Clonal Hematopoiesis of Indeterminate Potential Is Associated with Increased Age-Independent Morbidity and Mortality in Patients with COVID-19- the Beyond DNA COVID-19 Project

Abstract Background: SARS-Cov-2 infections are associated with increased mortality and morbidity, largely due to inflammatory cascades and cytokine release syndrome (CRS). Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of somatic, leukemia-associated driver mutations in apparently healthy individuals with normal blood counts. CHIP has been associated with increased inflammation, with cytokines such as IL1-b, IL6 and TNF-a being elevated at baseline in affected individuals. We hypothesized that the presence of CHIP in patients with COVID-19 would result in excessive inflammation-related mortality and morbidity. Methods: We used the Mayo Clinic COVID-19 database to identify patients with COVID-19 on whom peripheral blood mononuclear cells (PBMC) were available for research use (IRB approved). We carried out target-capture next generation sequencing for 220 CH related genes, by previously described methods (1000 x coverage, variant allele fraction/VAF detection limit >0.5%; Kusne Y et al AJH 2021). CHIP was defined by the presence of a CH mutation with a VAF>1% in an individual with normal baseline blood counts. Demographics, blood counts, and inflammatory markers (CRP and cytokine levels- ELISA assay) at COVID-19 diagnosis and during follow-up (as clinically indicated) were collected. COVID-19 disease severity was classified based on the presence and severity of CRS, graded using the Penn Grading Scale (Porter et. al., 2018), and the WHO ordinal scale (WHO Blueprint, 2020). We used Fisher's exact test and the Wilcoxon rank sum test to compare categorical and continuous variables. Survival analysis was performed using the Kaplan-Meier method. We accounted for differences in age and sex using multivariable-adjusted proportional hazards regression models. Results: Seventy-two CHIP mutations were detected in 56 (25%) of the 227 patients with COVID-19 that had PBMC available; median age 69 years (range; 42-99 years), 61% male. Fifteen (26%) patients had 2 CHIP mutations, while 1 patient had 3 CHIP mutations. Common mutations encountered included DNMT3A (32%) , TET2 (19%) , SF3B1 (8%) , ASXL1 (6%) , MPL (5%) , and TP53 (5%; Figure 1A). COVID-19 patients with CHIP were older in age (median 69 vs 57 years; p<0.0001) and had higher baseline MCP-1 (p=0.04) levels. However, there were no differences in sex, comorbidities, blood counts, IL1-b, IL6 and TNF-a levels between the two groups. The median follow-up for the entire cohort was 9 months. The relative change from baseline in blood counts and inflammatory markers (CRP and cytokines) during follow-up was similar in CHIP and non-CHIP patients, with the exception that COVID-19-onset neutropenia was more common in CHIP patients (8% vs 1%; p=0.017) compared to those without CHIP. At last follow up neutropenia had resolved in all patients. Both groups had comparable number of patients with CRS (61% CHIP vs 53% non-CHIP patients, p=0.354, Figure 1B), however, CHIP patients had more severe CRS (median Penn Grade 3 versus 2 in non-CHIP, p=0.018, Figure 1C). Based on the WHO ordinal scale, CHIP patients were more likely to experience hospitalization with severe disease and death (61% versus 45% in non-CHIP, p = 0.049). Moreover, COVID-19 CHIP patients experienced worse overall survival in comparison to patients without CHIP (median 13.1 months vs not reached, p<0.001, Figure 1D). This association remained consistent after adjusting for age and sex at the time of COVID-19 diagnosis (HR 3.15, 95% 1.32 - 7.55, p = 0.010). At last follow-up, 22 deaths were documented: 13 (23%) in patients with CHIP and 9 (5%) in the non-CHIP group (p=0.02), with the primary cause for mortality being hypoxic respiratory failure (62% in CHIP vs 44% non-CHIP, p=0.04). Conclusions: In this study, we observe an age-independent impact of CHIP on COVID-19 associated inflammatory morbidity (CRS) and mortality (hypoxemic respiratory failure). We are currently carrying out detailed single cell (ssDNA, RNA and ATAC-seq) and proteomic studies (O-link PEA assays) to better elucidate this pathophysiology. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; StemLine: Research Funding.

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Rapid Recovery in Six Patients with COVID-19 Respiratory Failure after Treatment with Vasoactive Intestinal Peptide

10.20944/preprints202008.0640.v1 ◽

2020 ◽

Author(s):

Jonathan Javitt ◽

Jihad Youssef

Keyword(s):

Respiratory Failure ◽

Vasoactive Intestinal Peptide ◽

Inflammatory Markers ◽

General Medicine ◽

Blood Oxygenation ◽

Ordinal Scale ◽

Alveolar Type ◽

Term Survival ◽

Radiographic Appearance

Background: Vasoactive Intestinal Peptide (VIP) is known to bind to and protect the Alveolar Type II cell by blocking replication of the SARS-CoV-2 virus, upregulating surfactant production, blocking apoptosis, and blocking cytokine effects. RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) has been granted Fast Track Designation and is currently in phase 2/3 placebo-controlled trials. FDA has granted Emergency Use IND and Expanded Access Protocol approval for the use of RLF-100 in patients whose comorbidities render them ineligible for inclusion in the ongoing pivotal trial. Methods: This report describes the first 6 patients with Acute Respiratory Failure in Critical COVID-19, enrolled under Emergency Use IND were treated with three successive 12-hour infusions of intravenous Aviptadil at 50/100/150 pmol/kg/hr, while continuing to receive maximal ICU care. Results: Median patient follow-up time is 14 days. So far, all treated patients have survived. Improved radiographic appearance of typical “ground glass” COVID-19 features to varying degrees is seen in all patients within 72 hours. Improvement in blood oxygenation is seen in all patients, with complete remission from respiratory failure in 4 of 6 patients. An average 56% reduction in inflammatory markers was seen, together with a median 4 point reduction in the NIAID Ordinal Scale. 2/6 patients were discharged from the hospital and 1 patient was downgraded to the general medicine floor. Comment: The short term survival of 6/6 patients with respiratory failure in the setting of COVID-19 and major comorbidity is the most dramatic response ever seen with an antiviral agent. Improvement in radiographic appearance, oxygenation requirement, and inflammatory markers is consistent with in vitro evidence of direct anti-viral effect.

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Upfront Imatinib Therapy in CML Patients with Rapid Switching to Nilotinib for Failure to Achieve Molecular Targets or Intolerance Achieves High Overall Rates of Molecular Response and a Low Risk of Progression - An Update of the TIDEL-II Trial

Blood ◽

10.1182/blood.v118.21.451.451 ◽

2011 ◽

Vol 118 (21) ◽

pp. 451-451 ◽

Cited By ~ 9

Author(s):

David T. Yeung ◽

Michael Osborn ◽

Deborah L. White ◽

Susan Branford ◽

Michael Kornhauser ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

De Novo ◽

Molecular Targets ◽

Molecular Response ◽

Advisory Committees ◽

Loss Of Response ◽

Oncology Research ◽

Highly Correlated

Abstract Abstract 451FN2 Background: While nilotinib and dasatinib produce faster responses than imatinib as first-line therapy in de novo Chronic Phase Chronic Myeloid Leukemia (CP-CML), an equally effective strategy may be to selectively use these more potent tyrosine kinase inhibitors (TKIs) only in patients who fail to achieve stringent early molecular targets or are intolerant. Aim: To update the molecular outcome and survival of patients in the TIDEL-II study. Method: TIDEL-II is a multicentre, single arm prospective ALLG trial for de novo CP-CML adult patients with two sequential cohorts each of 105 patients. All patients started on imatinib (IM) 600mg OD. Patients with IM trough levels <1000ng/mL on day 22 were dose escalated to 800mg OD (IM800). All patients were monitored for achievement of time-dependent molecular targets - BCR-ABL RQ-PCR of 10%, 1% and 0.1% IS at 3, 6 and 12 months (mo) respectively. Patients in cohort I who failed to meet these targets had dose escalation to IM800. Those patients who again failed to achieve these targets after a further 3 mo were switched to nilotinib 400mg BID (NIL). Patients in cohort 2 who failed their time dependent targets switched to NIL directly without escalating to IM800. In both cohorts, switching to NIL was also permitted for grade III/IV or persistent grade II non-haematological toxicity or loss of response. Primary end point was MMR at 12 mo (BCR-ABL '0.1%IS), with CMR4.5 being a secondary end point (BCR-ABL ≤0.0032%IS). Results: At 12 mo 69% of patients achieved MMR. With median follow up (f/u) of 20mo, AP/BC progression occurred in 5 cases (2.4%) ( Table 1). The 3 mo molecular response was highly correlated with the MMR at 12mo and progression events (table 2). COHORT 1: Using intention to treat analysis (ITT) with median follow-up of 30 mo the rate of MMR at 12 and 24 mo is 66% and 81% respectively (n=105); CMR4.5 was 12% and 24%, respectively. In total, 34/105 (32%) patients switched to NIL, 12 for failure to achieve molecular targets, 19 for intolerance and 3 for loss of response. Only 2/12 patients who failed to meet targets on IM have subsequently achieved MMR on NIL (median f/u on NIL 14 mo). Fourteen patients switched for intolerance when not in MMR, and 9 subsequently gained MMR (64%) (median f/u on NIL 19 mo). Two patients progressed to AP/BC, both in the first 12 mo in patients taking IM. One progression related death and one fatal myocardial infarction (on NIL) have been reported. Fourteen (13%) of patients remain on IM800. COHORT 2: With a median f/u of 12 mo the rates of MMR and CMR4.5 at 12 mo (n=50) were 72% and 16%, respectively (ITT). To date, 35/105 patients, (33%) have switched to NIL, of which 23 switched for failure to meet molecular targets. Subsequently, 3/23 (13%) have achieved MMR (median 6 mo on NIL). Eleven patients have switched to NIL for intolerance, 7 of them not in MMR at time of switch; 6/7 reached MMR in the subsequent 6 mo (median 5 mo on NIL). Seven patients (7%) remain on IM800. Three patients progressed to AP/BC (3%), 2 on IM and 1 on NIL. Three deaths were reported (3%), 1 from cardiac causes and 1 from stroke, both patients on IM at the time; and 1 from CML progression. Relatively short f/u precludes a meaningful comparison of results between the 2 cohorts. Conclusion: The TIDEL-II strategy has achieved a higher rate of MMR at 12 mo of 69% compared to 47% achieved with the strategy of IM intensification previously utilised in the TIDEL-I study. The improvement in molecular response is mostly attributable to improved responses in patients intolerant of IM as deeper responses were uncommon with patients who failed their early molecular targets despite intensification of kinase inhibition. Molecular response at 3 mo is highly correlated with response and progression events, underscoring the importance of early molecular targets. Disclosures: Yeung: Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. White:Novartis Pharmaceuticals: Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Hiwase:CSL: Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Arthur:Novartis Pharmaceuticals: Honoraria; BMS Oncology: Honoraria. Ross:Novartis: Honoraria, Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology: Sponsorship to professional meetings. Hughes:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS Oncology: Research Funding.

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Clinically Ascertained Monoclonal B-Cell Lymphocytosis: Risk of Progression to Chronic Lymphocytic Leukemia Requiring Therapy and Outcomes

Blood ◽

10.1182/blood.v128.22.3228.3228 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3228-3228

Author(s):

Sameer A. Parikh ◽

Kari G Chaffee ◽

Timothy G. Call ◽

Jose F. Leis ◽

Wei Ding ◽

...

Keyword(s):

High Risk ◽

General Population ◽

B Cell ◽

Cell Count ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Mutation Status ◽

Risk Of Progression ◽

Age And Sex

Abstract Background: Individuals with clinically ascertained monoclonal B-cell lymphocytosis (c-MBL) having the phenotype of the chronic lymphocytic leukemia (CLL) have a 1-4% per year risk of progression to CLL requiring therapy. The risk factors for progression and the outcomes of individuals with c-MBL are not well defined. Methods: Using the Mayo Clinic CLL Database, we identified individuals with c-MBL (absolute B-cell count of <5x109/L, in the absence of symptoms, organomegaly, splenomegaly and cytopenias) who were seen at Mayo Clinic, Rochester, MN between 01/1995 - 5/2016. Patients in whom an absolute B-cell count was not available were included in the analysis if the absolute lymphocyte count was <5x109/L. Baseline clinical characteristics and prognostic test results (including IGHV mutation status, genetic abnormalities detected by FISH, and expression of ZAP-70, CD38 and CD49d) were recorded. Time to first therapy (TFT) was analyzed using cumulative incidence methods accounting for competing risk of death. Multivariable Cox proportional hazards regression analysis was used to identify factors that predicted TFT. Because of missing data for some prognostic parameters, multiple models were run, introducing one novel prognostic factor at a time to the base model (which consisted of age and sex). Overall survival (OS) of these individuals was compared to age- and sex-matched population of the state of Minnesota. Results: Eight hundred and fifty-one individuals with c-MBL were identified and included in this analysis. Median age was 69 years (range, 38-95 years), and 527 (62%) were males. The median absolute B-cell count at the time of diagnosis was 2.6 x 109/L (range, 0.1-5.0 x 109/L). The median serum beta-2 microglobulin (β2M) was 2.2 mg/dL (range, 1.0 - 21.5 mg/dL). One hundred and nine (30%) individuals had unmutated IGHV genes, and 38 (7%) had high-risk FISH (defined as either del17p13 or del11q23). The CD38 (≥30%), ZAP-70 (≥20%), and CD49d (≥30%) status was positive in 19%, 23% and 34% individuals, respectively. After a median follow-up of 6.8 years, 99 individuals required therapy for progressive disease (at a rate of 2.1% per year, Figure 1). On multivariable analysis, the following factors were associated with a higher risk of progression to CLL requiring therapy: a) unmutated IGHV status (hazard ratio [HR]:3.8, 95%CI 2.1 - 7.0, p<0.0001); b) positive CD49d status (HR: 3.1, 95%CI 1.6 - 5.9, p=0.0006); and c) positive CD38 status (HR: 2.8, 95% CI 1.7 - 4.8, p<0.0001). Although the HR for high-risk FISH was 2.0 (95% CI 0.9 - 4.4), it was not significantly associated with TFT (p=0.11), likely due to small sample size. Age, sex, serum β2M, and ZAP-70 expression were not predictive of TFT. Among these individuals with B-cell counts <5x109/L, further stratification of the absolute B-cell count at diagnosis showed no association with TFT (Figure 2). The median OS of individuals with c-MBL was 11.8 years. Although the OS among individuals with c-MBL and the age- and sex-matched general population of Minnesota appeared similar for the first 10 years of follow-up, OS was significantly shorter in the c-MBL group during the full follow-up interval (p=0.004, Figure 3). Conclusion: In this large cohort of individuals with clinically ascertained MBL, the risk of progression to CLL requiring therapy was 2.1% per year. Biological characteristics of the B-cell clone including IGHV mutation status, and CD49d and CD38 status predicted time to first CLL therapy. On extended follow-up, the OS of individuals with c-MBL was significantly shorter relative to age- and sex-matched general population. These findings have important implications for counselling individuals with clinically ascertained MBL. Disclosures Parikh: Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding. Shanafelt:Pharmacyclics: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

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Mortality of Patients with Multiple Myeloma after the Introduction of Novel Therapies in the United States

Blood ◽

10.1182/blood-2019-124936 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 72-72 ◽

Cited By ~ 1

Author(s):

Moritz Binder ◽

Bharat Nandakumar ◽

Morie A Gertz ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Excess Mortality ◽

Early Mortality ◽

Advisory Committees ◽

Bottom Left ◽

Over Time ◽

Age And Sex

Introduction: Advances in the understanding of disease biology, the introduction of new drugs, and better supportive care have improved outcomes in multiple myeloma (MM). Most improvements have been observed in clinical trial and tertiary referral center populations but questions remain about the generalizability of these findings to patients treated in the community. Methods: We studied all patients diagnosed with MM between 01/01/2001 and 12/31/2015 who had complete demographic and overall survival (OS) data available and were seen at Mayo Clinic (MAYO) or followed in the Surveillance, Epidemiology, and End Results Program (SEER, 18 registry data 2000 - 2016, 11/2018 submission). We retrieved age at diagnosis, sex, date of diagnosis, date of last follow-up, and OS for all patients. OS was defined as the time from diagnosis to death from any cause. Patients who were alive at the end of follow-up (12/31/ 2016) were censored. OS estimates were calculated using the Kaplan-Meier method. Age- and sex-adjusted Cox models were used to assess the association between the 5-year interval of diagnosis and OS. Expected OS estimates were calculated based on United States general population rate tables (Human Mortality Database) using a conditional approach. Standardized mortality ratios (SMR) were calculated by dividing the number of observed deaths by the number of expected deaths in age- and sex-matched general United States population controls. Linear regression models were fit to test for linear trends in early mortality and SMR over time (per 5-year interval). P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 3 years lower in patients at MAYO (64 years, 15% ≥ 75 years, 60% male, n = 3293) compared to SEER (67 years, 29% ≥ 75 years, 55% male, n = 61779). After a median follow-up of 2.8 years the median OS was longer in MAYO compared to SEER (5.4 versus 4.0 years, HR 0.82, 95% CI 0.78 - 0.86, p < 0.001) and remained statistically significant after adjusting for age and sex (HR 0.91, 95% CI 0.86 - 0.95, p < 0.001). Early mortality (1-year mortality) decreased between 2001-2005 and 2011-2015: From 20% to 11% at MAYO and from 26% to 19% in SEER. When grouping OS by year of diagnosis (in 5-year-intervals) improvements were seen in both populations (A) and remained statistically significant after adjusting for age and sex. The relative improvements were similar comparing the 5-year period after the introduction of the novel therapies (2006 - 2010) to 2001 - 2005 and more pronounced in MAYO for the most recent 5-year interval (2011 - 2015, A). This trend was reflected in a steady temporal improvement in 5-year OS estimates in MAYO including the most recent 5-year interval (2011 - 2015, B bottom left). In SEER there was a comparable increase between the first two 5-year intervals but a lesser improvement in more recently (2011 - 2015, B bottom left). A diagnosis of MM remained associated with significant excess mortality in all age groups over time in both populations (B top). There was a decrease in excess mortality over time at MAYO (SMR decline per 5-year interval 1.3, 95% CI 0.9 - 1.8, p < 0.001) while there was little change in SEER (SMR decline 0.0, 95% CI -0.3 - 0.3, p = 0.917, B bottom right). Further stratifying by age at diagnosis, the decrease in excess mortality was observed mostly in patients < 75 years at MAYO (SMR decline per 5-year interval 1.7, 95% CI 1.5 - 2.0, p < 0.001, C bottom left) and to a lesser extent in older patients (SMR decline 0.4, 95% CI 0.2 - 0.6, p < 0.001, C bottom right). No such trends towards improvement were observed in either age group in SEER (C bottom). In older patients, early mortality remained approximately 30% in both populations despite continued improvements, while the 5-year OS estimates for the most recent 5-year interval (2011 - 2015) were 37% at MAYO and 26% in SEER (C top). Conclusions: Both early mortality and long-term survival have improved over time. Reductions in excess mortality were largely confined to younger patients with access to specialized care. Patients ≥ 75 years represent more than a quarter of all patients in the community, a third of them died within one year of the diagnosis, and only one in four was alive five years later. Older patients with MM remain a vulnerable population and have derived only limited benefit from recent advances in the field. Safe and effective therapies for older patients with MM remain an unmet need. Figure Disclosures Gertz: Ionis/Akcea: Consultancy; International Waldenstrom Foundation: Research Funding; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding. Dispenzieri:Alnylam: Research Funding; Akcea: Consultancy; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Celgene: Research Funding. Lacy:Celgene: Research Funding. Maurer:Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Takeda: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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High Rates of Undetectable Minimal Residual Disease Remissions with Time-Limited Bendamustine, Rituximab, and Venetoclax (BR-VR) in Untreated Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2021-150914 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1555-1555

Author(s):

Andrew H. Lipsky ◽

Brian T. Hill ◽

Allison M. Winter ◽

Joseph G. Jurcic ◽

Mark L. Heaney ◽

...

Keyword(s):

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Standard Dose ◽

Objective Response ◽

Tumor Lysis Syndrome ◽

Lymphocytic Leukemia ◽

Oncology Research ◽

Minimal Residual

Abstract Background: Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear. We hypothesized that cytoreduction with bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation for a fixed 1-year duration would be associated with an increased rate of undetectable minimal residual disease (uMRD) compared to historical controls and a reduction in the risk of tumor lysis syndrome (TLS). Here we report data from an ongoing phase 2 multicenter, US, single-arm, open-label study (NCT03609593) designed to assess the safety and efficacy of BR-VR in previously untreated CLL patients (pts). Methods: Previously untreated CLL/SLL pts ≥ 18 years requiring therapy per iwCLL criteria initially received 3 cycles of bendamustine 50-90 mg/m 2 daily for 2 days and rituximab 375 mg/m 2 every 28 days for 3 cycles. Following BR, VEN was initiated with a standard dose escalation from 20 mg to 400 mg daily over 5 weeks. This was followed by 6 cycles of VR with rituximab given monthly and 5 cycles of VEN alone (12 cycles of VEN in total). Additional eligibility included: ECOG PS ≤ 2, hemoglobin ≥8g/dL, ANC ≥1000/mm 3, and platelets ≥50,000/mm 3. Response was assessed by 2018 iwCLL criteria with uMRD testing by central flow cytometry at a level of <10 -4 in peripheral blood (PB) and bone marrow (BM). The primary endpoint was objective response rate (ORR). Secondary endpoints included uMRD rate, time to uMRD, and adverse events (AEs) assessed by CTCAE v 5.0. Results: As of data cutoff on 30 May 2021, 26 pts were accrued with additional recruitment ongoing. Baseline demographics were as follows: male/female (16/10), median age 60 yrs (range 44-77). Baseline prognostic studies showed unmutated IGHV in 16 (62%) pts, TP53 aberrant (either del(17p) and/or TP53 mutation) in 1 (4%) pt, del(11q) in 3 (12%) pts, and complex karyotype in 4 (15%) pts. TLS risk among 24 evaluable pts at baseline was high (H) in 3 (12.5%), medium (M) in 15 (62.5%), and low (L) in 6 (25%). At a median follow-up of 12.9 mo. (range, 1.9-27.5), 23 pts remain on study. Of 12 pts with at least 15 mo. follow-up (completing all therapy), the ORR was 100% (92% CR/CRi, 8% PR [due to small residual nodes]). 3 pts died on study (2 due to COVID-19 and 1 developed newly metastatic squamous cell carcinoma and taken off study after achieving a CR post-VEN ramp-up). Bendamustine was administered at doses of 50 mg/m 2 in 47%, 70 mg/m 2 in 11%, and 90mg/m 2 in 42% of pts. In 20 evaluable pts, response assessments after cytoreduction with BR demonstrated 15% of pts achieved CR/CRi and 85% achieved PR. For evaluable pts at 16 mo., uMRD (<0.01%) in the PB and BM was observed in 100% (10/10) and 90% (9/10) of pts, respectively. MRD was intermediate (0.01% - <1.0%) in 10% (1 patient) in BM (Figure 1 ORR and MRD). Median time to uMRD was 12 mo. (range 3-15) in PB and 14 mo. (range 5.5-15) in BM. The most common treatment-emergent AEs during BR induction were (any grade/grade ≥3) anemia in 6/2 (21%/7%) pts, nausea in 6/0 (21%/0%), neutropenia in 5/2 (18%/7%), rash in 5/0 (18%/0%), constipation 4/0 (14%/0%), and transaminitis in 3/0 (11%/0%). 2 pts (7%) developed febrile neutropenia during BR. Emergent AEs during VEN treatment included diarrhea in 10/0 (36%/0%) pts, neutropenia in 6/3 (21%/11%), leukopenia in 5/2 (18%/7%), and nausea in 4/0 (14%/0%). TLS risk was substantially reduced after BR lead-in. Of 3 H-risk pts at baseline, none remained H-risk after BR; of 15 M-risk pts, only 1 remained M-risk, with the remainder at L-risk (94% reduction in H- or M- risk TLS). Conclusions: BR-VR is a safe and well-tolerated regimen in untreated CLL pts. BR debulking substantially reduces TLS risk, and this sequential strategy achieves high rates of PB and BM uMRD across all prognostic risk groups. Figure 1 Figure 1. Disclosures Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Heaney: CTI: Honoraria, Research Funding; Blueprint: Honoraria, Research Funding; Novartis: Honoraria; Sierra Oncology: Research Funding; Cogent: Research Funding; BMS: Research Funding; Kartos: Research Funding. Lamanna: MingSight Pharmaceuticals, Inc.: Research Funding; Gilead Sciences, Inc.: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics, Inc.: Research Funding; Oncternal Therapeutics: Research Funding; Celgene Corporation: Consultancy; Genentech, Inc.: Consultancy, Research Funding; Verastem Oncology: Research Funding; TG Therapeutics, Inc: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy. OffLabel Disclosure: Venetoclax, Bendamustine, and Rituximab are all FDA approved for use in first-line CLL. The combination of these three agents and dosing schedule utilized in this clinical trial is novel and therefore technically reflects an off-label use.

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CD70 Expression in Mature T-Cell Lymphomas

Blood ◽

10.1182/blood-2021-146990 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4493-4493

Author(s):

Mario L. Marques-Piubelli ◽

Luisa Solis Soto ◽

Swaminathan Padmanabhan Iyer ◽

Jason Sagert ◽

Minh Thu Pham ◽

...

Keyword(s):

T Cell ◽

Mycosis Fungoides ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Advanced Age ◽

Oncology Research ◽

T Cell Lymphomas ◽

Pathologic Classification

Abstract Introduction Mature T-cell lymphomas (TCLs) represent about 15% of the non-Hodgkin lymphomas in U.S. and are a heterogeneous group of neoplasms. TCLs usually have poor outcomes and are resistant to conventional chemotherapy regimens. Therefore, there is a need for identifying biomarkers that could translate into effective novel treatments. CD70 is the TNF superfamily ligand of CD27 and it is being explored as a potential target in CAR-T therapy against TCLs and other neoplasms. Although CD70 expression has been documented in TCL cell lines, thus providing a potential rationale for its use as a therapeutic target, the expression of CD70 among the most frequent TCL subtypes in patient samples has not been previously evaluated. Methods Patients with de novo and/or relapsed mature TCLs diagnosed between 01/2010 and 06/2020 and with available tissue sections were included in the study. The assessment of CD70 expression was performed by immunohistochemistry (IHC) using a novel proprietary antibody developed by CRISPR Therapeutics. CD70 expression was scored using % of expression, intensity (negative, +1, +2, and +3) and H-score {H-score = [(%positive cells intensity 1+) x 1] + [(%positive cells intensity 2+) x 2] + [(%positive cells intensity 3+) x 3]} in neoplastic cells (Figure 1). Clinicopathologic characteristics were collected retrospectively and included age, sex, staging, biopsy site, WHO pathologic classification, immunophenotype, presence of other malignancies, treatment status, disease progression/relapsed, and follow-up. These characteristics were compared with CD70 expression using ANOVA or non-parametric analysis. Overall-survival (OS) was estimated using Kaplan-Meier method and compared using log-rank. A p< 0.05 was considered statistically significant. Results One hundred thirty-six patient samples representing the major subtypes of the 4 categories of mature TCLs were included [nodal TCLs (n=64; including PTCL Th1, and Th2 subtypes and angioimmunoblastic T cell lymphoma - AITL), extranodal (n=35; including primary intestinal lymphomas), cutaneous (n=24; including mycosis fungoides (MF) with large cell transformation), and leukemic (n=13; including adult T cell leukemia/lymphoma)]. Most patients were male (58.8%), in the 6 th or 7 th decade (47.1%), with advanced stage IV (55.7%), no previous malignancies (69.9%) and previously treated (57.2%); 59 of which (88%) received two or more lines of treatment. The median expression of CD70 was 40% (ranged from 0 to 100%) and the median H-score was 110 (ranged from 0 to 300) and was significantly higher (p= 0.006) in peripheral T-cell lymphoma, NOS, primary cutaneous TCLs (non-mycosis fungoides), and AITL (180, 150, and 150, respectively) (Figure 1). The expression of CD70 was more frequent in nodal and extranodal subtypes (including skin), compared to leukemic TCLs (p= 0.005). The expression of CD70 was associated with advanced age at the diagnosis (p= 0.003), CD2 expression (p= 0.01), CD3 expression (p= 0.001), CD16 negativity (p= 0.03), and absence of ALK-1 expression (p= 0.005). After a median follow-up of 19 months (range: 1 - 300 months), 42% of the patients died of disease. The median OS was 76 months (CI95, 38.5 - 113.4 months) and it was not associated with CD70 expression. Conclusions CD70 was highly expressed in most mature TCLs and it was negative in most ALK-positive ALCL. Its expression was associated with nodal and extranodal subtypes, advanced age, expression of CD2, CD3, and negativity for CD16. Therefore, CD70 can be used as a potential biomarker and a target in clinical trials of patients with mature TCLs. Figure 1 Figure 1. Disclosures Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding. Sagert: CRISPR Therapeutics: Current Employment. Pham: CRISPR Therapeutics: Current Employment. Tipton: CRISPR Therapeutics: Current Employment. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding.

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Hepcidin and GDF15 Levels during the First 2 Years Follow-up in Patients with Low and Int-1 Risk Myelodysplastic Syndromes (MDS) from the European Leukemianet MDS Registry

Blood ◽

10.1182/blood.v124.21.3267.3267 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3267-3267

Author(s):

Louise De Swart ◽

Chloé Reiniers ◽

Tim Bagguley ◽

Corine van Marrewijk ◽

David Bowen ◽

...

Keyword(s):

Lower Risk ◽

Research Funding ◽

Diurnal Fluctuation ◽

Ineffective Erythropoiesis ◽

Reactive Protein ◽

Oncology Research ◽

Iron Parameters ◽

Transfusion History ◽

Over Time

Abstract Background: The EUMDS registry is a prospective observational registry to collect data on lower risk MDS. 17 Countries and 133 centers are participating. We analyzed serum from 101 patients for ferritin, hepcidin, growth differentiation factor 15 (GDF15) and C-reactive protein (CRP) at six-month intervals in order to evaluate temporal changes in iron metabolism. Objective: To explore hepcidin and GDF15 levels over time in lower risk MDS patients and their relation with WHO2001 subtype, transfusion history and conventional iron parameters. Results: The median age of the study population was 73 years (range 44-95 years). The majority was male: 64%. Distribution according to WHO2001 MDS subtype was RCMD (41%), RARS (25%), RA (14%), RAEB (11%), 5q-syndrome (6%) and RCMD-RS (3%). Table 1 shows iron parameters at registration, 1 year and 2 years follow-up both in transfusion-dependent (TD) and transfusion-independent (TI) patients and stratified according to MDS subtypes: RS (RARS/RCMD-RS) or MDS Other (RA/RCMD/RAEB/5q-syndrome). Serum ferritin was increased in TD patients with a median concentration at registration of 550µg/L and at 2 years 818µg/L, compared to TI patients (median <250µg/L, all time points). During follow-up ferritin was most elevated in patients who received >10 red blood cell (RBC) units: median at registration 1482µg/L - 2 years 1970µg/L. Ferritin correlated significantly with hepcidin (r=0.57; p<0.001) as well as CRP: r=0.27, p<0.001. Median CRP was within reference range (<10mg/L) for both TD and TI patients at registration and during follow-up, but mainly TD patients had elevated CRP levels >50mg/L. Median serum hepcidin levels were elevated in TD patients at registration and remained elevated during follow-up, especially in patients with >10 RBC units transfused (median 27.4nmol/l at registration, 12.8nmol/l at 2 years). Remarkable fluctuation in hepcidin levels occurred in patients with elevated hepcidin during follow-up. Even in the longitudinal cohorts hepcidin fluctuated considerably, maybe due to the interval between the previous transfusion and the measurement of hepcidin or due to diurnal fluctuation. Hepcidin was lowest in MDS RS TI patients and showed a tendency to decrease over time from a median level of 4.4nmol/l at registration to 2.4nmol/l after 2 years, associated with ineffective erythropoiesis. This is supported by the high median GDF15 in these patients. Lowest GDF15 was found in TD patients with ‘MDS Other’ associated with transfusional load. The number of transfused RBC units did not affect the median GDF15 levels. Conclusions: Hepcidin levels were influenced by RBC transfusion history, but hepcidin levels appear to decrease over time in the RS subtype only. Interestingly, increase in hepcidin after transfusions was already visible early in follow-up, depending on the transfusional load and erythropoietic activity of the bone marrow. GDF15 concentration appeared to be most related to MDS subtype, functioning as a marker of ineffective erythropoiesis. Table1: ferritin, hepcidin and GDF15 during-follow-up Registration 1 yr follow-up 2 yrs follow-up N Median (p25-p75) N Median (p25-p75) N Median (p25-p75) Ferritin (µg/L) 101 286 (138 - 558) 83 287 (149 - 845) 66 347 (191 - 818) MDS Other: TI 53 205 (87 - 389) 31 148 (78 - 288) 25 202 (71 - 319) MDS Other: TD 20 479 (279 - 877) 29 845 (481 - 1538) 22 841 (323 - 2387) RARS/RCMD-RS: TI 25 268 (195 - 558) 19 233 (170 - 323) 10 319 (222 - 379) RARS/RCMD-RS: TD 3 610 (108 - 1382) 4 1909 (1206 - 2935) 9 712 (590 - 1222) Hepcidin (nmol/L) 100 5.2 (3.0 - 9.9) 83 5.8 (2.7 - 14.0) 66 5.2 (2.5 - 9.9) MDS Other: TI 53 4.6 (2.8 - 8.4) 31 4.4 (2.3 - 8.1) 25 4.2 (2.5 - 6.8) MDS Other: TD 20 11.1 (4.9 - 21.0) 29 17.2 (9.2 - 22.3) 22 9.6 (4.5 - 17.1) RARS/RCMD-RS: TI 24 4.2 (2.1 - 6.1) 19 3.5 (1.6 - 5.1) 10 2.4 (1.6 - 3.9) RARS/RCMD-RS: TD 3 9.8 (6.0 - 11.1) 4 9.3 (7.3 - 12.1) 9 5.2 (2.9 - 9.3) TI: 0 RBC units 81 4.5 (2.8 - 8.4) 51 4.0 (2.0 - 7.5) 37 3.1 (2.1 - 6.7) TD: ≤10 RBC units 17 10.6 (4.7 - 14.9) 14 9.2 (5.3 - 17.2) 14 4.3 (2.4 - 8.7) TD: >10 RBC units 2 27.4 (15.7 - 39.1) 18 18.1 (12.7 - 24.5) 15 12.8 (9.3 - 21.3) GDF15 (ng/L) 101 1945 (1207 - 3611) 82 2467 (1659 - 4318) 66 2582 (1519- 5332) MDS Other: TI 53 1831 (1100 - 3176) 31 1902 (1076 - 2698) 25 1702 (1136 - 3564) MDS Other: TD 20 1452 (1169 - 2789) 28 2583 (1937 - 4493) 22 2556 (1661 - 4050) RARS/RCMD-RS: TI 25 3532 (2124 - 4211) 19 3148 (2195 - 4560) 10 3661 (1986 - 5524) RARS/RCMD-RS: TD 3 2196 (1869 - 2893) 4 2996 (1806 - 5141) 9 5555 (3204 - 7488) Disclosures Hellström-Lindberg: Celgene: Research Funding. Symeonidis:Celgene: Research Funding; Novartis Oncology: Research Funding; Amgen: Research Funding; Novartis Oncology: Consultancy; Amgen: Consultancy. de Witte:Novartis: Research Funding; Novartis: Honoraria; Celgene: Consultancy; Novartis: Consultancy.

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Monitoring of Minimal Residual Disease (MRD) of DNMT3A Mutations (DNMT3Amut) in Acute Myeloid Leukemia (AML): A Study of the AML Study Group (AMLSG)

Blood ◽

10.1182/blood.v126.23.226.226 ◽

2015 ◽

Vol 126 (23) ◽

pp. 226-226 ◽

Cited By ~ 2

Author(s):

Verena I. Gaidzik ◽

Daniela Weber ◽

Peter Paschka ◽

Anna Kaumanns ◽

Stefan Krieger ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Continuous Variable ◽

Prognostic Impact ◽

Advisory Committees ◽

Clinical Endpoints ◽

Clonal Hematopoiesis ◽

Significant Difference ◽

The Impact

Abstract Background: The DNA methyltransferase 3A (DNMT3A) is one of the most frequent mutated genes in AML with a hot spot mutation at codon R882 in 80% of the DNMT3Amut cases. In most of the studies DNMT3Amut predicts for poor overall (OS) and relapse-free survival (RFS). Recently, DNMT3Amut have been associated with age-related clonal hematopoiesis, and they have been identified in early preleukemic stem cells. These findings suggest that DNMT3Amut represents an early event in leukemogenesis and may be part of the leukemia founder clone in most AMLs harboring a DNMT3Amut. We thought to address the question whether MRD monitoring in DNMT3Amut patients (pts) can be used for prognostic classification and risk stratification in these pts. Aims: We monitored MRD for the most common DNMT3Amut (DNMT3Amut -R882H, n=126 and -R882C, n=55) in a large cohort of adult AML pts entered on three AMLSG treatment trials [AML HD98A (n=14; NCT00146120), AMLSG 07-04 (n=86; NCT00151242), AMLSG 09-09 (n=81; NCT00893399)]. Methods: DNMT3Amut MRD monitoring was performed using a cDNA-based RQ-PCR-assay by TaqMan technology with a sensitivity between 10-3 and 10-4. MRD levels are reported as normalized values of DNMT3Amut transcripts per 104ABL1 transcripts (DNMT3Amut/104ABL1). Results: In total, 1,494 samples [bone marrow (BM), n=798; peripheral blood (PB), n=696] from 181 DNMT3Amut pts were analysed [diagnosis, n=287; during therapy, n=840; follow-up, n=367]. Median age of the patients was 50 years (range, 22 to 78); median BM DNMT3Amut transcript level (TL) at the time of diagnosis was 12690 (range, 1396-54280). There was no significant association of TL with presenting clinical characteristics, such as age, white blood cell count, platelet count, BM and PB blasts, lactate dehydrogenase, or with mutations in NPM1, FLT3 [ITD and TKD], CEBPA and cytogenetics. DNMT3Amut TL as log 10 transformed continuous variable and stratified by study did not impact OS (p=0.29), RFS (p=0.17) and EFS (p=0.28). Comparing TL after double induction (DI) did not show a significant difference between 13 patients without complete remission (CR) and 117 in CR (12983 and 12595, respectively; p=0.52). In Cox regression analyses, BM DNMT3Amut TL as log 10 transformed continuous variable during therapy did not impact the clinical endpoints death and relapse. In general, DNMT3Amut TL during therapy (after induction I, induction II, consolidation I and II) were significantly higher in BM than in PB (p=0.01; p=0.05; p=0.004; p=0.008, respectively). We observed the greatest TL reduction (one log) after induction I, whereas subsequent cycles of therapy did not significantly influence TL. To evaluate the impact of DNMT3Amut MRD monitoring with regard to the clinical endpoints OS, cumulative incidence of relapse (CIR) and remission duration (RD) after DI and after end of therapy (ET) we used different statistical approaches; all survival analyses were stratified by study. After DI and ET, only 8/90 and 4/88 BM samples became MRD negative. At these two time-points MRD positivity did not significantly impact OS (p=0.99; p=0.74), CIR (p=0.73; p=0.15) and RD (p=0.83; p=0.16). Next, we investigated the MRD DNMT3Amut log10-reduction (compared to levels at diagnosis) after DI and ET using the median as a cut-off. Again, we could not detect a significant correlation for pts with a higher TL reduction compared with pts with a lower TL reduction for OS and RD after DI and ET (p=0.83; p=0.30; p=0.04; p=0.21, respectively). Lastly, we evaluated the BM DNMT3Amut TL as 4 increasing equally sized intervals according to the quartiles of the distribution. There was no prognostic impact after DI on OS and RD (p=0.53; p=0.89) and ET (p=0.76; p=0.53). When combining PB and BM samples for the analyses we could not find significant changes in the results. Conclusion: In our study most pts had persistent DNMT3Amut TL with only a minority achieving MRD negativity, a finding that supports the presence of persistent clonal hematopoiesis in hematologic remission. Using different explorative approaches, DNMT3Amut TL did not impact clinical outcome neither during therapy nor during follow-up. Disclosures Horst: Gilead: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Boehringer Ingleheim: Research Funding; Amgen: Honoraria, Research Funding. Schlenk:Arog: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees.

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The Strategy of Early Nilotinib Switch Based on Failure to Achieve Optimal Molecular Targets on Imatinib May Not Overcome the Negative Impact of a Low OCT-1 Activity in De-Novo CP-CML Patients

Blood ◽

10.1182/blood.v118.21.1690.1690 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1690-1690

Author(s):

Deborah L. White ◽

Verity A Saunders ◽

Amity Frede ◽

Kelvin GrootObbink ◽

Cassandra Slader ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Molecular Targets ◽

Molecular Target ◽

Molecular Response ◽

Advisory Committees ◽

Log Reduction ◽

Oncology Research ◽

Significant Difference

Abstract Abstract 1690 Background: We have previously identified that low OCT-1 activity (OA) is a poor prognostic indicator in CP-CML patients treated with imatinib (IM). Importantly, a very low OA (OA≤4ng/200,000 cells) is associated with a significant risk of poor molecular response, kinase domain mutations and transformation. The TIDEL II strategy of early intervention, via dose escalation and/or switch to nilotinib (NIL) may reduce the incidence of poor response/therapeutic failure in CP-CML patients, particularly those with very low OA. Methods: Patients in Cohort I (n=105) of the TIDEL II trial were switched to NIL for either IM intolerance, or failure to demonstrate a clinical benefit from IM dose escalation which was triggered by failure to achieve time dependent molecular targets: ≤10% BCR-ABL by 3 m, ≤1% BCR-ABL by 6 m or ≤0.1% BCR-ABL by 12 m. In Cohort II (n=105) patients failing to achieve these molecular targets were switched directly to NIL without prior IM dose intensification. All patients, where possible, had OA measured at diagnosis. Only therapeutic changes prior to 24 months, and patients with a minimum of 6 months exposure to NIL are considered in this analysis. Results: (Table 1) Cohort I: Median follow-up 30 months. The overall rate of major molecular response (MMR) by 12 months was 66%. There was a significant difference in the rate of MMR between patients with low OA (n=49) compared to those with higher OA (n= 54): 49% vs 76%, p=0.007. The overall rate of MMR by 24 months was 81%. Again, patients with low OA (n=46) achieved MMR at a significantly lower rate compared to those with higher OA (n=54): 65% vs 91%, p= 0.003. Thirty patients have switched to NIL, 19/30 because of IM intolerance (av. time on IM 8.5m.) and 11/30 because of molecular target failure (av. time on IM 12.8m). 14/14 intolerant patients not in MMR at the time of switch have achieved MMR on NIL with an average log reduction of 2.8, and 9/18 have achieved CMR. In contrast, 1/9 patients switched for molecular target failure has achieved MMR on NIL, with an average log reduction of 0.65. Importantly, 3/19 withdrew from study due to CML related events. Cohort II: Median follow-up 12 months. To date, 22/105 patients have switched to NIL and have a minimum of 6 months follow-up: 11 for intolerance and 11 for molecular target failure. All patients switched for intolerance achieved and/or maintained MMR on nilotinib, with an average log reduction of 2.89. In contrast, 1/11 patients switched for molecular target failure achieved MMR, with an average log reduction of 0.95 and CCyR has been achieved in 5/10 patients not previously in CCyR. 2/11 of these patients have withdrawn from study. There was a significant difference in the time of switch to NIL, and the length of imatinib exposure between the 2 cohorts for intolerance, and a significant difference between the cohorts in the length of IM exposure for patients with target failure. However, this did not translate to a significant difference in molecular response between the 2 cohorts, suggesting the length of prior IM exposure is not a determinant of subsequent NIL response. Importantly in both cohorts, the OA of those patients switched to NIL based on molecular target failure was significantly lower than that of those who switched for intolerance (p=0.007 and p=0.003) and those patients remaining on IM (p=0.004). Conclusion: Switch to NIL significantly improves response in IM intolerant patients. The majority of patients who switch for molecular target failure on IM do not subsequently achieve MMR on NIL. This suggests that a low OA may delineate a group of CP-CML patients intrinsically insensitive to TKI therapy, for whom switch to NIL either following IM dose intensification (Cohort 1) or as a primary strategy (Cohort II) may not result in an improvement in response. A different first-line strategy may be more effective for this poor risk subgroup. Disclosures: White: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Slader:Novartis Pharmaceuticals: Employment, Equity Ownership. Yeung:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Osborn:Novartis Pharmaceuticals: Research Funding; BMS Oncology: Research Funding. Mills:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Sponsorship to professional meetings; BMS Oncology:. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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499. Rapid and Sustained Decline in CXCL-10 (IP-10) Annotates Clinical Outcomes Following TNF-α Antagonist Therapy in Hospitalized Patients with Severe and Critical COVID-19 Respiratory Failure

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.698 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S351-S352

Author(s):

Courtney Schroeder ◽

Hilal Hachem ◽

Amandeep Godara ◽

Daniel Fein ◽

Hashim Mann ◽

...

Keyword(s):

Respiratory Failure ◽

Primary Endpoint ◽

Inflammatory Markers ◽

Supplemental Oxygen ◽

Hospitalized Patients ◽

Infliximab Therapy ◽

P Value ◽

Antagonist Therapy ◽

Ifn Γ

Abstract Background TNFα and IFN-γ may synergize to induce cytokine-driven lethal hyperinflammation and immune exhaustion in COVID-19 illness. Methods To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay), secondary infections, duration of supplemental oxygen support and hospitalization. Consort diagram Hospitalized patients with SARS-COV2 infection and pneumonia that were referred to the infliximab-abda study team for evaluation. Results Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65 years age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infections. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant declines in IFN-γ, TNFα, IL-27, IL-6 (baseline above 10pg/ml), CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unaffected. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006). Demographics and clinical characteristics Demographics, comorbidities, clinical features, inflammatory markers, and outcomes of 18 patients with COVID-19 respiratory failure treated with infliximab-abda between April and December 2020. Changes in oxygen support status following infliximab-abda treatment Colored bars indicate the maximal level of oxygen support for each individual following treatment with infliximab-abda. The status of the patient at last follow-up (discharged, alive or dead) is indicated. ECMO: extracorporeal membrane oxygenation Control of inflammatory markers and cytokines following infliximab therapy Values from individuals are connected with solid lines, with deceased individuals indicated in red. Statistics: n=18, paired ratio t-test compared to baseline; *: P<0.05, **: P<0.01, ***: P<0.001, ****: P<0.0001, n.s.: not significant. Conclusion Consistent with a central role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are formally evaluating infliximab therapy in this context. Funding: National Center for Advancing Translational Sciences Disclosures All Authors: No reported disclosures

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