Updated Analysis of an Open-Label, Phase 2 Study of Blinatumomab As Second Salvage Therapy in Adults with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Introduction: In an open-label phase 2 study, blinatumomab demonstrated efficacy with a manageable safety profile as second salvage in patients with relapsed or refractory B-cell Non-Hodgkin's lymphoma (R/R B-NHL) following platinum-based salvage regimens (Coyle et al. Leukemia & Lymphoma. 2020: 1-10). Blinatumomab is a BiTE® (bispecific T-cell engager) immuno-oncology therapy that activates endogenous cytotoxic T cells to kill target B cells. Here, findings from the updated analysis are reported (NCT02910063). Methods: Patients aged >18 years with biopsy-confirmed B-NHL without prior complete response or complete metabolic response (CMR) following first-line treatment with anthracycline- based chemotherapy and anti-CD20 therapy, had progressive metabolic disease (PMD), no metabolic response (NMR), or partial metabolic response (PMR; Lugano Classification) after ≥2 cycles of platinum-based S1 therapy were eligible. Blinatumomab was given by continuous intravenous infusion for a single 70-day cycle 1 (9 µg/day for 7 days, 28 µg /day for 7 days, and 112 µg /day for 42 days, followed by a 14-day treatment free interval) and an optional 28-day second cycle (9 µg /day for 7 days, 28 µg /day for 7 days and 112 µg / day for 14 days) at the investigator's discretion. Primary endpoint was CMR by central PET. Additional endpoints included objective response rate (ORR; CMR plus PMR), overall survival (OS), progression- free survival (PFS), duration of response, post-response HSCT rate, and the incidence and severity of adverse events (AEs). Results: As of the data cut date (June 3, 2020) for this updated analysis, 41 patients were enrolled between 23 January 2017 and 15 January 2018; 28 (68%) patients were refractory and 13 (32%) relapsed to first-line therapy, 66% had progressive disease following first salvage (S1), and 9 (22%) had double or triple hit status at baseline (Figure 1). ORR was 37% (15/41; 95% CI, 22-53) after 12 weeks of treatment, including 9 (22%) patients who achieved CMR and 6 (15%) achieved PMR. Of the 41 patients enrolled, 17 (42%) were double refractory; of which, 3 (7%) achieved CMR, and 3 (7%) achieved PMR. Of the 41 patients who received blinatumomab, median OS (95% CI) was 11.2 (5.9-NE) months with median follow-up time of 27.9 months. Among the 9 patients who achieved CMR, median OS (95% CI) was NE (7.0, NE) and median PFS (95% CI) was 8.4 (4.9-11.6) months with median follow of time of 4.7 months; of which, 3 patients had disease progression and 0 died. Of the 13 patients who achieved HSCT, median OS (95% CI) was NE (13.1-NE) with 69% of patients alive at 30 months and median PFS (95% CI) was 8.4 (5.3-13.9) months with 21% of patients alive at 12 months (Figure 2 and 3). In total, 29 (71%) patients had grade ≥3 treatment-emergent AEs, including included infections (n=8; 20%), neutropenia (n=4; 10%), pulmonary embolism (n=1; 2%), and acute pancreatitis (n=1; 2%). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 23 (56%) patients, including 10 (24%) with grade 3 NEs and 3 (7%) with NEs leading to treatment discontinuation. Grade 3 cytokine release syndrome was reported in only 1 patient. 7 (17%) patients discontinued treatment due to AEs and 7 (17%) had fatal AEs of which were related to disease progression. Conclusions: In conclusion, durable complete remissions can be achieved with a manageable safety profile using blinatumomab as second salvage in patients with aggressive R/R B-NHL following platinum based first salvage regimens Figure 1 Disclosures Coyle: Amgen: Other: Travel support. Morley:Janssen: Honoraria, Other: Fees; AbbVie: Honoraria, Other: Fees; Roche: Other: travel support; Amgen: Honoraria, Other: Fees, travel support. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment. Furness:Amgen: Other: Travel Support. Desai:IQVIA: Current Employment. Mergen:Amgen: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Durable complete remissions can be achieved with a manageable safety profile using blinatumomab as second salvage in patients with aggressive R/R B-NHL following platinum based first salvage regimens

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An Open Label, Phase 2 Study to Assess the Efficacy and Safety of Tenalisib (RP6530), a PI3K δ/γ and SIK3 Inhibitor, in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2020-136031 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-25

Author(s):

Sebastian Grosicki ◽

Genadi Iosava ◽

Mamia Zodelava ◽

Nikolay Tzvetkov ◽

Tadeusz Robak ◽

...

Keyword(s):

Health Care ◽

Safety Profile ◽

Research Funding ◽

Efficacy And Safety ◽

Open Label ◽

For Profit ◽

Stage 1 ◽

Health Care Company ◽

Anti Tumor Activity ◽

Care Company

Introduction: Despite high response rates to initial treatment, relapse is common in CLL. Although newer agents are approved for treatment recently, CLL remains an incurable disease. Tenalisib (RP6530) is a highly specific and orally available PI3K δ/γ+SIK3 inhibitor. In in-vitro studies, Tenalisib was highly effective (62nM) in demonstrating a cytotoxic effect in patient derived CLL cells and showed very good synergism in combination with fludarabine and ibrutinib at very low concentrations in patient derived primary CLL cells. Tenalisib has demonstrated good clinical activity in patients with T cell lymphomas. Previously, a pooled safety analysis of 93 patients treated with tenalisib monotherapy demonstrated a differentiated safety profile which is largely devoid of immune mediated toxicities (Iyer, ASH 2018). Methods: This trial is a Phase II, open label, multi-center, Simon's two stage study design to evaluate the efficacy and safety of Tenalisib in patients with CLL who have relapsed or are refractory after at least one prior therapy. In stage 1, 20 patients were to be enrolled and an additional 41 patients to be enrolled in stage 2 based efficacy results of stage 1 (>8 responders needed to proceed to stage 2). Patients with previously treated CLL with adequate bone marrow, liver, and renal function, ECOG ≤2, and measurable disease are eligible. Patients with prior exposure to drug that specifically inhibits PI3K were excluded. The primary objective was to assess the anti-tumor activity. The secondary objectives were to assess safety and tolerability, and progression free survival (PFS). The responses were assessed using iwCLL criteria (Hallek 2018). Results: A total of 21 CLL patients predominantly male (86%) with median age was 66 years (range 44-79) were enrolled between Dec 2019 and March 2020 in Stage 1 of the study. 67% of patients had an ECOG score of 1, and 43% had Rai Stage III/IV disease with 67% having spleno/hepatomegaly. Patients had a median of 2 (range: 1-3) prior treatment regimens and 16 (76%) were refractory to last therapy. High risk patients included 15% del 17p, 10% del 11q, 5% ZAP and 5% TP53 mutations. In all 21 evaluable pts with a median follow-up of 4.9 months, 7 patients showed partial response (33%) while the remaining 14 patients showed stable disease (67%). 19 patients (90%) were still continuing therapy while 2 patients discontinued due to disease progression after showing a stable response. There was a median reduction in nodal disease to the extent of 54% in responding patients. The data readouts at C8D1 for all patients is currently awaited. The most common AEs which were mild-moderate in severity included transaminitis (19%), GGT elevation (5%) and neutropenia (5%). There was a related Grade 3 AE of neutropenia (5%). None of the related AEs led to study discontinuation. There were no events of diarrhoea/colitis or pneumonitis in patients who were on therapy for more than 6 months. Conclusions: Tenalisib showed promising single agent anti-tumor activity in patients with CLL with a favourable safety profile. Further data is awaited to estimate the response rates and the decision to move to Stage 2 of the study. Disclosures Robak: Momenta: Consultancy; BioGene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; Pfizer: Research Funding; UCB: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; UTX-TGR: Research Funding; Acerta: Research Funding; Morphosys: Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; Medical University of Lodz: Current Employment; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.

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Clonal Hematopoiesis Is Associated with Increased Risk for Therapy-Related Myeloid Neoplasms in Chronic Lymphocytic Leukemia Patients Treated with Chemo(immuno)Therapy

Blood ◽

10.1182/blood-2020-140232 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-20

Author(s):

Maria Teresa Voso ◽

Tatjana Pandzic ◽

Michail Iskas ◽

Marija Denčić-Fekete ◽

Eleonora De Bellis ◽

...

Keyword(s):

Health Care ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

For Profit ◽

Myeloid Neoplasms ◽

Health Care Company ◽

Care Company

Clonal haematopoiesis of indeterminate potential (CHIP) is defined by the detection of somatic mutations in genes recurrently mutated in myeloid neoplasms (MNs), in the blood of healthy individuals with normal blood values and lack of morphological evidence of MN. Recent studies have highlighted the potential association between CHIP and the development of MN, in particular therapy-related MN (t-MN) in patients with lymphoma treated with chemotherapy and/or autologous stem-cell transplantation. In the present study, we investigated whether the presence of CHIP is associated with a higher risk for the development of t-MN in patients with chronic lymphocytic leukemia (CLL) treated with chemo(immuno)therapy, including fludarabine and cyclophosphamide combinations. To this end, we studied 9 patients with CLL who developed a t-MN [acute myeloid leukemia (AML): n=6, myelodysplastic syndrome (MDS): n=3] after the administration of chemo(immuno)therapy (FCR: n=7, other, n=2), with available samples collected both before CLL treatment and at diagnosis of t-MN. The median interval between the two samples was 26 months (range: 9-38months). NGS was performed on DNA extracted from bone marrow mononuclear cells (MNCs) at t-MN diagnosis, using the Trusight Myeloid Sequencing Panel (n=4) and the Archer VariantPlex Myeloid kit (n=5). Backtracking of the variants detected at the t-MN phase was performed by NGS of DNA extracted from peripheral blood MNCs (n=8) or CD19+ selected cells (n=1) in the samples from the CLL phase. In case no variants were detected in the t-MN phase, targeted digital droplet PCR (ddPCR) was also performed in paired CLL samples to confirm the presence of the variants. Moreover, using the Trusight Myeloid Sequencing Panel, we evaluated the prevalence of CHIP in a population cohort of 285 patients with CLL at the time of diagnosis. The variant allele frequency (VAF) cut-off for the detection of the variants was set to 5%. Variants were reported if meeting the following criteria: (i) located within an exonic or splicing region; (ii) be non-synonymous; (iii) not listed in the gnomAD database, if not also recurrently reported in Cosmic v85. Overall, 16 variants were detected in 7/9 cases analyzed at the time of t-MN [NRAS (n=4), DNMT3A (n=3), TET2 (n=2), EH2 (n=2), TP53 (n=2), KRAS (n=1), U2AF1 (n=1) and SF3B1 (n=1)], while no variants were detected in 2 t-MN samples. In 6/7 cases with detectable variants at t-MN diagnosis, the same variants were present at the CLL phase with either lower (n=4) or similar (n=2) VAF. Overall, CHIP was detectable in 6/9 (66.7%) CLL patients who later developed a t-MN. Among the untreated CLL patients, 45 CHIP-related variants were detected in 35/285 cases (12%) as 7 patients harbored more than one variant. The median VAF was 12.7% (5.1-58.6%) with 27/45 (60%) having a VAF<20%. The affected genes were: DNMT3A (n=9), ASXL1 (n=8), KRAS (n=7), BCOR (n=3), NRAS (n=3), TET2 (n=2), U2AF1 (n=2), PTPN11 (n=2), HRAS (n=2), JAK2 (n=1), CBL (n=1), CALR (n=1), IDH2 (n=1), MPL (n=1), PHF6 (n=1) and ETV6 (n=1). CHIP was not associated with advanced age. Subgroup-analysis amongst CHIP-patients revealed: (i) enrichment of additional CHIP-related variants, male gender and younger age in carriers of ASXL1 variants and (p=0.1, p=0.008 and p=0.06; (ii) a bias towards female gender in patients with DNMT3A variants (p=0.008). The difference in the prevalence of CHIP between patients with CLL developing a t-MN (6/7) and those in the untreated cohort (35/285) was statistically significant (p<0.001). In conclusion, CHIP is significantly enriched in patients with CLL developing t-MNs after the administration of chemo(immuno)therapy, with obvious therapeutic implications especially in the era of targeted agents. The significance of CHIP in CLL should be further evaluated in the context of large clinical studies. MTV and TP contributed equally. EF and PB contributed equally. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Ghia:ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Celgene/Juno: Consultancy, Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding.

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Whimsical (Waldenstrom's Macroglobulinemia Study Involving CArt-wheeL): A Global Patient-Derived Data Registry Capturing Treatment, Quality of Life and COVID-19 Data

Blood ◽

10.1182/blood-2020-138945 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Ibrahim Tohidi-Esfahani ◽

Andrew Warden ◽

Elena Malunis ◽

Peter Liburdi deNardis ◽

Javier Haurat ◽

...

Keyword(s):

Health Care ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

For Profit ◽

Derived Data ◽

Health Care Company ◽

Waldenström's Macroglobulinemia ◽

Care Company

Introduction: Patient-derived data can increase breadth of knowledge in rare cancers like Waldenström's Macroglobulinemia (WM), including patient-reported outcomes (PROs). WhiMSICAL (Waldenström's Macroglobulinemia Study Involving CArt-wheeL) is the only global registry capturing patient-derived data for hypothesis generation in WM. Rapidly adaptable, it has been amended to capture Coronavirus Disease 2019 (COVID-19) data. Methods: An ethically-approved WM-specific extension to www.cart-wheel.org, an online rare cancer database for patient-derived data, was developed by clinician and patient investigators. Participants complete consent, and enter symptom, pathology, treatment and PRO (EORTC-QLQ-C30, Impact of Event Scale-6) data online. Recruitment strategies utilizing social media tools are driven by the International Waldenström's Macroglobulinemia Foundation investigators. A validation study compared patient-entered data with data-manager-entered data in the Australia & New Zealand Lymphoma & Related Diseases Registry (LaRDR). To capture the impact of COVID-19, additional questions on COVID-19 testing, symptoms and therapy, as well as effect on WM management in those without COVID-19, were included in April 2020. Results: 453 patients from 19 countries have been recruited, predominantly from USA (46%) and Australia (25%), with male predominance (62%). At diagnosis, median age was 61 (range 24-83), median IgM 2620 mg/dL (IQR 1320-3850 mg/dL, n=175) and median hemoglobin 11.4 g/dL (IQR 9.5-12.9 g/dL, n=181). Of the 365 (81%) patients providing symptoms at diagnosis, fatigue/muscle weakness was most common (46%) and 30% were asymptomatic. Using the Impact of Event Scale for symptoms of post-traumatic stress disorder (PTSD) resulting from a cancer diagnosis, the mean score among 387 patients was 5.9 (no stress=0, maximal stress=24), with 39/387 (10%) scoring >13 (PPV 94% for PTSD, Thoresen et al, 2010). This proportion did not increase for scores entered after March 1st, 2020 - 12/123 (10%) - when the COVID-19 pandemic became a global crisis. Marked treatment variation was noted, with 47 different first-line therapeutic combinations documented by 302 patients. Median time from diagnosis to first treatment for USA patients was 48 days (IQR 13-404, n=133) vs Rest of World (ROW) 176 days (IQR 20-885, n=163), (p=0.01). At median follow up of 38.5 months, first-line bendamustine rituximab had superior time to next treatment outcomes compared to other first-line therapies: rituximab monotherapy, dexamethasone-rituximab-cyclophosphamide and Bruton tyrosine kinase inhibitors (BTKi, Figure 1). 51 patients exposed to BTKi had a trend to higher EORTC QLQ-C30 global scales, mean 78.6±17.7, compared to 148 not exposed: mean 73.4±22.6 (p=0.13), despite higher treatment burden: median lines of treatment 2 (IQR 1-4) and 1 (IQR 1-2), respectively (p<0.0001). Paired analysis of global scales entered by patients prior to and after March 1 2020 demonstrated no impact of COVID-19 on quality of life: mean scores 74.4±18.8 and 76.0±17.1, respectively (n=69, p=0.45). Validation of patient-entered data with data-manager-entered data for 31 patients also in LaRDR demonstrated high concordance of >83%. 188/453 (42%) participants responded to the impact of COVID-19 questions; 75/188 (40%) had reduced face-to-face reviews, 4/188 (2%) had delays to starting treatment and 57/188 (30%) documented no impact. Of the 188 respondents, 23 (12%) had COVID-19 testing, with two returning a positive result and neither requiring hospitalization. Conclusion: WhiMSICAL is a robust, rapidly adaptable, global patient-derived data platform, providing insight into patient symptoms, real-world therapies and PROs. It is a scientific, ethically-approved portal for contributing the patients' voice in this rare lymphoma. Disclosures Warden: Janssen Cilag: Other: Personal fees for photoshoot event. Opat:CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kersten:Takeda: Research Funding; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Olszewski:Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding. Harrington:Calithera Biosciences: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; BeiGene: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Idera Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Trotman:Takeda: Research Funding; PCYC: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; BeiGene: Research Funding.

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Donor-Derived CAR T Cells Engineered with Sleeping Beauty Achieve Anti-Leukemic Activity without Severe Toxicity

Blood ◽

10.1182/blood-2020-141236 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Chiara F Magnani ◽

Giuseppe Gaipa ◽

Federico Lussana ◽

Daniela Belotti ◽

Giuseppe Gritti ◽

...

Keyword(s):

Health Care ◽

T Cells ◽

T Cell ◽

Board Of Directors ◽

Advisory Committees ◽

For Profit ◽

Car T Cells ◽

Car T ◽

Health Care Company ◽

Care Company

Background Significant efforts over the past few years led Chimeric Antigen Receptor (CAR) T cell therapy to success in relapsed and refractory (r/r) B-cell malignancies. Still logistical complexity, high costs and toxicities are currently the main barriers to the use of CAR T cell therapy. We therefore propose non-viral engineering of an allogeneic T cell population according to cytokine induced killer (CIK) cell protocol of differentiation. Methods We reported the updated results of our phase I/II trial in B-cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into CIK (CARCIK-CD19) according to the method enclosed in the filed patent EP20140192371. After lymphodepletion with Fludarabine (30 mg/m2/day) x 4 days and Cyclophosphamide (500 mg/m2/day) x 2 days, CARCIK-CD19 were infused following a four-dose escalation scheme (1x106, 3x106, 7.5x106 and 15x106 transduced CAR+ T cells/kg) according to the Bayesian Optimal Interval Design (BOIN). During the cell manufacturing period, bridging anti leukemic therapy from patient registration to the beginning of the lymphodepletion, was allowed. The primary endpoint was to define the Maximum Tolerated Dose (MTD) and the safety assessment. Key secondary endpoints included the assessment of complete hematologic response (CR), defined as < 5% bone marrow (BM) blasts, circulating blasts < 1%, no clinical evidence of extramedullary disease, as well as the characterization of CARCIK-CD19 persistence in PB and BM (NCT03389035). Results The cellular product was produced successfully for all patients starting from the donor-derived peripheral blood (PB) and consisted mostly of CD3+ lymphocytes (mean 98.85% ±SD 1.19%) with a mean of 38.6% CAR expression (range 15.10%-73.17%). From January 2018 to July 2020, a total of 24 patients were screened, and 15 were enrolled (4 children and 11 adults) and infused with a single dose of CARCIK-CD19 (n=3 HLA identical sibling, n=4 MUD, n=8 haploidentical donor). The leukemic burden in the BM post lymphodepletion/pre-infusion ranged from 0% to 96%. Robust expansion was achieved in the majority of the patients. The maximal expansion reached about 1x106 transgene copies per μg DNA and 70% of CAR+ T cells in PB. CD8+ T cells represented the predominant circulating CAR+ T cell subset. Persistence of central memory CAR+ T cells was observed after infusion and CAR T cells were measurable up to 9 months. CARCIK-CD19 were characterized by a high profile of safety in all treated patients. Toxicities reported were two grade I and two grade II cytokine release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GvHD), neurotoxicity, or dose-limiting toxicities. Seven out of 9 patients, receiving the highest doses, achieved CR and CRi at day 28. MRD-negative status for all responders was achieved by 6 out of 9 patients (1 currently in evaluation). The two patients in CR but with MRD+ relapsed with a CD19+ disease at +2.3 and +1.9 months post infusion, respectively. Among the 6 patients who achieved MRD-negative CR, two children underwent consolidation with a second allo-HSCT and are still alive and disease free (+17 and +13 months), two adult patients died of subsequent CD19+ disease relapse and two adult patients are still alive and disease free (+14 and +12 months) without additional therapies. The distribution profile of integration sites (IS) showed no preference for gene dense or promoter regions, and no particular differences between pre- and post- infusion sample IS. Samples harvested at early time points after infusion showed a highly polyclonal repertoire. At later time points (≥ 28 days after infusion) the repertoire of IS showed a marked reduction towards oligoclonality, in absence of specific dominant clones. Conclusions We can conclude that SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Sustained response was achieved without severe toxicities. All analyzed samples appear to have a highly polyclonal IS repertoire and no signs of genotoxicity by transposon insertions could be observed. Disclosures Gritti: IQVIA: Consultancy; Amgen: Honoraria; Autolus: Consultancy; Italfarmaco: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria; Jannsen: Other: Travel Support; Takeda: Honoraria; Kite: Consultancy. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

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Upfront Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Idiopathic Aplastic Anemia: A Study on Behalf of the Saawp of EBMT

Blood ◽

10.1182/blood-2020-136657 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-13

Author(s):

Audrey Françoise Petit ◽

Dirk-Jan Eikema ◽

Alexey Maschan ◽

Dalila Adjaoud ◽

Aleksander Kulagin ◽

...

Keyword(s):

Health Care ◽

Aplastic Anemia ◽

Board Of Directors ◽

Research Funding ◽

Unrelated Donor ◽

Advisory Committees ◽

Hematopoietic Stem ◽

For Profit ◽

Health Care Company ◽

Care Company

Introduction Young patients with idiopathic aplastic anemia (AA) respond better to immunosuppressive therapy (IST) but the long-term outcome is suboptimal with non-response in 30% of patients as well as significant risks of relapse, ciclosporine (CSA) dependence and clonal evolution. Excellent results of up-front unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) have been reported in a cohort of 29 children with idiopathic AA using an Alemtuzumab-based regimen, with low Graft versus Host Disease (GvHD) rates and only 1 death (Dufour C, BJH 2015). We took advantage of the SAAWP registry of the European Blood and Marrow Transplantation (EBMT) to analyze the outcomes of 65 young patients who received up-front UD HSCT in Europe. Methods : Patients who had received an UD HSCT for AA, between 2010 and 2018, registered in the SAAWP registry were included. Patients who had received IST (CSA or anti-thymocyte globulin (ATG)) before HSCT, cord blood, haplo-identical transplant were excluded as well as patients suffering from congenital bone marrow disorders. The primary endpoint was overall survival (OS) at 2 years. Secondary endpoints were GVHD-free/relapse-free survival (GRFS) - defined at 2 years as being alive, engrafted without acute GVHD grade III-IV, and extensive chronic GVHD during follow-up. Results : Sixty-five patients were included between 2010 and 2018; median age was 16 years old (9-26). Time to HSCT was 6.5 months (IQR 3.6-11.7). Thirty-nine patients were transplanted from a matched unrelated donor (at least 8/8 HLA matched), 11 patients had mismatched UD (HLA data missing for 14 patients). The two-year overall survival rate was 92% (95% CI, 85-99%) (figure 1,A) with a median follow-up of 32 months (25-43). Main cause of death was infection (2 out of 5 deaths). Failure occurred in 8% (1-15%) of the patients. Acute GVHD grade II-IV was observed in 13% (5-22%) of the patients and Grade III and IV happened for two patients (3%). Chronic GVHD at 2 years occurred for 12% (4-21%) of the patients, with no extensive case. GRFS was 87% (77-96%) at 2-years (Figure 1, B). In our cohort, 57 patients received in vivo T cell depletion using either ATG (n=33, 60%) or anti-lymphocyte globulin (n=4, 7%) or alemtuzumab (n=20, 30%). Due to low rate of events happening during outcome, no risk factor analysis could be driven. Conclusion: In this retrospective cohort of 65 patients with idiopathic aplastic anemia, up-front UD transplantation leads to promising results, confirming previous studies on a smaller cohort of patients. Moreover, we did not find any difference according to in vivo T-cell depletion type, suggesting excellent results are not exclusively related to alemtuzumab-based regimen. Because of obvious limitation related to retrospective studies, unreported events and information bias cannot be excluded. Prospective trials are on their way in the United States and in Europe to formally confirm upfront UD transplantation as standard of care for pediatric patients with idiopathic aplastic anemia. Disclosures Rambaldi: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Griškevičius:Novartis: Research Funding. Dalle:Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Real World Observational Study Using Clonoseq® Next Generation Sequencing in Hematologic Malignancies: The 'Watch' Registry

Blood ◽

10.1182/blood-2020-141440 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Krish Patel ◽

Neil Bailey ◽

Cristina J. Gasparetto ◽

Tomer Mark ◽

Bijal Shah ◽

...

Keyword(s):

Health Care ◽

Assessment Tool ◽

Lymphoblastic Leukemia ◽

Hematologic Malignancies ◽

Publicly Traded ◽

Advisory Committees ◽

For Profit ◽

Health Care Company ◽

Generation Sequencing ◽

Care Company

Background: Clinical response data from trials of investigational agents performed over the past several years in various B-cell malignancies has demonstrated significant improvements in the treatment of these diseases. Despite greatly improved overall response rates, a subset of patients relapses in the short-term while others enjoy prolonged disease-free intervals. These short-term relapses are attributable to residual tumor cells after treatment, but at levels too low for detection by standard clinical assessments. Minimal residual disease (MRD) has emerged as a highly sensitive response assessment tool to measure tumor cells present at a level of 1:10,000 cells or lower via a variety of technologies and platforms. The clonoSEQ® Assay has been cleared by the Food and Drug Administration to detect MRD in the bone marrow of patients with acute lymphoblastic leukemia (ALL) and multiple myeloma (MM) and in either blood or bone marrow for patients with chronic lymphocytic leukemia (CLL). The clonoSEQ Assay can also be used as a laboratory developed test (LDT) to detect MRD in other B-cell malignancies including non-Hodgkin lymphoma (NHL) and in additional sample types such as blood and plasma. Methods: The clonoSEQ Assay utilizes multiplex polymerase chain reaction (PCR) and next generation sequencing (NGS) to identify frequency and distribution of clonal sequences associated with a malignant lymphocyte population in an individual patient sample. The principle of this assay is based on the identification of rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences, as well as translocated BCL1/IgH (J) and BCL2/IgH (J) sequences. The sensitivity of the assay is < 1:1,000,000 when provided sufficient sample input. The Watch Registry is a prospective, multicenter observational study being conducted in the U.S. and is collecting data from health care providers who use the clonoSEQ Assay as part of routine clinical practice for their patients with ALL, MM, CLL, and NHL. Data collection is focused on the rationale for clonoSEQ Assay use and the subsequent treatment decisions by participating investigators in order to better understand the implementation and impact of this assay in the standard care of hematologic malignancies. The Watch Registry will also evaluate changing practice patterns over a period of at least 3 years. Patients are eligible if they are ³ 18 years old, have been diagnosed with NHL, MM, ALL, or CLL, are not simultaneously enrolled in an interventional clinical study, and their treating physician is currently or will be using clonoSEQ to monitor their disease burden over the course of the study. Patients may be in any phase of treatment at the time of enrollment. Planned enrollment is 528 patients in order to achieve a target of 476 who have their initial baseline sample plus at least one MRD tracking sample during the course of the study. The study will collect data on an ongoing basis for approximately 3 years in order to longitudinally understand the utilization of the clonoSEQ Assay and the impact this MRD assessment tool has on clinical care. The primary endpoint of the study is the assessment of the physicians' rationale for MRD testing with clonoSEQ, and the secondary endpoint is the assessment of how those MRD results inform and impact treatment decisions. For each clonoSEQ MRD test ordered, an eCRF questionnaire will capture the rationale for that order (e.g., patient is at end of induction, post-hematopoietic cell transplantation (HCT), monitoring during maintenance, etc) as well as any decisions made regarding patient treatment based upon those results (e.g., patient moved to maintenance therapy, patient will undergo HCT, next line of therapy initiated, etc). Changes in therapeutic regimens will be captured for each patient whether or not those changes are made based upon clonoSEQ results. The Watch Registry is anticipated to begin enrollment in Q3 2020. A ClinicalTrials.gov post will be submitted prior to study opening. Disclosures Patel: Adaptive Biotechnologies, AstraZeneca, Pharmacyclics, Janssen, Genentech, Celgene/BMS, BeiGene, Kite: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Sanofi: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria. Mark:Genzyme: Consultancy; BMS: Consultancy; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Shah:Kite/Gilead, Jazz, Incyte: Research Funding; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; Moffitt Cancer Center: Current Employment; NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Svoboda:AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Imbrium: Consultancy; Atara: Consultancy; Adaptive Biotechnologies: Consultancy; Genmab: Consultancy; BMS: Consultancy. Thompson:Denovo: Honoraria; UpToDate: Other; AIM Specialty Health: Consultancy; Doximity: Other; LynxBio: Honoraria; VIA Oncology (now Elsevier Clinical Path): Consultancy; Adaptive Biotechnologies: Consultancy; Lilly: Honoraria; Takeda: Consultancy, Honoraria; TG Therapeutics: Honoraria; GSK: Consultancy; Strata Oncology: Honoraria; Syapse Precision Medical Council: Consultancy; Abbvie: Honoraria; BMS/Calgene: Consultancy, Honoraria; CRAB CTC: Honoraria; Hoosier Research Network: Honoraria. Simmons:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Schliekelman:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Baldo:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company.

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Ocular Health of Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Baseline Data from the DREAMM-2 Trial of Belantamab Mafodotin (Belamaf)

Blood ◽

10.1182/blood-2020-139315 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Rakesh Popat ◽

Aikaterini Kazantzi ◽

Asim Farooq ◽

Praneetha Thulasi ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Dry Eye ◽

Research Funding ◽

Slit Lamp ◽

Publicly Traded ◽

Advisory Committees ◽

Slit Lamp Examination ◽

For Profit ◽

Health Care Company ◽

Care Company

Introduction: The treatment paradigm for RRMM is characterized by continuous treatment to suppress the malignant plasma cell clone. Some treatments may affect the eye, leading to a broad spectrum of ocular disorders, from dry eye to glaucoma, causing impaired quality of life. Therefore, we examined the baseline eye health of patients with RRMM receiving single-agent belamaf in the DREAMM-2 study (NCT03525678) and compared the findings to those of age-matched individuals in the general population. A better understanding of baseline ocular status is important as patients may have existing, undiagnosed eye conditions that may affect future treatment options. Methods: DREAMM-2 investigated belamaf, a B-cell maturation antigen-targeted antibody-drug conjugate in patients with RRMM. Eligible patients had received ≥3 prior therapies and were refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody. Prior to receiving belamaf, patients underwent systematic ocular history collection and eye examination and completed the eye-specific National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). We report pretreatment eye-related findings to describe the baseline ocular status of patients with RRMM in DREAMM-2. Results: Of 221 patients enrolled, 100 (45%) were female and 121 (55%) were male, with a median age (range) of 66 years (34-89), median time from diagnosis of 5.4 years (1.1-12.1), and median 6 (3-21) prior lines of therapy; 98% patients had received bortezomib. Previous ocular history reported by patients were cataract (60%), intraocular surgery and/or laser treatment (35%), dry eye (20%), and glaucoma (6%), and history of ocular disease requiring medical treatment (12%). On examination, the mean best corrected visual acuity (BCVA) Snellen score was worse than 20/50 in one or both eyes in 20 and 4 of 218 patients with data, respectively. Blepharitis (anterior) was evident in approximately 20% and the corneal epithelium was abnormal (mainly mild-grade keratopathy) in 43% of patients. Impaired tear film production was reported with meibomian gland dysfunction (MGD) in 33% of patients, and evidence of dry eye (Schirmer's test, median 8.2 mm [normal ≥15 mm] in the worse eye. Median worse-eye tear break up time was 8.6 sec [normal >10 sec]). Slit-lamp examination revealed a cataract in approximately 50% of patients. Ten (8%) patients had evidence of prior cataract surgery with an implanted lens (pseudophakia). Dilated fundoscopy identified an abnormal optic nerve in 10% of patients in either eye; of these, glaucomatous cupping was noted in 43% (right eye) to 50% (left eye) of patients. Median (range) overall composite vision score by NEI-VFQ-25 was 95.3 (28-100). Conclusions: There was a 60% prevalence of cataract in the study cohort and an increased prevalence of glaucoma (6% vs expected 3% in patients >65 years old; Kreft et.al. BMC Public Health 2019) in RRMM patients treated in the DREAMM-2 study. Both conditions can be associated with corticosteroids, often used in MM treatments, although cataract is also an age-related phenomenon. We noted a significant number of patients with blepharitis (anterior), dry eye, and MGD, which may be associated with prior bortezomib treatment. Forty-three percent of patients had an abnormal corneal epithelium at baseline, which may be related to dry eye. This is relevant as belamaf is associated with keratopathy (microcyst-like epithelial changes visible on slit-lamp examination, with or without symptoms). Overall NEI-VFQ-25 scores were comparable to those reported in patients >65 years old (Nickels et al. Health Qual Life Outcomes 2017). Patients with RRMM may have a number of baseline ocular abnormalities suggesting a need for regular ophthalmic examinations in this vulnerable population to identify and manage underlying conditions and treatment-related complications. Specifically, attention should be paid to patients who may have ocular conditions associated with prior treatment with corticosteroids or bortezomib. The optimization of ocular heath in this population is particularly relevant given that emerging RRMM therapies such as belamaf are associated with significant ocular side effects. Funding: GSK (Study 205678); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Disclosures Popat: GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria. Farooq:University of Chicago: Current Employment; GlaxoSmithKline: Consultancy. Thulasi:Emory University: Current Employment. Lonial:Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Sanofi: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; JUNO Therapeutics: Consultancy; Millennium: Consultancy, Honoraria; Onyx: Honoraria. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Jeng:University of Maryland: Current Employment; EyeGate: Current equity holder in publicly-traded company; Kedrion, Merck, GSK: Consultancy. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Byrne:Adaptimmune, Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Womersley:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Degli Esposti:Moorfields Eye Hospital: Current Employment; GlaxoSmithKline: Consultancy, Honoraria.

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Conservative Management of Hemochromatosis without Long-Term Maintenance Venesections in Patients with Moderate Iron Burden

Blood ◽

10.1182/blood-2020-136534 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 44-45

Author(s):

Jenny Sumin Yoon ◽

Ross Alistair Henderson ◽

Merit Hanna ◽

Eileen Merriman ◽

Anna Elinder ◽

...

Keyword(s):

Health Care ◽

Iron Overload ◽

Iron Reduction ◽

Hereditary Hemochromatosis ◽

Organ Damage ◽

Advisory Committees ◽

For Profit ◽

Health Care Company ◽

Historic Cohort ◽

Care Company

Introduction Hereditary hemochromatosis with serum ferritin (SF) greater than 1000µg/L at diagnosis has been associated with symptoms and end-organ damage from iron overload. However, clinical manifestation of iron overload is much less frequently observed when only a moderate iron overload of SF 1000µg/L or less is present at diagnosis. Data to guide optimal management with venesection of patients with moderate overload is currently limited and many clinical guidelines do not distinguish the degree of iron overload at presentation in their management recommendations. Since 2013, patients with hemochromatosis who present to our center with a SF of less than 1000µg/L without end organ dysfunction have been venesected to a target of <100µg/L before discharge without maintenance venesections. Patients and their primary care clinicians are advised to re-refer if iron reaccumulates to SF ≥500µg/L or if end-organ damage occurs. Here we present our experience in this practical approach in managing patients with moderate iron overload. Method Patients referred to our center for management of HFE mutated haemochromatosis between 1 January 2013 and 31 December 2017 were included (recent cohort). These patients were discharged after initial iron reduction. A second cohort of patients managed between 1 December 2001 to 31 December 2003 was also included for comparison (historic cohort). This historic cohort initially received maintenance venesections before being discharged in 2013, following a change in our policy. Patients were identified using the departmental electronic database and data was extracted from the patient electronic record. Time to re-referral was measured from the date of last venesection prior to discharge to the date of re-commencing venesection or referral to other services for iron related complications. Patients who had not been re-referred for resuming venesection or to other services for iron-overload complications were censored on 1 July 2020. Result A total of 109 patients were included for analysis (historic cohort: 54; recent cohort: 55). The median age was 45 (range: 45 - 81), and 74 (67.9%) patients were male. Homozygote C282Y mutation was the most common genotype (74.3%), followed by compound heterozygotes (C282Y/H65D or C282Y/S63C, 23.9%). The median SF prior to venesection was 539µg/L (range: 146 - 968), and a median of 8 venesections were required initially to achieve a SF of <100µg/L (range: 1-27). There was no significant difference between the two cohorts in baseline patient characteristics apart from gender, where the proportion of male patients was lower in the historic cohort (56% vs 80%, p = 0.006). The median time to re-referral was 151.5 months and there was no difference between the two cohorts (p = 0.507). The estimated rate of re-referral at 5 and 10 year was 36% and 44%, respectively. Compound heterozygotes had a lower rate of re-referral compared to homozygotes C282Y, albeit not statistically significant (p = 0.069). Age, gender, presenting SF (<500µg/L vs >500µg/L), and number of initial venesections needed for de-ironing (quartiles) were not predictive of re-referral. Conclusion Hereditary hemochromatosis patients who present with only a moderate iron overload at the time of diagnosis could be discharged to primary care following initial iron reduction. A significant proportion of patients do not accumulate significant levels of iron following cessation of venesection. The rate and pattern of iron re-accumulation was similar irrespective of whether patients received a period of maintenance venesection prior to discharge. Figure 1 Disclosures Chan: Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau.

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Epidemiology of Acute Myeloid Leukaemia in New Zealand: A National Cancer Registry Analysis

Blood ◽

10.1182/blood-2020-136524 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Henry Chan ◽

Alana Cavadino ◽

Clinton Lewis

Keyword(s):

Health Care ◽

Overall Survival ◽

New Zealand ◽

Pacific Islanders ◽

European Descent ◽

For Profit ◽

Economically Deprived ◽

Health Care Company ◽

Acute Myeloid ◽

Care Company

Background: Acute myeloid leukaemia (AML) is a blood cancer characterised by the expansion of a malignant myeloid progenitor. The estimated age-standardised incidence rate in many western countries has remained static over the last 2 decades at 3-4 per 100,000, whilst long-term survival has improved, especially for the younger individuals. However, disparities remain for the older individuals, people of ethnic minority background, and those who are more socio-economically deprived. Previous evaluation of population data from New Zealand has shown a similar pattern, but a more recent analysis has not been done. Here we present the incidence and long-term survival of patients with AML in New Zealand (NZ), using the New Zealand Cancer Registry (NZCR). Method: The NZCR was established in 1948 and it became mandatory by law to report all new cases of malignancy by 1994. We extracted all AML cases from the registry between 1 January 1997 and 31 December 2016. Cases with an ICD-10-CM code for acute myeloid leukaemia and its subtypes including acute promyelocytic leukaemia (e.g. C92.0) were included. Individuals residing overseas or without an address were excluded, and individuals with a diagnosis of acute promyelocytic leukaemia (APML) were analyzed separately. The socio-economic status of the individual was estimated based on their domicile area using the New Zealand 2013 Index of Deprivation (NZDep2013) which is a geographically based composite measure of deprivation. Overall survival was calculated from the date of diagnosis to the date of death or last follow-up (31 December 2016). Multivariable Cox-proportional hazard models were used to evaluate potential associations with survival time in NZ AML cases. Results: During this 20-year period, 154 cases of APML and 2876 cases of AML (excluding APML) were reported to the registry on individuals residing in New Zealand. Of the AML cases, 53% were male and the median age at the time of diagnosis was 67 (IQR 52-77), with a small positive correlation between year of diagnosis and age at diagnosis (Spearman's rho=0.05, p=0.009). The majority of cases (77%) were of European descent, 12% were New Zealand Maori, and 6% were Pacific Islanders. Individuals of European descent were significantly older at diagnosis compared to other ethnicities (median of 70 vs 51 for Maori, 56 for Pacific Islanders, and 58 for all other ethnicities, p<0.001). AML appeared to disproportionally affect those more socio-economically deprived, with 23% of cases reported in the most deprived 20% of the population, compared with only 16% of the cases in the least deprived 20%. The annual crude incidence remained stable during this period at an average of 3.42 per 100,000 (ranging from 2.57 to 4.29, figure 1), and was significantly higher in the older adults (figure 2). Age-standardised rates were lower (figure 1), with an average of 2.6 (range 1.9 to 3.4) cases per 100,000, and a small but significant average annual decrease over the study period. The estimated 1, 2, and 5-year survival for the entire cohort was 38%, 27%, and 22%, respectively. Age at diagnosis was a significant predictor of inferior survival, with a hazard ratio (HR) for all-cause mortality of 2.06, 3.95, 6.39 and 10.84 for the 50-59, 60-69, 70-79 and >80 age groups, respectively, compared to those aged <50. Shorter overall survival was also noted in individuals in the more socio-economically deprived 50% of the population (HR 1.13, 95% CI 1.03-1.23). Conclusion The incidence of AML in New Zealand has remained static in the last 2 decades, consistent with data from other western countries. Lower age-standardised rates and the small decrease in these observed over the study period are likely to reflect the increasingly and comparatively older population in NZ. Maori and Pacific Islanders appeared to present at a younger age than individuals of European descent. Age at diagnosis and socio-economic deprivation were shown to be an adverse prognostic factor for overall survival. Further in-depth analysis is required to determine the cause of these observations at a population level. Disclosures Chan: AbbVie:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau;Celgene:Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company);Amgen:Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company);Roche:Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).

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Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Blood ◽

10.1182/blood-2019-122497 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 863-863 ◽

Cited By ~ 4

Author(s):

Robert M. Rifkin ◽

Jason M. Melear ◽

Edward Faber ◽

William I. Bensinger ◽

John M Burke ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Induction Therapy ◽

Safety Profile ◽

Employment Equity ◽

Advisory Committees ◽

Depth Of Response ◽

Equity Ownership ◽

Grade 3

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (>2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (>5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the >CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

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