Trends in Prescribing Practices for Management of Hemophilia

Abstract Introduction: Over the past 21 years, treatment options for hemophilia have evolved significantly. The objective of this study is to describe the trends observed in clinician prescribing practices for management of hemophilia A (HA) and B (HB) in the United States (US) via three surveys from 1999-2021. Methods: We administered surveys to members of the Hemostasis & Thrombosis Research Society (HTRS) via an in-person paper survey at its annual symposia in 1999 and 2015, and an online survey in 2021. The survey participants included physicians, physician assistants, and nurse practitioners who manage the care of hemophilia patients at hemophilia treatment centers in the US. The surveys collected information regarding: 1) characteristics of clinician practice, 2) prescribed clotting factor products and dosages used for routine bleeds or major life-threatening bleeding, total joint replacement, and port placement, 3) reasons for changing doses, 4) frequency of recommendation for prophylaxis and inhibitor treatment for associated factor and non-factor products, and 5) gene therapy. Results: Forty-one clinicians completed the survey in 1999 and 2021, 53 in 2015. The mean number of patients seen by respondents increased from 142 (range: 0-314) for children and 101 (0-480) for adults in 1999 to 202 (0-900) for children and 154 (0-500) for adults in 2021. The proportion of clinicians prescribing >40 units/kg of Standard Half Life (SHL) Factor IX concentrates for routine bleeding events in HB patients increased from 22.5% in 1999 to 50.9% in 2015, and 87.8% in 2021. The proportion of clinicians reported SHL Factor VIII usage for routine bleeding at a dose of >40 units/kg in HA patients increased from none in 1999 to 11.3% in 2015 and 29.3 % in 2021. The reported rates of prescribing an average >60 units/kg factor to treat major life-threatening bleeds increased from 67.5% in 1999 to 90.3% in 2021 for HB; rates were 2.5% in 1999, 17.3% in 2015 and 7.3% in 2021 for treating HA. For children <4 years old, 22.2% of clinicians prescribed primary prophylaxis all of the time in 1999. This rose to 68.2% in 2015, and 86.5% in 2021. For adults, 12.5% of clinicians prescribed secondary prophylaxis all of the time in 1999, 27.3% in 2015 and 42.5% in 2021. For treatment of patients with HA or HB inhibitors, the proportions of clinicians who reported prescribing immune tolerance induction (ITI) therapy all of the time for pediatric patients were 50%, 75.0% and 63.2% in three surveys, but <25% for adult patients. In the 2021 survey, >91% of clinicians reported prescribing emicizumab to treat HA inhibitors in patients of all ages, while >87% reported prescribing it to treat HA without inhibitor. Clinicians were more likely to always prescribe emicizumab to treat HA patients with inhibitors (63.2% for children and 57.1% for adults), as compared to always prescribing it for those without inhibitors (13.2% for children and 5.7% for adults). The most frequent reported method to treat a patient with a history of inhibitors on emicizumab who had break through bleeds was rFVIIa: 85.4% for children, and 75.6% for adults. The most frequently reported reasons for switching from FVIII to emicizumab were fewer injections/visits (87.8%), and improved patient quality of life (82.9%). Thirty-nine percent of clinicians reported caring for patients currently in gene therapy trials, 27.5% had patients who had completed gene therapy. When asked about potential future prescribing practices, 14.6% reported that they would prescribe gene therapy "all the time", 4.9% would prescribe it "about 3/4 of the time", 29.3% "about 1/2 the time", 29.3% "about 1/4 the time", and 22.0% "rarely or never". Conclusion: These data indicate changes in prescribing practices among hemophilia specialists in the US over the past 21 years. Prescribing of high doses of factor (>40 units/kg) increased, while ITI prescribing practices remained similar over time. To treat patients with major life-threatening bleeds, a larger proportion of clinicians prescribed high doses of factor (>60 units/kg) for patients with HB as compared to HA. Most clinicians frequently prescribed emicizumab for patients with HA inhibitors, but less frequently for those without inhibitors. At this time, there is wide diversity among clinicians in the expected uptake of gene therapy. Disclosures Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Decker-Palmer: Genentech Inc. --A member of the Roche Group.: Current Employment, Current equity holder in publicly-traded company. Khairnar: Genentech Inc - A Member of The Roche Group: Current Employment; University of Maryland, Baltimore: Ended employment in the past 24 months; Roche: Current equity holder in publicly-traded company. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

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Treatment Patterns and Outcomes of Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Treated with Hypomethylating Agents (HMA) in the United States (US)

Blood ◽

10.1182/blood-2020-134830 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-16

Author(s):

Timothy S. Pardee ◽

Jessica Oschwald ◽

Esprit Ma ◽

Tao Xu ◽

Melissa Montez ◽

...

Keyword(s):

Clinical Practice ◽

Research Funding ◽

Community Setting ◽

Patient Characteristics ◽

Treatment Patterns ◽

Survival Outcomes ◽

Newly Diagnosed ◽

Publicly Traded ◽

The Past ◽

The Us

Introduction: AML is an aggressive disease with poor prognosis that predominantly affects older adults. Due to advanced age and associated comorbidities, many patients are not fit for intensive induction chemotherapy. Monotherapy with HMAs such as azacitidine (AZA) or decitabine (DEC) is often still considered as standard of care for these patients, despite mixed evidence from studies regarding the benefit of HMAs alone (Duchmann & Itzykson. Int J Hematol 2019). The aim of the current study is to evaluate patient characteristics, treatment patterns and outcomes of patients with AML treated with HMA monotherapy as first line (1L) in clinical practice in the US. Methods: This is a retrospective observational study of the Flatiron Health database; a nationwide, longitudinal, demographically and geographically diverse database representing more than 2.4 million patients with cancer in the US. The database contains de-identified data derived from electronic health records from over 280 cancer clinics, which are predominantly community oncology practices. Patients ≥18 years, diagnosed with AML between 1/1/2014 and 3/30/2020 (excluding acute promyelocytic leukemia and clinical trial enrollment), and who received HMAs as 1L treatment ≤30 days from AML diagnosis were evaluated. Descriptive analyses were conducted on patient characteristics and treatment patterns. Kaplan-Meier analyses were used to estimate time to last administration (TTLA; from initiation to last observed administration before death, end of follow-up or a gap of 60 days) and median overall survival (OS). Results: A total of 2589 patients with an AML diagnosis were included for analysis, where 574 (22%) were treated with 1L HMAs (AZA: n=341 [59%]; DEC: n=233 [41%]). The median age of 1L HMA patients was 79 years with 63% male. Most patients were treated in the community setting (n=511 [89%]; median age: 79 years); those treated in academic centers were slightly younger (n=63 [11%]; median age: 77 years). Characteristics for non-antecedent hematological disorder (AHD)-AML (n=327) and AHD-AML (n=247) patients are presented in Table 1. Median TTLA with 1L HMA was 77 days with a median of 3 cycles of both AZA and DEC. Of the 168 patients who received second-line (2L) therapy, 82% (n=138) received another low-intensity therapy or combination (of which only 14 received targeted therapies) (Figure 1). Overall, 44% of 1L HMA patients (n=254) had evidence of molecular testing before 1L treatment initiation (this was more common in later years). Of the 228 patients tested for FLT3, 30 (13%) were FLT3 positive; 7 (23%) FLT3-positive patients were treated with 2L or third-line (3L) FLT3-targeted therapies (gilteritinib, midostaurin or sorafenib). Of the 152 patients tested for IDH1/2, 35 (23%) were IDH1/2 positive; 5 (14%) IDH1/2-positive patients were treated with 2L or 3L targeted agents (enasidenib or ivosidenib). A median OS of 6.3 months (95% CI: 5.5-7.5) was observed in the overall 1L HMA cohort. Median OS in 1L HMA patients did not differ with respect to different types of AML (non-AHD-AML: 6.6 [95% CI: 5.5-7.9] months; AHD-AML: 6.0 [95% CI: 4.8-7.5] months, p=0.34) or practice setting (community: 6.0 [95% CI: 5.3-7.0] months; academic: 8.3 [95% CI: 6.9-13.3] months, p=0.14). One-year OS was 31.4% and 30.1% for non-AHD-AML and AHD-AML patients, respectively. Patients treated in the community setting had numerically lower 1-year OS (29.7% [95% CI: 25.8-34.3]) than those treated in the academic setting (39.5% [95% CI: 28.6-54.6]), which reflects the higher rates of 2L treatment in academic practice, though this analysis is unadjusted. Conclusions: This new database enabled a detailed analysis of 1L HMA-treated patients with newly diagnosed AML in routine clinical practice predominantly in the community setting. 1L HMA patients have poor survival outcomes (median OS 6.3 months) which are comparable to other real-world data from SEER-Medicare (Zeidan et al. Blood Adv 2020; median OS 7-8 months; median age: 77 years); but shorter than the median OS of 9-10 months observed in 1L HMA-treated AML patients in clinical trials (DiNardo et al. EHA 2020). Limitations of the study included limited conduct of bone marrow biopsies for response and lack of transfusion data. The observed survival outcomes highlight the importance of further treatment advances to address the unmet need in older patients with AML ineligible for intensive induction chemotherapy. Disclosures Pardee: Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau; Rafael Pharmaceuticals: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy; Genentech, Inc.: Consultancy; Karyopharm: Research Funding. Oschwald:Roche Products Limited: Current Employment. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ramsingh:Genentech, Inc.: Current Employment; NEKTAR: Current equity holder in publicly-traded company; Exelixis: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Choi:AbbVie: Current Employment, Current equity holder in publicly-traded company. Flahavan:Roche Products Ltd.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. OffLabel Disclosure: Discussion will include the use of decitabine for the treatment of AML.

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Real-World Treatment Patterns and Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) Receiving First-Line (1L) Therapy in the United States (US)

Blood ◽

10.1182/blood-2021-148472 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4086-4086

Author(s):

Anthony R. Mato ◽

Arliene Ravelo ◽

Tu My To ◽

Robert Schuldt ◽

Juliana M.L. Biondo

Keyword(s):

High Risk ◽

Research Funding ◽

Treatment Patterns ◽

Publicly Traded ◽

Treatment Regimens ◽

The Past ◽

Oral Agents ◽

The Us ◽

Testing Patterns ◽

Over Time

Abstract Background: There have been many advances in CLL treatments over the past decade, with a number of novel agents targeting molecular pathways within CLL cells receiving approval from the US Food and Drug Administration. Here, we assessed the evolution of molecular testing patterns, treatment patterns, and clinical outcomes over time in patients receiving 1L CLL treatment in a real-world US database. Methods: This was a retrospective cohort study using the Flatiron Health database, a longitudinal database comprising de-identified, patient-level, structured and unstructured data, curated via technology-enabled abstraction. During the study period, the de-identified data originated from approximately 280 cancer clinics (~800 sites of care) in the US. Patients aged 18 years and older who were diagnosed with CLL and initiated 1L treatment between December 2015 and December 2020 were selected. Participants who took part in a clinical trial in any line of therapy, or who had any other primary cancer diagnosis, were excluded. Baseline characteristics, including testing patterns, at initiation of 1L treatment were assessed using descriptive statistics. Treatment patterns and outcomes, such as time to next treatment or death (TTNTD), were analyzed. Kaplan-Meier analysis was used to estimate TTNTD. Results: Among 3654 patients with treatment-naive CLL who were selected from the de-identified database, the mean age at 1L treatment initiation was 70 years (range, 29-85); 64.3% of patients were male; 72.1% were White, 8.2% Black, 3.9% Hispanic/Latino, 1.0% Asian, and 14.9% were of other ethnicity/race. Approximately one-third (34.7%) of patients had Rai stage 0-I disease, 6.9% had stage II, 6.3% stage III, 11.5% stage IV, and 40.6% had undocumented Rai stage. Testing patterns: The majority of identified patients (3202/3654; 87.6%) had undergone cytogenetic testing, fluorescence in situ hybridization, or IGHV mutation testing. Compared with 2015-2016, testing rates were higher in 2019-2020 for chromosome 17p deletion (del(17p); 36.1% vs 45.7%, respectively; p<0.001) and for IGHV mutation status (84.7% vs 89.2%, respectively; p=0.003). Overall, 11.0% of patients had del(17p). Of those tested for IGHV (1472/3654; 40.3%), 58.3% had unmutated IGHV. Treatment patterns: The 10 most commonly used 1L CLL treatments, which overall represented 91.8% of all 1L treatments, and their evolution over time, are reported in Table 1. Of the patients receiving these top 10 1L treatment regimens overall, 45.7% received regimens including novel targeted oral agents, 33.4% received chemo-immunotherapy (CIT), and 19.7% received anti-CD20 monotherapy. Evaluation of each 2-year period shows that treatment patterns for the top 10 1L treatment regimens shifted, with use of novel targeted oral agents increasing from 27.1% (2015-2016) to 63.8% (2019-2020) (p<0.001), while use of CIT and chemotherapy decreased over time (Table 2). Approximately 30.0% (1088/3654) of 1L-treated patients went on to receive second-line treatments. Outcomes: Median TTNTD was 34.4 months for all patients receiving 1L CLL treatment, and 36.5 months for patients who received the 10 most common 1L treatments across the 6-year study period (n=3360). Median TTNTD was 47.0 months for patients who received novel targeted oral agents and 41.5 months for patients who received CIT (unadjusted p=0.16). When evaluating outcomes in patients with high-risk cytogenetics, median TTNTD was 29.1 months for patients with del(17p) and 37.2 months for those with unmutated IGHV, but was longer in those patients who received treatment with novel targeted oral agents (median TTNTD of 43.9 and 46.7 months, respectively; Table 3). Conclusions: This analysis provides the current state of 1L CLL testing and treatment patterns and outcomes in the US from 2015 to 2020. As expected, the use of novel targeted oral agents increased over time, with a corresponding increase in TTNTD. Clinical outcomes were improved in patients receiving novel targeted oral agents, both overall and in high-risk subgroups. Following on from this, a comparative study of TTNTD for novel oral agents versus CIT, and analyses of outcomes of different sequencing of therapies, will be conducted. Figure 1 Figure 1. Disclosures Mato: Nurix: Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genmab: Research Funding; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ravelo: Genentech, Inc.: Current Employment; Roche Holdings: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. To: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Schuldt: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Johnson & Johnson: Divested equity in a private or publicly-traded company in the past 24 months. Biondo: Genentech, Inc.: Current Employment; Roche: Current holder of individual stocks in a privately-held company.

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Perceptions of Patient Disease Burden and Management Approaches of Systemic Mastocytosis (SM) By Healthcare Providers: Results from the TouchStone SM Survey

Blood ◽

10.1182/blood-2020-137544 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Ruben A. Mesa ◽

Erin M. Sullivan ◽

David Dubinsky ◽

Brittany Carroll ◽

Valerie M. Slee ◽

...

Keyword(s):

Disease Management ◽

Symptom Onset ◽

Research Funding ◽

Healthcare Providers ◽

Diagnostic Tools ◽

Treatment Goals ◽

Publicly Traded ◽

Similar Treatment ◽

The Us ◽

Kit D816v

Introduction: SM is a rare, mast cell neoplasm characterized by uncontrolled proliferation, accumulation, and activation of abnormal mast cells (MCs). Approximately 95% of patients with SM harbor the D816V mutation, which results in constitutive activation of the KIT receptor, causing debilitating symptoms across all SM subtypes such as pruritus, headaches, bone pain, nausea, vomiting, diarrhea, brain fog, and anaphylaxis. Patients with SM are managed across specialties depending on symptom severity and organ involvement. Hematologists/oncologists and allergists/immunologists both play key roles in the management of disease. With few multidisciplinary SM practices in the US, more information is needed across specialties to enable optimal SM care. Here we report findings from the TouchStone SM survey of healthcare providers (HCPs) in the US to inform perceptions of disease and disease management strategies. Methods: HCPs completed an online survey containing 47 items covering a range of concepts related to diagnosis (how made, how long it takes), symptoms (how assessed, what symptoms patients experience, how HCPs discuss symptoms with patients, treatment and management), perceived impact on daily life, treatment received (prescription and over-the-counter, treatment goals, unmet needs) and satisfaction (symptom management, overall treatment and disease management). The focus of these analyses are HCP perceptions of disease severity, treatment goals, and disease management. Practicing hematologists/oncologists and allergists/immunologists were eligible if caring for ≥4 SM patients and in practice ≥3 years post fellowship. HCPs were recruited through double-blinded market research survey panels, with individual responses kept confidential. Descriptive analyses were performed on survey responses. Results: Of 304 HCPs contacted, 60 allergists/immunologists and 59 hematologists/oncologists were enrolled with an average of 14 years of practice experience. On average, participating HCPs had 25 SM patients (range: 4-100) under their care. HCPs reported perceived prevalence of the KIT D816V mutation at 46% of patients (range 0-100), substantially lower than published prevalence rates of up to 95%.1 Among HCPs, the average perceived time from patient symptom onset to diagnosis was 8 months, in contrast to 7 years as reported by patients.2 Allergist/immunologists reported primarily seeing patients with non-advanced disease (80%), while hematologists/oncologists reported managing both non-advanced (50%) and advanced patients (50%). Participating HCPs reported that 58% of their patients have moderate-severe SM. HCP treatment goals for SM patients were consistent across specialties. The 2 most important treatment goals for non-advanced patients were improved quality of life (QoL) (40%; 48/120) and improvement of symptoms (24%; 29/119), while the 2 most important treatment goals for advanced patients were improved progression-free survival /improved overall survival (34%, 35/104) and improved QoL (25%, 26/104). Conclusions: Allergists/immunologists co-manage SM care with hematologists/oncologists, particularly in non-advanced SM, and have similar treatment goals for this patient population, including improvement in QoL and symptom control. In this sample of HCPs, the perceived prevalence of the KIT D816V mutation as well as the perceived time from symptom onset to diagnosis were substantially lower than published estimates. These gaps identified suggest a need to improve HCP awareness of SM symptoms and diagnostic tools to help facilitate earlier patient diagnosis. 1. Garcia-Montero et al. Blood. 2006;108(7):2366-2372. 2. Jennings SV et al. Immuno Allergy Clin North Am. 2018;38(3):505-525. Disclosures Mesa: Promedior: Research Funding; Incyte: Research Funding; Genetech: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Sierra Onc: Consultancy; Novartis: Consultancy; LaJolla Pharma: Consultancy; Samus: Research Funding. Sullivan:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Dubinsky:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Carroll:Blueprint Medicines Corporation: Consultancy, Current equity holder in publicly-traded company. Mathias:Blueprint Medicines Corporation: Other: employed by Health Outcomes Solutions, which received funding Blueprint for providing assistance in developing the Touchstone survey. Castells:Blueprint Medicines Corporation: Consultancy, Other: Clinical trials: Principle Investigator; UpToDate: Other: Author fee; Annals of Allergy, Asthma & Immunology: Other: Editorial Board.

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Comparison of Denosumab Versus Intravenous (IV) Bisphosphonate Use for Hypercalcemia in Multiple Myeloma

Blood ◽

10.1182/blood-2020-140702 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-16

Author(s):

Matthew M Lei ◽

Erica Tavares ◽

Uvette Lou ◽

Evan Buzgo ◽

Noopur S. Raje ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Dysfunction ◽

Board Of Directors ◽

Research Funding ◽

Additional Dose ◽

Newly Diagnosed ◽

Median Dose ◽

Publicly Traded ◽

Advisory Committees ◽

The Past

Background Hypercalcemia (HC) is a frequent complication of multiple myeloma (MM) occurring in 20-30% of patients. This is often associated with renal dysfunction and both features are important myeloma defining events resulting in significant morbidity and mortality. Denosumab, a fully human monoclonal antibody that inhibits RANKL, has been evaluated in the prevention of skeletal related events in patients with newly diagnosed MM, as well as the treatment of bisphosphonate-refractory HC of malignancy (HCM). Cases of denosumab for HCM in MM patients with renal dysfunction have been described. Both denosumab and IV bisphosphonates (IVB) represent treatment options for HC in MM. We describe a comparison of patients with MM with HC who received denosumab vs IVBs. Methods We retrospectively identified patients age ≥18 with a diagnosis of MM with HC (corrected serum calcium level [CSC] >10.5 mg/dL). Patients were included if they received either denosumab or IVB (zoledronic acid [ZA] or pamidronate), between April 2016 and June 2020. The primary endpoint was complete response (CR), defined as normalization of CSC to less than 10.5 mg/dL. Secondary endpoints included HC relapse (CSC >10.5 mg/dL) and safety. Hypocalcemia was graded per CTCAE v5. Acute kidney injury (AKI) was defined using KGIDO criteria. Patients were followed-up for 56 days. Bivariate analyses were performed. Results A total of 40 patients were included with 18 in the denosumab group and 22 in the IVB group, of whom 15 (68%) received ZA and 7 (32%) received pamidronate. Baseline characteristics are described in Table 1. Patients with newly diagnosed MM composed 33% and 55% of the denosumab and IVB groups, respectively. All patients in the denosumab group received 120 mg except one who received 60 mg, while in the IVB group, dose reductions occurred in 5/15 patients who received ZA (median dose, 4 mg; range, 3.3-4) and 4/7 patients who received pamidronate (median dose, 60 mg; range, 30-90). Most patients received HC treatment as an inpatient (58% inpatient vs. 42% outpatient). A minority of patients had received IVBs in the past 90 days. The mean CSC was 12.5 mg/dL (standard deviation [SD], 1.40) and 13.3 mg/dL (SD, 2.39) in the denosumab and IVB groups, respectively. Baseline serum creatinine (SCr) was higher and creatinine clearance (CrCl) was lower in the denosumab group (median SCr, 2.06 vs. 1.24 mg/dL, p=0.048; median CrCl, 33 vs. 48 mL/min, p=0.048). The CR rate by day 3-4 was 92% and 94% in the denosumab and IVB groups, respectively (p=NS). HC relapse occurred in 2 (12%) and 6 (29%) patients in the denosumab and IVB groups, respectively (p=0.257). Incidence of grade 1 hypocalcemia was similar between groups; however, incidence of grade ≥2 hypocalcemia was higher in the denosumab group. Incidence of new AKI was 28% (5/18) in the denosumab group 23% (5/22) in the IVB group (p=0.71). No patients in the denosumab group received an additional dose of denosumab within 14 days of initial dose. Three patients in the IVB group received an additional dose of an IVB within 14 days of initial dose. One patient, who was in the denosumab group, had refractory hypercalcemia and had not achieved CR at day 56. Conclusions We describe our experience with denosumab and IVB for the management of HC in patients with MM. The CR rate at 3-4 days was similar with either agent in our MM only population that was not bisphosphonate refractory. A higher incidence of grade 2 hypocalcemia was noted in the denosumab group. Conclusions on renal safety are limited by the small sample size and that patients in the denosumab group had a higher SCr on presentation. Denosumab and IVB represent acceptable agents for the management of HC in MM patients with further investigation necessary in those with renal dysfunction. Disclosures Lei: Fresenius Kabi USA: Consultancy; Trapelo Health: Consultancy; Bluebird Bio: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company; Clovis Oncology: Current equity holder in publicly-traded company; Blueprint Medicines: Divested equity in a private or publicly-traded company in the past 24 months. Lou:Fresenius Kabi USA: Consultancy. Raje:Bluebird, Bio: Consultancy, Research Funding; Takeda: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Astrazeneca: Consultancy. Yee:Karyopharm: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Denosumab is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. We describe the use of denosumab for hypercalcemia of malignancy in a multiple myeloma only patient population that is not bisphosphonate refractory. The use of denosumab for these patients was part of normal clinical practice in adherence to institutional policies and guidelines.

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Understanding the Association between Red Blood Cell Transfusion Dependency and Humanistic, Psychosocial, and Psychological Burden in Patients with β-Thalassemia from the Patients' Perspective

Blood ◽

10.1182/blood-2021-145302 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4062-4062

Author(s):

Kwanza Price ◽

Shaloo Gupta ◽

Kacper Perkowski ◽

Halley Costantino ◽

Bryan Inyart ◽

...

Keyword(s):

Blood Cell ◽

Research Funding ◽

Severe Depression ◽

Average Score ◽

Publicly Traded ◽

Psychological Burden ◽

The Past ◽

The Usa ◽

Transfusion Dependency ◽

Rbc Transfusion

Abstract Introduction: A recent systematic literature review (Betts M, et al . Clin Ther 2020;42:322-337) perceived that in the past 2 decades, advancements in the treatment and management of β-thalassemia have resulted in improvements in iron control. However, clinical complications, including alloimmunization, iron overload, and resultant cardiac and liver disease, remain a challenge. While red blood cell (RBC) transfusions are used to treat anemia in patients with β-thalassemia, those who are transfusion dependent reported poorer health-related quality of life (HRQoL) compared with the US general population. The literature misses a holistic understanding of the humanistic, psychosocial, and psychological burden of transfusion dependency in β-thalassemia in terms of the impact of disease and treatment on patients' daily lives, distress arising from the possibility of adverse events, and comorbidities. Methods: First, concept elicitation qualitative interviews (n=3) and cognitive pre-test interviews (n=3) were conducted with patients from the Cooley's Anemia Foundation (CAF) to test and revise a 30-minute web-based patient survey questionnaire for clarity and relevance. Following, a larger cross-sectional study included adult patients with β-thalassemia in the USA identified by the CAF. Patients were recruited via email invitation or social media, and invited by CAF to take the survey, at which point informed consent was obtained. Inclusion criteria included ≥18 years of age, self-reported physician diagnosis of β-thalassemia, and ≥1 RBC transfusion in the past 6 months. Survey instruments included the Functional Assessment of Cancer Therapy-Anemia (FACT-An), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), ad hoc questions around patient treatment experience, side effects resulting from β-thalassemia treatment, and psychological burden due to treatment. All results were reported descriptively, with frequency counts and percentages for categorical/ordinal data and mean and standard deviations (SD) for continuous data. Results: Overall, 100 patients in the USA completed the survey; 65% were female, average age was 36.0 (SD=10.4) years, 42% were Asian/Pacific Islander, and 33% reported a household income of USD 100,000 or more. On average, patients had been diagnosed with β-thalassemia for 34.4 (SD=10.3) years and received 9.6 (SD=4.3) RBC transfusions in the past 6 months. Among all patients, 70% reported moderate to extremely high burden of RBC transfusions, 81% reported experiencing iron overload due to RBC transfusion, and 42% reported not being as social with friends/family due to the time needed for RBC transfusions and the associated recovery time. Over 50% of patients reported mild to severe depression (52%) via PHQ-9 and anxiety (53%) via GAD-7 symptoms over the previous 2 weeks. The FACT-An (0-188), where higher scores indicate better outcomes, average score was 132 (SD=33.5), while fatigue symptoms (0-52) average score was 33.3 (SD=12.3), and anemia symptoms (0-28) average score was 20.4 (SD=5.5) in the past 7 days. A week prior to receiving an RBC transfusion, 18% of patients reported their overall health as "very well" versus 52% 1 week after an RBC transfusion. Conclusions: Although upon RBC transfusion HRQoL temporarily improves, overall, these results demonstrated patients with transfusion-dependent β-thalassemia experienced poor health prior to RBC transfusion, mild to severe depression and anxiety, increased psychological burden, and suboptimal HRQoL. These findings contribute to the understanding of the humanistic and psychological burden of RBC transfusion dependency in patients with β-thalassemia and suggest that new treatment options that can improve outcomes in this population are needed. Disclosures Price: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gupta: Bristol Myers Squibb: Consultancy, Research Funding; Kantar Health: Current Employment. Perkowski: Kantar Health: Current Employment; Bristol Myers Squibb: Consultancy, Research Funding. Costantino: Kantar Health: Current Employment; Bristol Myers Squibb: Consultancy, Research Funding. Inyart: Kantar Health: Current Employment; Bristol Myers Squibb: Consultancy, Research Funding. Ashka: Kantar Health: Current Employment; Bristol Myers Squibb: Consultancy, Research Funding. Clapp: Kantar Health: Current Employment; Bristol Myers Squibb: Consultancy, Research Funding. Knoth: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

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Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

Blood ◽

10.1182/blood-2021-152892 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1864-1864

Author(s):

Julie Kanter ◽

John F. DiPersio ◽

Patrick Leavey ◽

David C. Shyr ◽

Alexis A Thompson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Gene Correction ◽

Publicly Traded ◽

Advisory Committees ◽

Hematopoietic Stem ◽

The Past ◽

Adult Hemoglobin

Abstract Background Sickle cell disease (SCD) is a recessive monogenic disease caused by a single point mutation in which glutamic acid replaces valine in Codon 6 of the human beta-globin gene (HBB) leading to the production of abnormal globin chains (HbS) that polymerize and cause erythrocytes to sickle. This results in hemolytic anemia, vaso-occlusion and organ damage, which leads to lifelong complications and early mortality. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only known cure for SCD, however, its use is limited by the lack of well-matched donors, need for immunosuppression, risk of graft versus host disease and graft rejection. GPH101 is an investigational, autologous, hematopoietic stem cell (HSC) drug product (DP) designed to correct the SCD mutation in the HBB gene ex vivo using a high fidelity Cas9 (CRISPR associated protein 9) paired with an AAV6 (adeno-associated virus type 6) delivery template, efficiently harnessing the natural homology directed repair (HDR) cellular pathway. This approach has the potential to restore normal adult hemoglobin (HbA) production while simultaneously reducing HbS levels. In preclinical studies, HBB gene correction in SCD donor HSCs resulted in ≥60% of gene-corrected alleles in vitro with minimal off-target effects. Gene corrected cells were successfully differentiated toward the erythroid lineage and produced ≥70% HbA in vitro. Long-term engraftment of gene-corrected HSCs was demonstrated in vivo, following transplant into immunodeficient mice, with multi-lineage allelic gene correction frequencies well above the predicted curative threshold of 20%, with potential of this approach to be equivalent or superior to allo-HSCT. In addition, HSC-based correction in an SCD mouse model led to stable adult hemoglobin production, increased erythrocyte lifespan and reduction in sickling morphology, demonstrating the therapeutic potential of this gene correction platform as a curative approach in SCD. Study Design and Methods CEDAR (NCT04819841) is a first-in-human, open-label, single-dose, multi-site Phase 1/2 clinical trial in participants with severe SCD designed to evaluate safety, efficacy and pharmacodynamics (PD) of GPH101. Approximately 15 adult (18-40 years) and adolescent (12-17 years) participants will be enrolled across 5 sites, with adolescent enrollment proceeding after a favorable assessment of adult safety data by a Safety Monitoring Committee. Participants must have a diagnosis of severe SCD (βS/βS), defined as ≥ 4 severe vaso-occlusive crises (VOCs) in the 2 years prior and/or ≥ 2 episodes of acute chest syndrome (ACS), in 2 years prior with at least 1 episode in the past year. Participants on chronic transfusion therapy may be eligible if required VOC and ACS criteria are met in the 2 years prior to the initiation of transfusions. Key exclusion criteria include availability of a 10/10 human leukocyte antigen-matched sibling donor, or prior receipt of HSCT or gene therapy. After eligibility confirmation including screening for pre-treatment cytogenetic abnormalities, participants will undergo plerixafor mobilization and apheresis, followed by CD34+ cell enrichment and cryopreservation, undertaken locally at each trial site before shipment to a centralized manufacturer for GPH101 production. After GPH101 release, participants will undergo eligibility reconfirmation prior to busulfan conditioning and DP infusion. Safety, efficacy and PD measurements will occur for 2 years post-infusion; a long-term follow up study will be offered to participants for an additional 13 years of monitoring. The primary endpoint for this study is safety, measured by the kinetics of HSC engraftment, transplant related mortality, overall survival and frequency and severity of adverse events. Secondary endpoints will explore efficacy and PD, including levels of globin expression as compared to baseline, gene correction rates, clinical manifestations of SCD (including VOC and ACS), laboratory parameters, complications and organ function. In addition, cerebral hemodynamics and oxygen delivery will be assessed by magnetic resonance techniques. Key exploratory endpoints include evaluation of patient-reported outcomes, erythrocyte function, on-target and off-target editing rates, and change from baseline in select SCD characteristics. Disclosures Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: 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; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Thompson: Agios Pharmaceuticals: Consultancy; Graphite Bio: Research Funding; Vertex: Research Funding; Beam Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; CRISPR Therapeutics: Research Funding; Global Blood Therapeutics: Current equity holder in publicly-traded company; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding. Porteus: Versant Ventures: Consultancy; CRISPR Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Intondi: Graphite Bio: Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lahiri: Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Dever: Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Petrusich: bluebird bio: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Lehrer-Graiwer: Global Blood Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Graphite Bio: Current Employment, Current equity holder in publicly-traded company.

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Management of Status Epilepticus

Journal of Neuroanaesthesiology and Critical Care ◽

10.1055/s-0039-1700446 ◽

2019 ◽

Vol 06 (03) ◽

pp. 267-274

Author(s):

Ritesh Lamsal ◽

Navindra R. Bista

Keyword(s):

Status Epilepticus ◽

High Risk ◽

Critically Ill Patients ◽

Initial Treatment ◽

Refractory Status Epilepticus ◽

The Past ◽

Anesthetic Agents ◽

Refractory Status ◽

Life Threatening ◽

High Doses

AbstractStatus epilepticus (SE) is a life-threatening neurologic condition that requires immediate assessment and intervention. Over the past few decades, the duration of seizure required to define status epilepticus has shortened, reflecting the need to start therapy without the slightest delay. The focus of this review is on the management of convulsive and nonconvulsive status epilepticus in critically ill patients. Initial treatment of both forms of status epilepticus includes immediate assessment and stabilization, and administration of rapidly acting benzodiazepine therapy followed by nonbenzodiazepine antiepileptic drug. Refractory and super-refractory status epilepticus (RSE and SRSE) pose a lot of therapeutic problems, necessitating the administration of continuous infusion of high doses of anesthetic agents, and carry a high risk of debilitating morbidity as well as mortality.

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Unmet Medical Need Among Elderly Patients with Previously Untreated DLBCL Characterized Using Real-World Data in the United States

Blood ◽

10.1182/blood-2020-136271 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-8 ◽

Cited By ~ 1

Author(s):

Ashwini Shewade ◽

Adam J Olszewski ◽

Nelson Pace ◽

Andy Surinach ◽

Gila Sellam ◽

...

Keyword(s):

Elderly Patients ◽

Real World ◽

Research Funding ◽

Publicly Traded ◽

Real World Data ◽

World Data ◽

Reduced Dose ◽

The Past ◽

Medical Need

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a significant source of cancer morbidity and mortality. More than half of all newly diagnosed patients are older than 65 years, among whom the 5-year relative survival rate is 54% (SEER 2020). Prior research has shown that not all elderly patients (≥80 years old) receive R-CHOP or mini-R-CHOP regimens as the first line of therapy (LoT); those who do not may have suboptimal outcomes (Williams, et al. Cancer 2015; Hamlin, et al. Oncologist 2014; Juul, et al. Eur J Cancer 2018). This study leverages two real-world data (RWD) sources, Flatiron Health (FH) electronic health record-derived de-identified database and SEER-Medicare (SEER-M) to characterize elderly patients with DLBCL (including observed treatment patterns), summarize overall survival (OS) outcomes, and identify unmet medical needs in this population. Methods: RWD from FH included patients with a DLBCL diagnosis on or after January 1, 2011, with follow-up until May 31, 2020. The SEER-M database is a linkage of two population-based RWD sources: the SEER Cancer Registry and Medicare claims database. RWD from SEER-M for this study included patients with a DLBCL diagnosis between January 1, 2011 and December 31, 2015, with follow-up until December 31, 2016. All fee-for-service Medicare enrollees in SEER-M had to have complete claims. RWD for basic demographics, treatments and outcomes were analyzed from both datasets; FH's database included data on certain clinical characteristics including granularity for dosing data when available, in comparison to SEER-M. This descriptive analysis included patients who were aged ≥80 years at diagnosis. Among patients in the FH database who received R-CHOP as first LoT and had available dosing data, those who received <80% of standard full doses for cyclophosphamide (750mg/m2) and doxorubicin (50mg/m2) at first administration were classified as "reduced-dose" R-CHOP. OS data were summarized using an unadjusted Kaplan-Meier survival function and 95% confidence intervals (CI). Results: The study included 725 patients from the FH database and 2613 patients from the SEER-M database; patient characteristics and outcomes were generally consistent between the two datasets. In total, 16% and 35% of the elderly patients had no record of systemic treatment in FH and SEER-M respectively (Table). More than half of the treated patients received R-CHOP in the first LoT (63% and 53% in FH and SEER-M, respectively); other patients received attenuated regimens, including rituximab plus bendamustine (R-Benda), rituximab plus cyclophosphamide, vincristine and prednisolone (R-CVP), and rituximab (R) monotherapy. Patients who received R-CHOP in the first LoT had numerically longer median OS (Flatiron: 55.0 months [95% CI: 41.8-NA]; SEER-M: 50.7 months [95% CI: 45.9-62.9]) compared with those who received other regimens (Figure A, B). Untreated patients had a median survival of 3.1 months (95% CI: 2.3-5.2) in the Flatiron dataset and 2.0 months (95% CI: 1.8-2.2) in the SEER-M dataset. Among those who received R-CHOP and with available dosing data, 51% received reduced-dose R-CHOP in the first LoT and OS appeared shorter than for patients who received full-dose R-CHOP (Figure C). Conclusions: Despite differences between the databases, RWD in FH and SEER-M both demonstrate considerable variation in the regimens received by elderly DLBCL patients, with 16-35% receiving no treatment and >50% receiving attenuated regimens including reduced-dose R-CHOP. Patients receiving regimens other than R-CHOP had a numerically lower survival probability compared with the standard of care (SoC) R-CHOP/reduced-dose R-CHOP. These data show a high unmet medical need among elderly patients with DLBCL who may not be able to tolerate immunochemotherapy regimens that have been evaluated in trials for a carefully selected patient population. Further research will aim to assess prognostic factors at the time of treatment initiation, as well as gather information on comorbidities and other factors that may prevent elderly patients from receiving SoC R-CHOP; these patients may be candidates for better-tolerated novel approaches. Disclosures Shewade: Genentech, Inc.: Current Employment. Olszewski:TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding. Pace:Genentech, Inc.: Current Employment; Exponent: Ended employment in the past 24 months; Prior employer was a consulting firm. No expert testimony given. No relevant consulting work done.: Consultancy. Surinach:Seattle Genetics: Research Funding. Sellam:F. Hoffmann-La Roche: Current Employment. Mueller:Genentech, Inc.: Current Employment, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.

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Hydroxyurea Treatment History and Quality of Life in Patients with Polycythemia Vera: Results from the MPN Landmark Survey in the United States

Blood ◽

10.1182/blood.v126.23.4077.4077 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4077-4077

Author(s):

Ruben A. Mesa ◽

Carole B. Miller ◽

John O. Mascarenhas ◽

Maureen Thyne ◽

Sara Goldberger ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Symptom Burden ◽

Employment Equity ◽

Treatment History ◽

The Past ◽

Patient Reported ◽

The Us ◽

Equity Ownership

Abstract Background: Patients with the myeloproliferative neoplasm (MPN) polycythemia vera (PV) require treatment to manage blood cell counts and reduce the risks of cardiovascular/thromboembolic events. Hydroxyurea (HU) is a common cytoreductive treatment; however, some patients discontinue HU treatment because of resistance, intolerance, or frequently a combination of both limitations. Patients may also continue to receive HU despite diminishing or nonexistent clinical benefit, sometimes in combination with persistent need for phlebotomy procedures. This analysis of MPN Landmark survey data examined patient-reported quality of life (QoL) outcomes in patients with PV who were naive to HU (HU-N), were continuing HU (HU-C), or had discontinued HU (HU-D). Methods: Patients with an MPN under active management in the US were eligible to complete an online survey (fielded May - July 2014). This is a report of responses given by patients with PV to questions about symptom burden, QoL, activities of daily living (ADL), and work/productivity. PV-related effects on patients feeling depressed/discouraged, patients feeling anxious/worried, or interference with ADLs were considered to be at high levels if the patient-reported score was ≥4 on a scale of 1 (not at all) to 5 (a great deal). Symptom severity was rated on a scale of 0 (absent) to 10 (worst imaginable). Results: The survey respondents included 380 patients with PV (HU-N, n=159; HU-C, n=181; HU-D, n=40). Mean age was 62.2 years, 65.1 years, and 64.2 years in the HU-N, HU-C, and HU-D groups, respectively. Mean duration of PV was 8.3 years, 10.3 years, and 13.9 years in the HU-N, HU-C, and HU-D groups, respectively. Patients who had not received HU were currently or previously treated with phlebotomy (87.4%), interferon (11.3%), or anagrelide (9.4%); 66.0% of HU-N patients were classified as high-risk based on information provided by the patients in the survey (ie, age 60 or older or history of thrombosis). Among HU-C and HU-D patients, treatment history included phlebotomy (89.5% and 100%, respectively), interferon (7.2% and 52.5%), or anagrelide (15.5% and 35.0%); 79.6% and 82.5%, respectively, were classified as high-risk. Ruxolitinib was not FDA-approved for PV at the time of this survey. Patients reported high levels of feeling anxious/worried and depressed/discouraged as a result of their PV across all subgroups: HU-N, 27.7% and 15.1%, respectively; HU-C, 22.7% and 15.5%; HU-D, 32.5% and 22.5%. Many patients also experienced a high level of PV-related interference with ADLs, which was more common in the HU-D group (30.0%) than the HU-N (11.3%) or HU-C (18.2%) groups. HU-D patients were more likely to have reported ever reducing their work hours (54.2% of the patients who responded) compared with the HU-N (33.3%) and HU-C groups (36.8%). Among all patients, HU-D patients reported a mean of 8.3 doctor visits in the past 12 months, compared with 5.6 in the HU-N group and 6.6 in the HU-C group. Most patients had experienced PV-related symptoms in the past 12 months (Table 1), particularly fatigue, itching, and day/night sweats; fatigue was ranked first as the symptom that patients would most like to resolve. Conclusion: Patients with PV in a large retrospective real-world survey across the US are found to experience burdensome PV-related symptoms and reduced QoL. The findings from this study also show that standard treatments do not address these aspects of PV in many patients, and patients who have discontinued HU may experience an even greater disease burden, possibly because of a lack of effective and/or safe alternative treatment options. Importantly, while 66.0% of the patients in the HU-N group were classified as high-risk, the majority of the high-risk patients in the HU-N group (81.0%) were not treated with cytoreductive agents, suggesting a potential knowledge deficit regarding recommendations for PV management. Collectively, these results illustrate the adverse impact of PV-related symptom burden on patient QoL and reinforce the importance of unmet control of PV-related symptoms in choosing PV therapy. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Miller:Incyte Corporation: Honoraria, Research Funding. Mascarenhas:Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Kalobios: Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Paranagama:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Naim:Incyte Corporation: Employment, Equity Ownership. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

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Gene Therapy for Fanconi Anemia, Complementation Group a: Updated Results from Ongoing Global Clinical Studies of RP-L102

Blood ◽

10.1182/blood-2020-137106 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-14

Author(s):

Agnieszka Czechowicz ◽

Rajni Agarwal ◽

Julián Sevilla ◽

Paula Río ◽

Susana Navarro ◽

...

Keyword(s):

Gene Therapy ◽

Bone Marrow ◽

Fanconi Anemia ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Medicinal Products ◽

Publicly Traded ◽

Hematopoietic Stem

Background: Fanconi anemia (FA) is a rare inherited disorder of defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities and characterized by progressive bone marrow failure (BMF) and a predisposition to hematologic malignancies and solid tumors. Approximately 60-70% of all cases result from mutations in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). 80% of FA patients develop BMF within the first decade of life. Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potentially curative treatment for BMF, its utilization and efficacy are limited by availability of suitable human leukocyte antigen (HLA)-matched donors, risk of graft-versus-host disease (GVHD) and transplant-related toxicities. Ex-vivo lentiviral mediated gene therapy of autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) has been shown to confer a survival advantage to gene-modified HSPCs in preclinical studies and, most recently, in the investigator initiated Phase 1/2 FANCOLEN-I clinical trial conducted in Madrid, Spain. Based on the highly favorable safety profile and promising preliminary efficacy data, global studies using "Process B" optimization including transduction enhancers, commercial-grade vector, and modified cell processing are underway. Herein, we report updated results from the US Phase 1 clinical trial and preliminary data from the global Phase 2 study in US and EU. Design and Methods: Subjects with a confirmed FANCA gene mutation aged 1 year or older, with no HLA-matched sibling donor and at least 30 CD34+ cells/µL in bone marrow (BM) were eligible for enrollment. Peripheral blood (PB) mononuclear cells were collected via leucocytapheresis on two consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. CD34+ HSPCs were enriched, transduced with a lentiviral vector (PGK-FANCA-WPRE) and infused fresh (not cryopreserved) without any antecedent conditioning. Patients are being followed for 3 years post-infusion for safety assessments (replication competent lentivirus (RCL), insertion site analysis (ISA)) and to ascertain evidence of efficacy (increasing PB vector copy number (VCN) and BM mitomycin-C (MMC) resistance), along with stabilization/correction of cytopenias. Results: As of August 2020, 2 subjects (aged 5 and 6 years) have received RP-L102 infusion on the Phase 1 study with over 12 months of follow up. Preliminary evidence of gene marking in PB post-RP-L102 infusion at various timepoints has been observed in both subjects. Increased bone marrow (BM) mitomycin-C (MMC) resistance post treatment has also been identified in at least 1 subject. Subject L102-001-1001 has had blood count stabilization over the 12 months following gene therapy administration. Subject L102-001-1002's course has been complicated by influenza B infection with concomitant decreases in blood counts requiring red blood cell transfusions. Transfusion requirements have decreased following resolution of infection. Since November 2019, 5 additional subjects have been enrolled onto the global Phase 2 study and received investigational infusion. Updated preliminary safety and efficacy data including PB VCN, blood counts and BM MMC resistance will be available at the time of presentation for subjects with over 12 months of follow up; drug product (DP) information (VCN and CD34+ cell dose) will be available for all treated subjects. Conclusions: DP has been successfully manufactured in the Phase I (N=2) and Phase 2 (N=5) to meet the required specificationsSafety profile of RP-L102 continues to be highly favorable.Evidence of engraftment has been seen in at least 1 subject with follow up of at least 12 months as indicated by PB genetic markings and increasing BM CFC MMC resistance; 12+ months of follow-up may be required to observe the proliferative advantage of transduced HSPCs. Disclosures Czechowicz: Rocket Pharmaceuticals, Inc.: Research Funding. Sevilla:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Río:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: PR has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: SN has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Beard:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Wagner:BlueRock: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from this company., Patents & Royalties, Research Funding.

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