Comorbidities Are Frequent in Older Patients with De Novo Acute Lymphoblastic Leukemia (ALL) and Correlate with Induction Mortality: Analysis of More Than 1200 Patients from GMALL Data Bases

Abstract Outcome of adult ALL has improved considerably during the past decades by intensive chemotherapy, which still remains a challenge in older pts. This may be partly due to comorbidities. So far there are no standards to differentiate pts who will be able to tolerate even age-adapted chemotherapy (fit vs unfit). In addition, little is known about the prevalence of comorbidities. Clinical trials with new compounds often represent a selection of pts w/o comorbidities. There is also no generally accepted tool for comorbidity scoring. The goal of this analysis is to provide reference data for pre-existing comorbidities in a large set of adult ALL pts, to compare two different tools and to evaluate the impact on early death (ED) in older pts. The German Multicenter Study Group for Adult ALL (GMALL) has collected data from trials for younger (18-55 y) and older (>55 y) pts and from a prospective registry. Trials had very limited exclusion criteria and in the registry there are no exclusion criteria. The Charlson Comorbidity Index (CCI) was assessed in the GMALL Elderly trial, whereas the Sorror Score (HCT-CI) was used in trials for younger pts and in the registry. 879 pts had a documented HCT-CI score from GMALL 08/2013 trial (N=282;group 1) and 3 groups from the registry: >55 y but eligible for intensive therapy (N=56, group 2), > 55 y in GMALL Elderly protocol (N=505, group 3) and >55 y in GMALL Frail protocol (N=36; group 4) (Table 1). In addition the CCI was documented in 333 pts treated in the GMALL Elderly Trial. HCT-CI-Score: The most frequent comorbidities were infections (17%), prior malignancies (16%), diabetes (16%), cardiac (14%) and moderate pulmonary disease (12%), obesity (11%) and mild liver disease (10%). Arrhythmias (<1%, 5%, 12% and 22% resp. in groups 1, 2, 3, 4), cardiac disease (2%, 7%, 19% and 42% resp.), prior malignancies (2%, 11%, 25% and 22% resp.) and diabetes (4%, 16%, 22% and 22% resp.) increased with age. Infections (15%, 18%, 22% and 22% resp.) or obesity (9%, 7%, 11% and 14% resp.) were not strongly correlated to age. Comorbidity rates were lower in pts >55 y (group 2) considered eligible for intensive therapy (57%) compared to those considered for the Elderly protocol (76%) (group 3). The proportion of low risk (LR) scores decreased with age (54%, 43%, 25% and 8% resp.;p=.01), whereas high risk (HR) increased (18%, 25%, 50% and 59% resp; p=.01). CCI: The most frequent comorbidities were prior malignancy (14%), diabetes (25%) with (3%) or w/o (22%) end organ damage, cardiac (11%) and vascular disease (8%). The incidence of prior malignancy within the last 5 y was 7%. Risk classification was: LR (0) 51%, intermediate risk (IMR) (1-2) 42% and HR (≥3) 7%. HCT-CI vs CCI in pts >55 y: With HCT-CI the incidence of heart diseases (21% arrhythmias, cardiac disease or valve damage) was higher compared to CCI (9%), which differentiated better into cardiac failure (7%) and myocardial infarction (4%). Peripheral vascular disease (8% with CCI) is not assessed by HCT-CI. Liver disease was less frequent with CCI (1.5%) vs HCT-CI (14%) due to different definitions, whereas moderate pulmonary disease (12%) or infections (18%) are not assessed by CCI. The incidences of prior malignancies and diabetes were comparable. Of note, the overall incidence of distinct comorbidities e.g. cardiac was lower than the sum of subentities because some pts had several comorbidities. ED in pts >55 y: ED rates in pts >55 y in group 3 and in GMALL Elderly trial were comparable (13% vs 12% resp). In group 3 ED rates in risk groups (HCT-CI) were 7% vs 13% vs 15% (p>.05). In the GMALL Elderly trial ED in risk groups (CCI) were 9%, 12% and 35% (p=.05; p=.003 LR/IMR vs HR). Overall the analysis reveals a high incidence of comorbidities in older (57-92%) and even in younger pts (46%), which partly would represent contraindications in clinical trials with novel compounds; thus real world data in pts with comorbidities are required after marketing authorisation. HCT-CI and CCI have a different focus and shortcomings. For ALL pts a more specific score with different organ modules would be helpful. Comorbidity is significantly correlated to ED risk. CCI allows to identify a small HR group (7%) with a mortality of 35%. HCT-CI (24% of pts) and even more CCI (51% of pts) allow to identify LR groups with <10% early mortality. It will be of interest to analyse the impact of individual comorbidities on ED rate. Overall structured comorbidity assessment should be part of all clinical trials in ALL. Disclosures Viardot: Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Fiedler:Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Amgen: Other: support for meetíng attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Stelljes:JAZZ: Honoraria; MSD: Consultancy; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Serve:Bayer: Research Funding. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

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Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽

10.1182/blood-2021-153037 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4076-4076

Author(s):

Abi Vijenthira ◽

Xinzhi Li ◽

Michael Crump ◽

Annette E. Hay ◽

Lois E. Shepherd ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Frailty Index ◽

Secondary Analysis ◽

Advisory Committees ◽

Frail Patients ◽

The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

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The Impact of gain1q on Mutational Structure and Clonal Evolution in a Uniformly Treated High-Risk Series of Patients at First Relapse

Blood ◽

10.1182/blood-2021-152123 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2683-2683

Author(s):

John R Jones ◽

Charlotte Pawlyn ◽

Niels Weinhold ◽

Timothy Cody Ashby ◽

Brian A Walker ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Mutational Load ◽

Advisory Committees ◽

The Impact ◽

Support Research

Abstract Introduction In Multiple Myeloma (MM) the emergence of treatment resistant clones is a characteristic feature of relapse and this is particularly so for high-risk cases. A key driver event mediating progression, risk status and relapse is gain(1q) (1q+). We report on the impact of 1q+ on the genetic profile seen at first relapse in a uniformly treated, newly diagnosed series of 56 patients enrolled to the NCRI Myeloma XI Trial. Methods We included 56 high risk patients, defined as relapse within 30 months of maintenance randomisation (median 19 months, range 8-51). Of the 56 patients, 30 received lenalidomide maintenance and 26 were observed. Whole exome sequencing was conducted at presentation and relapse to a median depth of 122x for tumour samples and 58x for controls. Libraries were prepared using the SureSelectQXT sample prep kit and SureSelect Clinical Research Exome kit. MuTect was used to determine gene variants and SciClone clustering was undertaken to map mutation variant allele frequencies. MANTA was used to determine translocations and Sequenza for copy number aberrations. Clonal structure and mechanisms of clonal evolution were assessed using kernel density estimation of the cancer clonal fraction for all mutations. Wilcoxon matched-pairs signed rank tests (2-sided) were used to determine the significance between paired data sets, including mutational load. Fishers exact test was used to determine the difference between two nominal variables. Results We looked at mutational, structural and clonal evolution events in all patients based on 1q+ status at relapse. At diagnosis, 34% (19/56) patients had evidence of 1q+, increasing to 46% (26/56) at relapse, with all patients harbouring 1q+ at presentation having the lesion at relapse. There was a significantly higher non-synonymous mutational load at relapse in patients with 1q+, 107 vs 126 (p=0.047), compared to those without 1q+, 36 vs 44 (p=0.140). Twenty two genes known to be significant in MM and mutations within the genes known to be important in IMiD mechanism of action were reviewed. Of the patients with 1q+, 92% (24/26) had at least one mutation during the course of the disease, compared to 77% in those without 1q+ (p=0.15). The impact on tumour suppressor gene regions including deletions of chromosome 1p, 13, 14 and 17p was analyzed. Of the patients with 1q+, 77% (20/26) of patients had a deletion of one of these regions during the disease course, compared to 57% (17/30) of patients without 1q+ (p=0.16). At relapse a change in the profile of these lesions was noted in 23% (6/26) patients with 1q+, compared to 20% (6/30) patients without 1q+ (p=1). Translocations involving MYC (t MYC) were also determined and found in 27% (7/26) of patients with 1q+ and 27% (8/30) of patients without (p=1). As with 1q+, t MYC was always preserved at relapse. Mechanisms of evolution leading to relapse were established for all patients. Branching and linear evolution predominated, noted to be the mechanism leading to relapse in 88% (23/26) patients with 1q+ and 83% (25/30) without (p0.71). Stable evolution was noted in the remaining patients. 1q+ occurring as a new event at relapse was associated with branching or linear evolution in all patients (n=7), consistent with a change in clonal structure. Conclusion These data reveal that 1q+ is conserved throughout the disease course, suggesting it imparts a survival advantage and treatment resistant phenotype to the clone(s) containing it. The presence of 1q+ is associated with a significant increase in mutational load at relapse and a greater incidence of tumour suppressor gene structural deletions, mechanisms that may contribute to clonal evolution and therapeutic escape. Disclosures Jones: BMS/Celgene: Other: Conference fees; Janssen: Honoraria. Pawlyn: Celgene / BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weinhold: Sanofi: Honoraria. Walker: Sanofi: Speakers Bureau; Bristol Myers Squibb: Research Funding. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Kaiser: AbbVie: Consultancy; Seattle Genetics: Consultancy; BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Amgen: Honoraria; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Takeda: Consultancy, Other: Educational support. Cook: Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jackson: oncopeptides: Consultancy; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Davies: BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees.

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Impact of Charlson Comorbidity Index (CCI) and Refining the MIPI Index in Mantle Cell Lymphoma (MCL)

Blood ◽

10.1182/blood.v128.22.2973.2973 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2973-2973

Author(s):

Andre Goy ◽

Tommy Wu ◽

Eric Hansen ◽

Srikesh Arunajadai ◽

Ewelina Protomastro ◽

...

Keyword(s):

Clinical Trials ◽

Risk Stratification ◽

Board Of Directors ◽

Research Funding ◽

Intensive Therapy ◽

Advisory Committees ◽

Ki 67 ◽

Mantle Cell ◽

Equity Ownership ◽

Intensive Group

Abstract Introduction: The outcome of MCL patients (pts) has improved over the last three decades, although this is debated outside clinical trials (Chandran, Leuk Lymphoma Aug 2012; Smith, Br J Cancer. April 2015). The Mantle Cell International Prognostic Index (MIPI) (Hoster, Blood Jan 2008) is based on 4 variables which predict survival: age (host factor), PS (tumor/host), LDH (tumor burden) and WBC (leukemic phase). The additional value of including co-morbidities into risk stratification has not been fully explored. Methods: Using the COTA database we retrospectively analyzed MCL cases treated at John Theurer Cancer Center and the affiliated practices of Regional Cancer Care Associates from 2004 to 2016. Clinical and treatment characteristics, including calculation of the CCI index (Charlson J Chronic Diseases 1987) were captured via the COTA platform by extracting data from the electronic health records. Results: 490 pts with MCL were evaluated and full longitudinal data from diagnosis is currently reported on 195 subjects. Pts characteristics included: male (66.15%), med age (65, range 34-94), stage IV (87%), LDH (elevated 26%; median 197, range 112-7950), MIPI (low 38%, interm 32%, high 30%), Ki-67 (≥30%: 51%, 86 NA), blastoid variant (16%, 35 NA), SOX-11 positive (87%, 143 NA), 17p abnormalities (p53 del or overexpression/mutation (24%, 88 NA) and b-2 microglobulin (b-2m) > 3 mg/L (52%). Frontline therapy consisted of R-Hyper-CVAD (with or without bortezomib on study) (36%), R-HyperCVAD or R-CHOP followed by high-dose therapy followed by autologous stem cell transplantation (ASCT) (9%), BR alone (8%), BR+ maintenance (8%), R-CHOP alone (4%), Rituximab (3%), R-BAC (3%), BR+ Ibrutinib vs placebo (2%), radiation (2%), R-Lenalidomide (1%), R-CHOP + maintenance (1%), other treatments (10%) while 10% of patients were treated expectantly Seventeen pts underwent ASCT consolidation (15 auto vs 2 allo (del17p/blastoid at presentation). Overall and progression free survival was computed using Kaplan Meier curves and significance tested using log-rank tests. The 5y OS for this entire cohort was 81. Overall, dose-intensive strategies (with or without ASCT) approach was associated with a 23 mo difference in PFS (median 74 mo, range 0-111 mo (intensive) vs median 51 mo, range 2-57 mo for the non-intensive group (p=0.37). The median OS was not reached for either group, with a 5y OS of 88% in intensive vs. 71% non-intensive regimens (p=0.14). Using MIPI as stratification, low/intermediate risk pts had similar outcome in intensive and non-intensive therapy groups (5y OS 88% vs 71%; p=0.13). Pts with high MIPI had a 5 year OS of 80% in the intensive therapy group vs 46% for non-intensive group (p=0.376). The CCI scores for the whole cohort were 0 in 16 pts (8%), 1-3 in 81 pts (41%), and ≥ 4 in 98 pts (50%). Baseline CCI score (pre-treatment) was highly predictive of outcome with a 5y OS of 90% in CCI 0-3 vs 62% in CCI 3+ (p=0.001) (Figure 1). CCI did not predict complete response rate (CR) to induction therapy (CCI 0-3 94% vs CCI 3+ 80%). The median MIPI scores were 5.7 for CCI 0-3 and 6.3 for CCI 3+. Age is a component of both indexes but more heavily weighted in the CCI. Adding CCI to MIPI defined a subset of pts among the high MIPI group who did better than expected with a 5y OS of 88% in combined high MIPI / CCI 0-3 vs 31% for high MIPI / CCI 4+/ (p=0.03). b-2m (cut-off 3mg/L) correlated with 5y OS 93% vs 80%; (p=0.04) as previously reported but did not add to MIPI or CCI risk stratification. Ki-67 (30% cut-off) was marginally associated with OS: 5-y 89% vs 77% (p=0.06). Conclusions: Our cohort is consistent with the improvement of MCL outcome comparing to historical controls and illustrates the importance of comorbidities captured at baseline. A combined CCI-MIPI approach might help identify pts who can still benefit from current therapy approaches in spite of age. Among the high MIPI score group, CCI further refines cohorts with significantly different outcomes. Figure 1 Figure 1. FIgure 2 FIgure 2. Disclosures Goy: Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Research funding for clinical trials through institution; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; COTA: Membership on an entity's Board of Directors or advisory committees; Janssen/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution. Wu:COTA: Employment. Hansen:COTA: Employment. Arunajadai:COTA: Employment. Protomastro:COTA: Employment. Valentinetti:COTA: Employment. Murphy:COTA: Employment. Smith:COTA: Employment. Pe Benito:COTA: Employment. Hasan:COTA: Employment. Suryadevara:COTA: Employment. Feldman:Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy; Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead Sciences: Speakers Bureau; Abbvie: Consultancy. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Pecora:COTA: Employment, Equity Ownership. Goldberg:Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership; Novartis: Consultancy; COTA Inc: Employment; Pfizer: Honoraria.

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Acute Myeloid Leukemia with Myelodisplasia-Related Changes (AML-MRC) Defined Only By Morphological Findings May Not Represent a Poor Prognosis AML

Blood ◽

10.1182/blood-2019-129153 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2612-2612

Author(s):

Ana Pérez ◽

Olga Salamero ◽

Helena Pomares ◽

Maria Julia Montoro ◽

Montserrat Arnan Sangerman ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Poor Prognosis ◽

Advisory Committees ◽

Group 3 ◽

Group 2 ◽

Acute Myeloid ◽

Group 1

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response were defined according to the European Leukemia Net recommendations. Overall survival (OS) was considered as the time from the diagnosis to the last visit. Survival analysis were performed with Kaplan Meier method and comparisons with the log-rank test. Among 575 cases of AML identified, 186 (32.3%) met AML-MRC criteria and were included in the study. The main patient characteristics are shown in Table1. Median age was 72 (range, 22-88) years and 32% were female. Adverse karyotype was present in 29% of patients, being more prevalent in the AML-MRC group 2. Sixty one patients (33%) received an intensive chemotherapy approach and 36 (19%) an allogeneic stem cell transplantation. Patients in group 3 exhibit a higher probability of achieving a complete response than groups 1 and 2 (Table 2). After a median follow-up for survivors of 28.5 months (range, 5-130), 149 (80%) died in this period. Three years Overall Survival (OS) for patients in groups 1, 2 and 3 was 3 (0-117), 5 (0-93) and 10 (0-130) months, respectively (p=0.012) (Figure 1). Type of treatment (intensive, non intensive or best supportive care) and cytogenetic risk also showed impact on OS. Multivariant analysis adjusting these factors showed that patients in group 3 also presented better OS than patients in group 1 (HR=0,42 [IC95% 0,18-0,84], p=0,02), both with around a 30% of patients with adverse cytogenetics. To conclude the present study suggests that group 3 of AML-MRC, for which the diagnosis is based solely on morphologic findings, showed better prognosis than the other groups. A more detailed molecular characterization might contribute to improve prognostic stratification of this heterogeneous AML entity, particularly in patients with non-high risk cytogenetics. Disclosures Salamero: Pfizer: Honoraria; Daichii Sankyo: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Valcárcel:Jazz Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: spouse is an employee in the company, Speakers Bureau; Pfizer: Honoraria. Bosch:AstraZeneca: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Kyte: 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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Clinical Outcomes for Patients with Myeloid Malignancies Harboring IDH1/2mutations after Intensive Chemotherapy

Blood ◽

10.1182/blood-2018-99-119306 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1389-1389 ◽

Cited By ~ 1

Author(s):

Swapna Thota ◽

Bhumika J. Patel ◽

Hetty E. Carraway ◽

Elizabeth A. Griffiths ◽

Amanda Przespolewski ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Response Rate ◽

Intensive Therapy ◽

Response To Therapy ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

The Impact

Abstract Background: AML and MDS are heterogeneous myeloid neoplasias (MN) characterized by varied pathogenic mechanisms and associated with mixed clinical outcome. Five-year overall survival rates for younger AML patients (pts) are between 40-50% and for elderly pts, a dismal 10%. Until recently, molecular information has informed risk stratification for MN patients, but targeted therapies were limited (i.e ckit, flt3 inhibitors). Clinical characterization of IDH1/2mutant MN is of particular interest since the recent availability of specific IDH1/2inhibitors (i.e., enasidenib and ivosidenib). Datasets describing the outcome for patients with MN harboring IDH1/2mutations are critical to inform the potential utility of these novel IDH inhibitors as single agents or in combination with standard of care. Ongoing clinical trials are investigating the addition of IDH inhibition for upfront AML therapy. In this retrospective study, we combined cohorts from three institutions to enable reporting of the largest cohort (N=425) of IDH mutated MN pts in order to establish a baseline for therapeutic outcomes in an era which pre-dates the availability/addition of IDH inhibitors. Methods:We identified 425 patients from three large academic centers with a confirmed diagnosis of IDH1/2mutant AML (n=387), MDS (n=29) or MPN (n=9). Blood and bone marrow samples were analyzed for the presence of recurrent somatic mutations using NGS based multi-gene targeted sequencing panels. Demographic and disease related variables were annotated for initial treatment, response to therapy (IWG criteria) and subsequent survival details (overall survival, progression free survival). Time to first relapse and duration of remission was collected for 107 patients to date. Comprehensive response assessment details were available for 234 patients. Results: Of the 425 patients, 165 had a mutation inIDH1and 264 had a mutation in IDH2(82% IDH2R140, 18% R172K). Four cases had co-occurring mutations in IDH1 & IDH2. IDH1mutant cases were younger than IDH2mutant cases (62 vs. 65 years, p=0.05), predominantly male (50% vs.38%, p=0.01) and more likely to have intermediate risk AML (68% of IDH1/IDH2mutant cases had normal karyotype). A majority of these patients were treated with cytarabine-based intensive chemotherapy (n=362). Hypomethylating agents (n=29) or other less intensive therapies (n= 27) were also used. The overall response rate (ORR) to initial therapy was 65%. Response rates were similar for patients with both IDH1and IDH2mutation (i.e, 66% to any therapy). Response to intensive chemotherapy was 68% and 64% in IDH1and IDH2mutant cases respectively. As expected IDH1/2 mutant younger pts (<60 years) had a higher response rate to intensive chemotherapy (81% and 80 % respectively). The ORR for HMA therapy was 73% (64% IDH1, 80% IDH2mutants). 34% of IDH1mutants and 30%IDH2mutant patients underwent allogeneic stem cell transplantation. We have analyzed the impact of co-occurring somatic mutations on response to intensive chemotherapy. Non-responders to intensive therapy were enriched for RUNX1(26% vs.7%, p=0.002), SRSF2(34% vs.19%, p=0.045), and ASXL1 (18% vs.9%, p=0.11) mutations and were less likely to have NPM1 (24% vs. 51%, p=0.001) mutation. The median overall survival for IDH1 and IDH2 mutant MN caseswas 16.6 and 19.1 months, respectively. Conclusions: IDH1/2 mutated young AML patients appear to have chemo-sensitive disease. Despite excellent initial responses to intensive and non-intensive chemotherapy, the overall survival for IDH mutated pts was poor with shorter than expected remissions. Co-occurring mutations in RUNX1 and SRSF2 appeared to confer therapeutic resistance. Ongoing combination and maintenance strategies with targeted IDH1/2 inhibitors in conjunction with traditional therapies offer the potential to improve upon these outcomes in IDH1/2mutant MN. Future studies exploring the impact of early transplantation on overall survival for IDH1/2mutated MN are needed Disclosures Thota: Incyte: Speakers Bureau. Carraway:Novartis: Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Griffiths:Pfizer, Inc.: Research Funding; Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Alexion Inc.: Honoraria, Research Funding. Nazha:MEI: Consultancy. Gerds:CTI Biopharma: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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To Treat or Not to Treat? Understanding Treatment Patterns in Patients with Lower-Risk Myelofibrosis at the Time of Enrollment in the MOST Study

Blood ◽

10.1182/blood-2020-134958 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-51

Author(s):

Rami S. Komrokji ◽

Brady L. Stein ◽

Robyn M. Scherber ◽

Patricia Kalafut ◽

Haobo Ren ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Symptom Burden ◽

Risk Groups ◽

Treatment Patterns ◽

Low Risk ◽

Publicly Traded ◽

Advisory Committees ◽

Therapy Initiation

Background: Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and diminished quality of life. Treatment decisions may involve a variety of factors including prognosis and symptomatology. Data regarding real-world disease and demographic factors that contribute to therapy initiation and choice in pts with lower risk MF are limited. This analysis of data from the ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) assessed whether these factors differ for lower risk pts who were treated vs untreated at enrollment. Methods: MOST is a longitudinal, noninterventional, prospective, observational study in pts with MF or essential thrombocythemia enrolled at clinical practices within the US. Pts included in the analysis (≥18 y), had low risk MF by the Dynamic International Prognostic Scoring System (DIPSS; Blood. 2010;115:1703), or intermediate-1 (INT-1) risk by age >65 y alone. Pt data were entered into an electronic case report form during usual-care visits over a planned 36-month observation period. Pt-reported symptom burden was assessed using the MPN-Symptom Assessment Form (MPN-SAF); Total Symptom Score (TSS) was calculated (0 [absent] to 100 [worst imaginable]; J Clin Oncol. 2012;30:4098). Data were analyzed with basic descriptive and inferential statistics. Results: Of 233 pts with MF enrolled at 124 sites between 11/29/2016 and 03/29/2019, 205 were included in this analysis; 28 were excluded for being INT-1 risk for reasons other than age. Of the 205 pts, 85 (41.5%) were low- and 120 (58.5%) were INT-1 risk; 56.5% (48/85) and 59.2% (71/120), respectively, were being treated at enrollment. Pt characteristics are listed in Table 1A. Fewer low- vs INT-1 risk pts were JAK2 V617F or MPL positive, and more were CALR positive. The proportion of pts with palpable splenomegaly was similar for treated low- and INT-1 risk pts. In low risk pts, the proportion of pts with palpable splenomegaly was higher in untreated vs treated pts; whereas, in INT-1 risk pts, the opposite was observed (ie, lower proportion in untreated vs treated pts). Blood counts were generally similar across cohorts, except median leukocytes were lower for low risk treated pts and platelet counts were elevated in low- vs INT-1 risk pts. The proportion of pts with comorbidities was similar across cohorts, except for fewer cardiovascular comorbidities in low- vs INT-1 risk pts. Mean TSS was lower in low- vs INT-1 risk pts, but the proportion of pts with TSS ≥20 was greater in treated vs untreated pts in both low- and INT-1 risk groups. Fatigue was the most severe pt-reported symptom in all cohorts. Differences in mean TSS and individual symptom scores between risk groups were not significant (P > 0.05), except itching was worse among INT-1 risk pts (P=0.03). Physician-reported signs and symptoms were generally more frequent for untreated vs treated pts, irrespective of risk (all P > 0.05). Most low risk (69.4%) and INT-1 risk pts (61.2%) who were currently untreated at enrollment had not received any prior MF-directed treatment (Table 1B); the most common prior treatment among currently untreated pts was hydroxyurea (HU) in both risk groups. Of currently treated pts, HU was the most common MF-directed monotherapy at enrollment in low-risk pts, and ruxolitinib was most common in INT-1 risk pts. No low risk pts and few INT-1 risk pts were currently receiving >1 MF-directed therapy at enrollment. Conclusion: These real-world data from pts with MF enrolled in MOST show that a substantial proportion of both low- and INT-1 risk pts who had received treatment before enrollment were not being treated at the time of enrollment. Although watch-and-wait is a therapeutic option, the finding that many of these lower risk pts had in fact received prior therapies suggests an unmet need for effective and tolerable second-line treatment options. Treated pts had greater pt-reported symptom burden vs untreated pts, which suggests that high symptom burden may contribute to the decision for treatment. Prospective studies are needed to evaluate symptom burden change with therapy initiation. In this regard, future analyses of data from MOST are planned to assess the longitudinal evolution of the clinical characteristics, treatment patterns, and management of pts with MF. Disclosures Komrokji: Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria. Stein:Incyte: Research Funding; Kartos: Other: educational content presented; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kalafut:Incyte: Current Employment, Current equity holder in publicly-traded company. Ren:Incyte: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding.

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Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽

10.1182/blood-2019-128958 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1357-1357 ◽

Cited By ~ 2

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Groups ◽

Initial Therapy ◽

Intermediate Risk ◽

Advisory Committees ◽

Significant Difference ◽

Frontline Therapy ◽

Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

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

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

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

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Profiling T-Cell Receptor Diversity and Dynamics during Lymphoma Immunotherapy Using Cell-Free DNA (cfDNA)

Blood ◽

10.1182/blood-2020-141655 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-50

Author(s):

Navika D Shukla ◽

Alexander F. M. Craig ◽

Brian Sworder ◽

David M. Kurtz ◽

Charles Macaulay ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T ◽

Tcr Repertoire ◽

Support Research

Background: Characterization of T-cell receptor (TCR) diversity and dynamics is increasingly critical to understanding therapeutic immune responses targeting tumors. Current TCR profiling methods generally require invasive tissue biopsies that capture a single snapshot of immune activity or are limited by the sheer diversity of the circulating TCR repertoire. In theory, T-cells with the greatest turnover could best reflect pivotal immune dynamics from both circulating and tissue-derived compartments, including non-circulating tissue-resident memory T-cells (Trm). To noninvasively capture such responses in the blood, we developed and benchmarked a high-throughput TCR profiling approach using plasma, optimized for the fragmented nature of cfDNA and the non-templated nature of rearranged TCRs. We then applied this method for residual disease monitoring in mature T-cell lymphomas (TCL) without circulating disease and for characterizing immune dynamics after anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy of B-cell lymphomas with axicabtagene ciloleucel. Methods: We developed SABER (Sequence Affinity capture & analysis By Enumeration of cell-free Receptors) as a technique for TCR enrichment and analysis of fragmented rearrangements shed in cfDNA and applied this method using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). We used SABER to profile a total of 381 samples (300 cfDNA and 81 PBMC samples) from 75 lymphoma patients and 18 healthy controls. After mapping sequencing reads (hg38) to identify candidate rearrangements within TCR loci, unique cfDNA fragments were resolved by a novel strategy to define consensus of unique molecular identifiers clustered by Levenshtein distances, followed by CDR3-anchoring for enumeration of final receptor clonotypes. SABER thus leverages information from fragmented TCRs, a critical requirement for cfDNA, to make V gene, CDR3, and J gene assignments after deduplication-mediated error-correction. We benchmarked SABER against established amplicon-based TCR-β targeted sequencing (LymphoTrack, Invivoscribe) and repertoire analysis methods (MiXCR; Bolotin et al, 2015 Nature Methods) when considering both cfDNA and PBMC samples from healthy adults and TCL patients. We assessed SABER performance for tracking clonal molecular disease in patients with mature TCLs from both cellular and cell-free circulating compartments (n=9). Malignant TCL clonotypes were identified in tumor specimens using clonoSEQ (Adaptive Biotechnologies). Finally, we evaluated TCR repertoire dynamics over time in 66 DLBCL patients after CAR19 T-cell therapy. Results: SABER demonstrated superior recovery of TCR clonotypes from cfDNA compared to both amplicon sequencing (LymphoTrack, Invivoscribe) and hybrid-capture methods when enumerating receptors using MiXCR (Fig. 1A). When applied to blood samples from TCL patients, SABER identified the malignant clonal TCR-β rearrangement in 8/9 (88.9%) cases, with significantly improved detection in cfDNA (p=0.015, Fig. 1B). Specifically, tumoral TCR clonotype was detectable only in cfDNA in 6 cases (75%), cfDNA-enriched in 1 case (12.5%), and detectable only in PBMCs in 1 case (12.5%). We applied SABER to monitor TCR repertoire dynamics in cfDNA after CAR T-cell therapy of patients with relapsed/refractory DLBCL and observed increased T-cell turnover and repertoire expansion (greater total TCR-β clonotypes) (Fig. 1C). As early as 1-week after CAR19 infusion, TCR repertoire size was significantly correlated both with cellular CAR19 T-cell levels by flow cytometry (p=0.008) as well as with retroviral CAR19 levels in cfDNA (p=2.20e-07) suggesting faithful monitoring of CAR T-cell activity (Fig. 1D). TCR repertoire size one month after infusion was significantly associated with longer progression-free survival (HR 0.246, 95% CI 0.080-0.754, p=0.014). Conclusions: SABER has a favorable profile for cfDNA TCR repertoire capture when compared to existing methods and could thus have potential broad applicability to diverse disease contexts. Given the higher abundance of lymphoma-derived TCRs in cfDNA than intact circulating leukocytes, SABER holds promise for monitoring minimal residual disease in T-cell lymphomas. This approach also holds promise for monitoring T-cell repertoire changes including after CAR T-cell therapy and for predicting therapeutic responses. Disclosures Kurtz: Genentech: Consultancy; Foresight Diagnostics: Other: Ownership; Roche: Consultancy. Kim:Corvus: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company; Apricity Health: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy. Miklos:Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Diehn:Varian Medical Systems: Research Funding; Illumina: Research Funding; Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy. Khodadoust:Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding.

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Proposal of a Novel Latin American International Prognostic Index (LATAM-IPI) for Diffuse Large B-Cell Lymphoma (DLBCL) By the Grupo Para El Estudio De Linfoproliferativos En Latino-America (GELL)

Blood ◽

10.1182/blood-2020-142836 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-27

Author(s):

Luis Villela Villela ◽

Ana Ramirez-Ibarguen ◽

Brady E Beltran ◽

Camila Peña ◽

Denisse A. Castro ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Scoring Systems ◽

Risk Groups ◽

Training Set ◽

Extranodal Involvement ◽

Advisory Committees ◽

Internal Validation ◽

Biological Variables

Introduction. There are different scoring systems to differentiate risk groups in patients with DLBCL treated with chemoimmunotherapy. Those systems have used the same 5 variables (age, performance status, LDH, stage, extranodal involvement) for 27 years. However, LATAM data have not been included in the development of previous scoring systems. It is important to mention that novel biological variables, such as albumin, beta-2-microglobulin (B2M) and platelet/lymphocyte ratio (PLR), have been reported and could improve discrimination (Villela et al. Blood 2019; 134Suppl_1: 1613). Therefore, we carried out a large, multinational study to develop and validate a LATAM-IPI score. Methods. This is a retrospective cohort of 1030 patients with a diagnosis of DLBCL treated with standard chemoimmunotherapy with curative intent between 2010 and 2018. Data were obtained from 8 LATAM countries: Argentina, Colombia, Chile, Guatemala, Mexico, Paraguay, Peru, and Venezuela. The five classic IPI variables (age, ECOG, extranodal involvement, LDH, stage) were analyzed and albumin and PLR were added (Villela et al. Blood 2019; 134Suppl_1: 1613). B2M was not included because it was not requested regularly in all countries. Development of LATAM-IPI: The training set consisted of 85% of the sample, randomly selected, and the remaining 15% was reserved for internal validation. Using the training set, the univariate and multivariate association between clinical prognostic factors and OS was analyzed fitting Cox proportional-hazard models. Outcomes. Clinical characteristics of the training (n=878) and internal validation (n=151) cohorts are shown in Table 1. There were no statistical differences in baseline characteristics between the cohorts. The median follow-up for the whole cohort was 36 months (IQR: 11-57). When exploring the classic IPI variables on the training set, all variables were associated with high risk of mortality [age 65-74, Hazard Ratio (HR) 1.24, 95% CI 0.96 to 1.58, p=0.08; age ≥75, HR 1.71, 95% CI 1.28 to 2.28, p=0.0003), ECOG (≥ 2, HR=2, 95% CI 1.61 to 2.53; p<0.0001), EN (≥2, HR=1.53, 95% CI 1.18 to 1.97; p=0.0012), stage (III/IV, HR=2.1, 95% CI 1.64 to 2.69; p<0.0001) and LDH (ratio 1.1-2.9, HR=1.55, 95% CI 1.22 to 1.97; p=0.0003; ratio ≥3, HR= 2.68, 95% CI 1.93 to 3.7, p<0.0001). Similarly, the biological variables Albumin (≤3.5 mg/dL, HR 2.37, 95% CI 1.9 to 2.95, p<0.0001) and PLR (≥273, HR= 1.52, 95% CI 1.23 to 1.87; p=0.0001) were associated with high risk of death. Next, these variables were evaluated by multivariate analysis. The independent variables were albumin (<3.5 mg/dL, HR 1.84, 95% CI 1.45 to 2.3, p<0.0001, 1 point), LDH (ratio 1.1 to 2.9, HR 1.30, 95% CI 1.02 to 1.67, p=0.03, 1 point; ratio ≥3, HR=1.84, 95% CI 1.31 to 2.5, p=0.0004, 2 points), advanced stage (HR 1.65, 95% CI 1.27 to 2.13, p=0.0001, 1 point), age (≥75, HR= 1.51, 95% CI 1.15 to 1.98, p=0.003, 1 point), and ECOG (≥2, HR 1.40, 95% CI 1.10 to 1.77, p=0.005). Now, for the development of LATAM-IPI, the groups were distributed as follows: 0 points, low; 1-3 points, intermediate; 4-6 points, high risk. There were no differences in the distribution of the risk groups between training and validation sets (Table 2). In the learning cohort, the 5-year OS rates for low, intermediate and high risk were 81%, 63% and 33%, respectively (p<0.0001). In the validation cohort, the 5-year OS rates for low, intermediate and high risk were 81%, 63% and 44%, respectively (p=0.02) (Figure 1). Conclusions: Using multinational learning and validation cohorts including over 1,000 DLBCL patients treated with standard chemoimmunotherapy in LATAM, we developed a novel LATAM-IPI score using age ≥75 years, ECOG ≥2, advanced stage, LDH ratio (1.1-29 and ≥3) and albumin <3.5 mg/dl. Next steps are to disseminate our results with other involved researchers in LATAM to prospectively assess and reproduce our results. We expect this score will help to further define the prognosis of DLBCL patients in LATAM. Disclosures Villela: amgen: Speakers Bureau; Roche: Other: advisory board, Speakers Bureau. Idrobo:Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Tecnofarma: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Castillo:Janssen: Consultancy, Research Funding; TG Therapeutics: Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

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