem Cell Transplantation

Incidence and Outcomes of Toxoplasma Reactivation in Patients with Hematologic Diseases after Allogeneic Hematopoietic Stem Cell Transplantation