Fit Pts Research Articles

Frailty risk assessment and impact on acute myeloid leukemia outcomes (FRAIL-AML): A population-based study from Ontario, Canada.

6506 Background: In acute myeloid leukemia (AML), treatment decisions, specifically intensive versus non-intensive approaches, depend on the clinician’s assessment of patient fitness. Frailty as a measure of fitness is a broader concept than commodities and is associated with worse outcomes in many cancers. Frailty assessment is incorporated to provide the precision to oncology treatment selections in addition to disease-related factors. The impact of frailty on outcomes in AML is not well studied. Methods: This retrospective cohort study from population-based health administrative databases in Ontario, Canada (ICES) included all patients (pts) ≥18 years diagnosed with AML between 2006 and 2021, treated within 90 days after diagnosis. Frailty was measured using McIsaacs’s frailty index (MFI)- a validated tool. Progressively increasing tertiles of MFI were categorized as fit (FT), pre-frail (PFR), or frail (FR). Treatment intensity was classified as intensive (IT) or non-intensive (NIT) based on standard practices. The primary outcome was overall survival (OS). Association of frailty with OS was measured using Cox regression separately for IT and NIT AML. Results: Out of 5450 pts, with a median age of 65 (IQR 54-74), 55.8% were males and 44.2% were females. 65% (n=3543) received IT, out of which 29.4% and 35.5% pts were FR and PFR respectively. Remaining 35% (n=1907) received NIT, with 41.1% and 32.3% pts being FR and PFR. Median overall survival in months (OS, 95% CI) for the entire group, IT, and NIT were 12.5 (12.0-13.2), 16.7 (15.7-18.2), and 7.6 (7.0-8.2), respectively. OS (table) was notably lower in FR pts compared to fit pts (p<0.0001) in both IT and NIT. Univariate and multivariate analyses identified frailty, advanced age, and previous non-AML malignancy as risk factors associated with worse OS in both IT and NIT groups (table). Conclusions: Higher frailty is independently associated with worse OS in AML pts after adjusting for advanced age. A substantial proportion of AML pts in both IT and NIT groups exhibit a mismatch in treatment intensity assignments based on their frailty status, with about 30 % FR pts receiving IT and over 25 % FT pts receiving NIT. This study sheds light on the need for frailty evaluations using standardized tools to optimize treatment decisions in AML pts. [Table: see text]

The Impact of Fitness and Dose Intensity on Safety and Efficacy Outcomes after Venetoclax-Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia

Introduction Following the results of two phase-III studies, the CLL14 study, recruiting elderly and unfit patients (pts) with chronic lymphocytic leukemia (CLL), and the CLL13 study, recruiting younger and fit pts, venetoclax-obinutuzumab (Ven-Obi) is a standard of care for pts with treatment-naive CLL. However, it is unclear whether age and/or fitness have an impact on the tolerability and efficacy of Ven-Obi. Furthermore, the impact of dose reductions on response and survival has not been explored yet. Here, we present a pooled analysis detailing the toxicity and efficacy of Ven-Obi in pts treated within the CLL13 and CLL14 studies. Methods Patients randomized to the Ven-Obi arm in CLL14 (2015-2016) and CLL13 (2016-2019) with at least one dose of study drug were considered and categorized as fit or unfit pts (cumulative illness rating scale [CIRS] > 6 and/or creatinine clearance < 70 ml/min). Patients with TP53 aberrations were excluded to ensure balanced features across the CLL13 and CLL14 populations. Correlations regarding minimal residual disease (MRD) in peripheral blood and response (both assessed at the end of treatment [EOT]) were assessed by chi² test. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier methodology and Cox proportional hazard regression modeling. Dose intensity was calculated as the relative fraction within the administered treatment cycles (excluding pts with treatment discontinuation due to PD/death). Adverse events were analyzed up to 28 days after EOT. Results In total, 410 pts were considered for this analysis, 228 from CLL13 and 182 from CLL14. The median observation time was 49 months (interquartile range [IQR] 37.0-65.8 months); for CLL13, median observation time was 38.9 months (IQR 33.8-46.3), and 66.7 months in CLL14 (IQR 64.4-70.8). Median age at enrollment was 67 years (IQR 58-73); 55.7% were grouped as unfit (median age 72), 44.3% as fit (median age 58) ( A). Overall response rate (ORR) was 89.5% in unfit and 96.1% in fit pts (p=0.011), CR rates were 51.8% and 54.1% (p=0.63), respectively. The undetectable MRD (<10 -4) rates were 80.3% in unfit and 85.1% in fit pts (p=0.2). The 3-year-PFS rates were 86.4% in unfit vs 87.5% in fit pts (HR 1.12, 95%-CI 0.70-1.81, p=0.63, B). The 3-year-OS was 91.8% in unfit vs 96.9% in fit pts (HR 2.02, 95% CI 0.90-4.55, p=0.088). Adverse events (any grade) considered of interest included neutropenia, which occurred in 62.7% of unfit and 56.9% of fit pts (febrile neutropenia 4.4% in each group), respectively. Infusion-related-reactions (IRR) occurred in 44.3% of unfit and 56.9% of fit pts. Fatigue was reported in 15.8% of unfit and 35.9% of fit pts; headaches in 9.2% of unfit and 18.2% of fit pts. Infections occurred in 57.5% of unfit and 69.6% of fit pts; in particular, nasopharyngitis was reported for 10.5% of unfit and 24.3% of fit pts. Covid-19 occurred in 3 unfit (3 fatal) and 5 fit (2 fatal) pts. Other common adverse events were balanced between fit and unfit pts. Comparable patterns were also observed when comparing young vs older pts according to exploratory age cut-offs between 65 to 80 years. Early venetoclax discontinuations for reasons other than PD or death (e.g., adverse events, withdrawal) were more common in unfit than in fit pts (15.8% vs 5.0%). Median time to early discontinuation was 6.3 months (3.1-8.7). Patients with early venetoclax discontinuation had a 3-year-PFS from EOT of 71.2%, compared with 83.0% in pts who completed venetoclax as planned (HR 2.25, 95%-CI 1.32-3.83, p=0.003). The 3-year-OS from the EOT was 84.3% and 94.0% (HR 2.48, 95%-CI 1.10-5.59, p=0.029), respectively. Dose reductions <80% (excluding PD/death) occurred in 15.7% of all pts (14.7% unfit, 16.5% fit). ORR in pts with venetoclax dose intensity <80% was 82.5% and 95.9% in pts with dose intensity ≥80% (p<0.001). CR rates were 42.9% and 55.5% (p=0.066), uMRD rates were 76.2% and 85.3% (p=0.073). The 3-year-PFS from the EOT for pts with and without venetoclax dose intensity <80% was 81.0 % and 82.2%, respectively (HR 1.47, 95%-CI 0.84-2.57, p=0.175). Conclusion This analysis confirms the feasibility and efficacy of Ven-Obi for both fit and unfit pts with CLL. The incidence of toxicities was comparable between both patient groups, although IRR and fatigue were more common in fit pts. Reduced venetoclax dose intensity had no impact on PFS, suggesting that dose modifications may have limited impact on long-term clinical outcomes.

Applicability of SIE/Sies/GITMO Fitness Criteria to Therapy-Related and AML-MRC Receiving CPX-351: Results from a Large, Retrospective, Multicentric, Observational Study

Introduction: Treatment of therapy-related AML (t-AML) and AML evolving from an antecedent myelodysplastic syndrome (AML-MRC) represent a clinical unmet need being characterized by an unfavorable outcome. Among the emerging treatment options, CPX-351 has been approved by Regulatory Authorities for the treatment of fit patients (pts) affected by these AML sub-types. Although patented for the treatment of pts fit for intensive chemotherapy, in real-life CPX-351 is also administered to unfit ones, raising the case of tolerability in these categories. Among scores for fitness definition, SIE/SIES/GITMO criteria were extensively validated in large cohorts of AML pts receiving intensive chemotherapy and are increasingly incorporated into clinical trials. However, since these criteria have not been tested yet in the subset of t-AML and AML-MRC, we investigated their applicability in these pts receiving CPX-351. Methods: Patients classified as t-AML or MRC-AML according to WHO2016 classification receiving at least one cycle of CPX-351 were included in the present analysis. Genetic and cytogenetic data were classified according to ELN2017 risk stratification. SIE/SIES/GITMO criteria were retrospectively applied to the whole series to categorize pts as fit or unfit to intensive chemotherapy (Ferrara et. al, Leukemia 2013), aiming at evaluating early-death rate and overall survival (OS). We also verified if ELN2017 risk-stratification might provide further information about long-term outcome, independently of fitness assessment. Results: This retrospective study includes 398 pts with t-AML (19.3%) or AML-MRC (80.7%) enrolled from 29 Italian Institutions between 2018 and 2023. Median age was 65 years (range 32-79), with a slight male prevalence (56.8%). According to SIE/SIES/GITMO criteria, 323 (81.2%) pts qualified as fit and 75 (18.8%) as unfit. Based on ELN2017 risk stratification, 17 (4.3%) pts were classified as favorable, 162 (40.7%) as intermediate, 217 (54.5%) as adverse risk. Only 2 (0.5%) pts were not classifiable due to incomplete genetic data. No differences were observed in terms of ELN2017 risk distribution among the fit and unfit groups. After first induction, 188 of 323 (58.2%) fit and 42 of 75 (56%) unfit pts achieved a complete remission (CR), for a total of 230 (57.8%) pts entering CR. From CPX-351 start, 18 and 55 deaths at 28 days and at 100 days occurred, respectively. Early death rate at these early timepoints statistically differed between the two groups (3% vs. 10.7% at 28 days and 10% vs. 28% at 100 days for fit and unfit pts respectively; p<0.05). No excess of mortality was observed for unfit patients at any timepoint after 100 days from first CPX-351 induction. Competitive risk analyses showed no differences in terms of early death by relapse between the two groups. With a median follow up of 24 months, unfit pts were characterized by a significantly shorter OS as compared to fit ones (median OS of 8 months [CI 95%: 4.1-11.8] and of 18 months [CI 95%: 14.7-21.1] for unfit and fit pts, respectively; p<0.0001) [Figure 1]. When stratified according to genetic/cytogenetic, median OS of fit pts was commensurate with ELN2017 risk (median OS not reached vs 20 months vs 13 months for favorable vs intermediate vs adverse risk, respectively; p < 0.01), whereas no differences in median OS were observed between favorable, intermediate, and adverse categories in unfit pts (median OS of 20 months vs 11 months vs 7 months, respectively; p=NS). Conclusions: In our real-life analysis, we demonstrated that fitness assessment according to SIE/SIES/GITMO criteria identifies populations with discrete outcome among t-AML and AML-MRC pts receiving CPX-351. In unfit patients, outcome prediction seems independent from ELN 2017 risk stratification. Fit and unfit groups achieved similar CR rates but different long-term OS. Such discrepancy can be justified by the higher early mortality observed among unfit pts that translated into shorter long-term survival. In a future perspective, modulating CPX-351 schedule in this group may be a reasonable option to spare toxicity without giving up the opportunity to deliver curative-intended therapies.

Targeted Agents in Chronic Lymphocytic Leukemia (CLL): Advancements in Overall Survival Outcomes?

The impact of targeted agents (TAs) in fully mitigating the detrimental effects of CLL on overall survival (OS) remains uncertain. To address this, we compared the 5-year OS of treatment-naïve CLL pts who received targeted agents (TAs) in phase 3 clinical trials with the 5-year OS of age- and gender-matched general population (AGMGP) in Italy and the US. For this analysis, we included clinical trials that involved elderly or unfit pts (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW). We also considered trials enrolling fit pts eligible for FCR (Fludarabine, Cyclophosphamide, and Rituximab) treatment (ECOG1912, FLAIR, and CLL13). We used the method proposed by Liu et al. [BMC Med Res Methodol 2021;21(1):111] to reconstruct individual patient data (IPD) from published Kaplan-Meier survival curves. The expected OS rate for the control population was calculated using 2019 Italian data from the Istituto Nazionale di Statistica (ISTAT) and the 2019 US database. OS of CLL pts and AGMGP were compared for restricted mean overall survival time (RMOST). The treatment effect on OS was then measured as the difference of RMOST and expressed in months. The elderly CLL trial analysis group (2,222 pts) received TAs (58.1%) or chemo-(immunotherapy)(CT/CIT) (41.8%). TAs included Bruton Kinase inhibitors (BTKis) (i.e., ibrutinib [I] or acalabrutinib [A]) alone or with anti-CD20 (75%) or fixed-duration (FD) venetoclax [V] combos (25%). The control CT/CIT arm mainly consisted of CLB+Obinu (66%). The median age of pts was 70 years (range 47-93). The prevalence of del(17p)/mutated TP53, unmutated IGHV, or CIRS score>6 were 9.1% (0-16%), 62.4% (43-66.5%), and 48.6% (11.7-86.1%), respectively. In the aggregate analysis, the 5-year RMOST of elderly pts treated with CT/CIT (RESONATE2, ILLUMINATE, ALLIANCE, ELEVATE-TN, CLL14, and GLOW) was found to be inferior compared to the 5-year RMOST of Italian [Difference (D), -4.2 months; 95% CI: -5.3 to -3.0; P < 0.0001] and US [D, -3.6 months; 95% CI: -4.7 to -2.4; P < 0.001] AGMGP (Fig 1). The analysis of pts treated with TAs provided conflicting results. In the cross-matched comparison between Italian AGMGP and pts treated with BTKi single-agent or combined with anti-CD20, the 5-year RMOST difference indicates an OS advantage for the former (Fig 1). The same applied in the comparison between pts who received FD V-based therapies and Italian or US AGMGP. Notably, the 5-year RMOST of elderly CLL pts treated with BTKi single-agent (RESONATE2, ALLIANCE, ELEVATE-TN) or combined with anti-CD20 (ILLUMINATE, ALLIANCE, ELEVATE-TN) was similar to the 5-year RMOST of US AGMGP [D, -1.2 mo. (-2.5 to 0.1); P = 0.07 for both](Fig 1). OS comparisons between elderly CLL pts and control populations, although controlled for age and gender, do not account for the interaction between comorbidity burden and OS. The proportion of pts with CIRS score > 6 varied widely across trials: RESONATE2, 31%; ELEVATE-TN, 11.1% in the A-arm and 16.8% in the AO-arm; ILLUMINATE, 32.7%; CLL14, 86.1%; and GLOW, 69.0%. Since CLL pts eligible for FCR enrolled in the ECOG1912, FLAIR, and CLL13 trials typically have fewer comorbidities, they enable a clearer evaluation of the TA's impact on OS. Overall, 1,437 patients (64.5%) received TAs, and 789 (35.4%) received CIT. TAs consisted of I+R (51.5%) or FD V-based combinations (VO, VI, VO+Ibr) (48.5%). The median age of pts was 62 years (range 27-84). The prevalence of ECOG PS 0 and unmutated IGHV were 68% and 56%, respectively. The 5-year RMOST of younger/fit pts treated with FCR was inferior to the 5-year RMOST of Italian AGMGP [D, -1.1 mo; 95% CI: -1.8 to -0.3; P = 0.003] but similar to the 5-year RMOST of US AGMGP [D, -0.4 mo; 95% CI, -1.1 to 0.4; P = 0.28]. Interestingly, no significant difference could be observed between the 5-year RMOST of younger/fit pts treated with TAs (IR or Ven-based) and the 5-year RMOST of Italian or US AGMGP (Fig 2). In conclusion, our results suggest that in comparison to CIT, TAs mitigate but do not fully abrogate the detrimental impact of CLL on OS. The intricate interaction between CLL characteristics and the burden of comorbidities can potentially lead to misleading results in clinical trials of elderly pts. The extent of OS improvement obtained with TAs seems higher in younger/fit CLL pts who have fewer comorbidities. However, longer follow-up is needed to discern the ability of these treatments to mitigate the impact of CLL on OS over longer time intervals.

Extended Nutritional Monitoring in Patients Undergoing Intensive Chemotherapy for Acute Myeloid Leukemia

Background Fit patients (pts) with acute myeloid leukemia (AML) are conventionally administered repeated cycles of intensive chemotherapy, often followed by allogeneic hematopoietic stem cell transplant. AML pts need to be long hospitalized in a protected setting, they are often prescribed a neutropenic diet and chemotherapy-induced gastro-intestinal toxicity is common. As a result, malnutrition is frequently observed, it sensibly reduces the quality of life and has the potential to undermine eligibility for intensive treatment, increase treatment-related toxicity, and ultimately reduce survival. Aims Aim of this study was to systematically assess the nutritional status of fit pts undergoing treatment for AML and to explore early predictors and associations with known nutritional risk scores and relevant clinical outcomes. Methods Nutritional Risk Screening 2002 (NRS) score was calculated for each patient at time of diagnosis (a score of 3 or more is considered high). Then, nutritional monitoring included standard anthropometric measurements (body weight, BW; body mass index, BMI) and a bioelectrical impedance analysis (BIA) performed by a registered dietitian to assess fat-free mass, body cell mass (BCM, the metabolically active component of body mass), fat mass and the phase angle. Variations in nutritional parameters between admission and day 7 (end of CHT, called “dif7”) or between admission and day 14 (called “dif14”) were calculated and tested for correlation with variations of the same parameter at discharge from the same cycle (called “dif30”) or at discharge after the first consolidation (called “dif60”). Results Up to now, 26 pts with newly diagnosed AML (median age 55y, range 21-74) were prospectively monitored during a total of 61 cycles of intensive chemotherapy (35 induction cycles, 26 consolidation cycles). Median NRS score at enrolment was 3 (range 2-6). Median follow up for surviving pts is 300 days. We observed a significant reduction in fat-free mass and body cell mass during induction cycles. Similar trends, although not significant, were observed for consolidation cycles as well. These trends were observed irrespectively of baseline NRS, disease response, or whether admission was complicated by a fever lasting more or less than 7 days. A high NRS score was only associated with a greater fat mass loss between diagnosis and discharge after first consolidation (FM dif60), but the score failed to predict any meaningful nutritional parameter variation. For fat-free mass, body cell mass and the phase angle (but not for BW or BMI), dif7 correlated with dif30 for induction and consolidation cycles. For body cell mass and the phase angle, both dif7 and dif14 also correlated with dif60. Only variations in body cell mass at day 7 (BCM dif7) correlated with cumulative weight loss at discharge after the first consolidation cycle (BW dif60). Reduction in BW, BMI and fat mass at day 7, and of phase angle at day 14, were associated with extended length of stay for consolidation chemotherapy cycles only. Conclusions In this study, pts intensively treated for AML suffered a significant reduction in the metabolically active component of body mass during admission for induction chemotherapy and, cumulatively, during the first two treatment cycles. Bioelectrical impedance analysis performed as early as seven days from admission could already reveal the first signals of nutritional deterioration: body cell mass loss between day 0 and day 7 correlated with both cumulative body cell mass loss and cumulative body weight loss after two cycles of chemotherapy. Notably, a commonly used nutritional risk screening tool failed to predict the risk of malnutrition in our cohort of patients. “NUTRIAMO” is a prospective, observational trial currently starting at our institution, where pts intensively treated for AML are monitored via known nutritional assessment tools, new biochemical markers (e.g., prealbumin and retinol-binding protein) and microbiome analysis and variations. Our aim is to find more sensitive nutritional triggers to activate earlier and more effective support measures (e.g., oral nutritional supplements, diet variations, psychological support) and ultimately improve AML patients' quality of life and survival beyond the cure of their disease.

A Phase 2 Study of Minimal Residual Disease (MRD)-Adapted Front Line Venetoclax and Obinutuzumab in Fit Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Obinutuzumab on Tumor Lysis Syndrome (TLS) Risk and Safety of Outpatient Venetoclax Dose Escalation

Introduction: Venetoclax (V) / Obinutuzumab (O) is an effective one-year fixed duration therapy for patients (pts) requiring first-line CLL treatment (tx). In CLL14, tumor lysis syndrome (TLS) risk assessment (including lymph node measurements by imaging and ALC) was required once prior to tx initiation, and O's impact on TLS risk prior to introduction of V was not a pre-planned study endpoint. Therefore, TLS prophylaxis (ppx) and tx setting for V dose escalation did not account for the possibility that O may decrease TLS risk prior to V escalation. Based on this approach, 22% of pts in the CLL14 study were high risk for TLS, thus requiring hospitalization for intensive laboratory monitoring during V dose escalation. (Fischer, NEJM 2019) We hypothesized that cycle (C) 1 of O would significantly decrease TLS risk prior to V escalation and that all pts, regardless of TLS risk category, could safely undergo a standard 5-week V dose escalation in the outpatient setting. Methods: We are conducting a Phase 2 study (NCT04447768) designed to examine the efficacy of a minimal residual disease (MRD)-adapted approach to V/O combination for fit pts in the front-line setting (study schema, Figure 1). A planned secondary study endpoint is to evaluate the effect of O monotherapy in C1 on TLS risk. Here we present interim results of TLS risk modification for the first 80 patients. Per protocol, TLS risk assessment including CT imaging and ALC measurement was performed at two defined timepoints: (1) prior to C1 day (D) 1 and (2) immediately prior to V initiation on C1D22. Key eligibility criteria: adult pts with CLL requiring first line tx per iwCLL guidelines, CIRS score ≤ 6, adequate heme function (Hgb ≥8 g/dL, ANC ≥1 x 10 9/L, Plt ≥30 x 10 9/L), creatinine clearance >50 mL/min. O was administered on C1 D1/2, 8 and 15. Per protocol, pts underwent V dose escalation in the outpatient setting, regardless of TLS risk. For pts with low and medium (med) tumor burden, TLS ppx was per FDA label. For pts who remained high TLS risk at the time of V initiation, TLS ppx throughout dose escalation included allopurinol to start at least 3 days prior to V initiation, sevelamer to start 12 hours prior to V initiation, and oral intake of ≥2 L water daily. On days of dose escalation, ppx additionally included kayexalate, rasburicase, and IV normal saline on D1 and D2 of each dose escalation. TLS labs were monitored according to FDA label guidance. Statistical analysis of TLS risk and adverse events was descriptive. Results: As of 5/2023, 80 pts have enrolled in this study. Seventy-eight pts completed the 5-week V ramp-up. Two pts were removed after receiving at least one dose of O but before repeat assessment of TLS risk and initiation of V (1 death unrelated to tx/disease, 1 patient with recurrent grade 3 (G3) O infusion-related reaction (IRR) leading to consent withdrawal). Median pt age was 57.5 years, 68% male, 95% white. Prior to tx initiation, TLS risk categories were low: 16%, med: 58%, and high: 26% (n=80). Change in TLS risk from baseline to C1D22 is detailed in Figure 2. Of the 20 pts who had sequential assessments with high baseline TLS risk, TLS risk after C1 O (C1D22) was low: 55%, med: 35%, high: 10%. For pts with med TLS risk at baseline with sequential assessments (n=45), TLS risk at C1D22 was low: 82%, med: 18%. One patient developed laboratory TLS on C1D3 following administration of O; no clinical TLS was observed. All pts accomplished V dose escalation in the outpatient setting with no observed laboratory or clinical TLS as defined by Howard Criteria. Grade 3 / 4 tx emergent AEs that occurred in >5% between C1D1 and C3D1 included neutropenia (35% G3, 11% G4), IRR (11% G3, 0% G4), and thrombocytopenia (9% G3, 3% G4). Conclusions: A single cycle of O effectively reduced TLS risk prior to introduction of V escalation with most pts achieving low or med TLS risk by C1D22. Notably, 90% of pts with high pre-tx TLS risk converted to low or med risk following C1 of O allowing for outpatient V escalation per FDA label. Further, we demonstrate that V dose escalation can be safely accomplished in the outpatient setting with close monitoring regardless of TLS risk. With this strategy, we observed no laboratory or clinical TLS during V dose escalation. Eliminating the need for hospitalization during V dose escalation may enhance patient and provider convenience and decrease the economic burden of this regimen. This study is ongoing; efficacy results of this MRD-guided approach to V/O are forthcoming.

Outcomes in Patients with Acute Myeloid Leukemia Treated with CLAG (cladribine, cytarabine, filgrastim) and/or Mitoxantrone with Venetoclax

Introduction: CLAG (cladribine, cytarabine, filgrastim) with or without M (mitoxantrone) has anti-leukemic activity in newly diagnosed (ND) and relapsed/refractory (R/R) AML (Wierzbowska et al. 2008, Jaglal et al. 2014, Seiter et al. 2016). Venetoclax (Ven) with hypomethylating agents (HMA), approved for patients (pts) who are not candidates for intensive chemotherapy (IC), is increasingly being employed even for pts who are fit for IC. R/R disease remains a major cause of mortality in fit pts with AML, and thus improved IC regimen is an area of active research. Various combination of IC with Ven are ongoing with promising early findings (DiNardo et al. 2021, Reville et al. 2022). In this study, we examined the outcomes of AML patients treated with CLAG and/or mitoxantrone with Ven, CLAG(M)/Ven. Methods: This was a retrospective study of pts with AML who received CLAG(M)/Ven (Days 2-8) in 2022-2023. Clinical responses were reported using ELN 2022 criteria. Kaplan-Meier analyses were used to estimate overall survival (OS) from the date of CLAG(M)/Ven initiation. Results: This cohort of 19 pts (8M/11F with median age of 60 [23-74] at diagnosis) is comprised of 68.4% (13/19) R/R and 31.6% (6/19) ND AML who had prior MDS directed therapy. There were 57.9% (11/19) with secondary/therapy-related AML and when including de novo AML pts who had mutations highly specific for secondary AML ontogeny, it increased to 78.9% (15/19). Most of the pts (68.4%, 13/19) had adverse risk disease by ELN 2022. Common mutations being TP53 (26.3%, 5/19) followed by IDH1/2 (21.1%), ASXL1 (15.8%), and RUNX1 (15.8%). There were 36.8% (7/19) who had received allogeneic hematopoietic cell transplant (alloHCT) (Table 1). Similar number of pts received CLAG/Ven (47.5%) and CLAG-M/Ven (52.6%). Pts received on average 2.6 lines of treatment prior to CLAG(M)/Ven with 1 pt received 5 prior lines of treatment after AML diagnosis. Most of the pts, 78.9% (15/19), had prior HMA/Ven. The 30-day and 60-day morality was 5.3% (1/19) (disease status unknown at the time of death) and 26.3% (5/19) (disease status: 3 yes, 1 no, 1 unknown), respectively. Among these 5 early deaths within 60 days, 3 were ND AML that were heavily pretreated for prior MDS (average 3 lines of prior therapy) and 2 were R/R AML. All of them had prior HMA/Ven. Eighty percent (4/5) had adverse risk disease and received CLAG-M/Ven. Forty percent (2/5) had TP53 mutation. Objective response rate (ORR) of the entire cohort was 26.3% (5/19) (2 CR, 1 CRi, and 2 MLFS). Among those with evaluable response (n=10), ORR was 50%. Two CR/CRi pts achieved undetectable MRD by flow cytometry. MRD was not tested in the other 3 pts. Notably, ORR was higher in pts who received CLAG/Ven (44.4%, 4/9) compared to CLAG-M/Ven (10%, 1/10). No response in ND AML and 38.5% (5/13) ORR in R/R AML. Of the 47.4% (9/19) nonevaluable pts, 6 had aplastic marrow (2 died while getting induction, 2 transitioned to alloHCT, 1 moved onto next line of treatment, and 1 lost to follow up) and 3 had recovery marrow pending. For pts who achieved a response, 60% (3/5) underwent alloHCT (all of them alive without disease at data cutoff). The median time to count recovery was 42.5 days (27 days to never recovered). Prior HMA/Ven failure, high dose cytarabine failure, and mutations did not significantly impact response in this small cohort. The median OS from the time of CLAG(M)/Ven initiation was 5.5 months with a median follow up of 8.6 months (Figure 1). OS from the date of CLAG(M)/Ven was significantly shorter in pts with TP53 mutation vs. wild-type (2 vs. 11.2 months, p=0.031). Conclusions: Our findings showed the combination regimen CLAG(M)/Ven is feasible in pts with AML. It also provided better characterization in terms of early mortality and survivals in these pts, which can help inform future clinical trial design. ORR was similar to what was previously reported with CLAG(M); however, it is encouraging that those who achieved CR/CRi and had MRD testing also achieved MRD negativity. Outcomes of TP53-mutated subset is dismal suggesting IC-based approach in this setting is limited. Larger cohort and longer follow up is needed to confirm the impact of factors such as specific regimen, mutations, and prior therapies on outcomes.

A Two-Part Study Evaluating the Combination of Tazemetostat and CPX-351 (Part 1) and Palbociclib with CPX-351 (Part 2) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

BACKGROUND AND SIGNIFICANCE Acute myeloid leukemia (AML) is an aggressive cancer of early hematopoietic progenitor cells with only 25-30% of patients (pts) surviving 5 years from diagnosis. For fit pts, conventional chemotherapy with DNA-damaging agents remains the mainstay of treatment. Conventional chemotherapeutic agents cause DNA-damage by targeting cells during DNA replication. Chromatin structure is highly influential in the efficacy of DNA-damaging agents, as areas of compacted chromatin are more resistant to DNA-damaging effects. Areas of DNA marked with histone 3 lysine 27 trimethylation (H3K27me3) are transcriptionally repressed and exhibit reduced accessibility to DNA-damaging agents. Enhancer of Zeste Homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repressive complex 2 which methylates H2K27 to produce a di- or trimethylated state (H3K27me2/3). In preclinical studies, treatment of AML cell lines with the combination of an EZH2 inhibitor (EZH2i) and doxorubicin resulted in an increase in DNA damage and apoptosis compared to those treated with doxorubicin alone. Further, a significant decrease in leukemia burden was seen in mice injected with THP-1 (AML) cells and treated with an EZH2i and doxorubicin and cytarabine compared to doxorubicin and cytarabine alone. This effect was further enhanced by pre-treatment of AML cells with palbociclib (PALB), a CDK4/6 inhibitor, by significantly increasing the number of cells in S phase when exposed to the EZH2i and doxorubicin combination, resulting in an increase in DNA damage and apoptosis compared to cells that were not pre-treated with PALB. These findings were reproduced in in vivo studies with mice injected with the primary AML cells (Porazzi P, et al. Cancer Res., 2021). STUDY DESIGN AND METHODS We will perform a 2-part phase I dose escalation study utilizing EZH2i tazemetostat (TAZ) in combination with CPX-351 induction chemotherapy and of PALB pre-treatment followed by CPX-351 in pts with relapsed or refractory (R/R) AML (NCT05627232). All pts will receive CPX-351 at standard dose on days 1, 3 and 5. Part 1 evaluate the addition of TAZ to CPX-351 via traditional 3+3 design. Pts will be treated with TAZ on days -1 to 6 at a starting dose of 600 mg twice daily to open chromatin concurrent with CPX-351 administration. Part 2 evaluate the pre-treatment with PALB via traditional 3+3 design. Pts will be treated with PALB starting dose of 100 mg daily on days -3 to -1 to induce cell cycle G1. PALB will be held on day 1 to allow cells to then enter S phase prior to administration of CPX-351. ( Figure 1). The study will enroll pts with R/R AML treated at Sidney Kimmel Cancer Center. Pts must be ≥18 years of age with R/R AML (non-acute promyelocytic leukemia) and have received at least 1 prior line of therapy and have adequate performance status and organ function. Pts whose participation would result in a total cumulative dose of daunorubicin greater than 550 mg/m 2 (450 mg/m 2 if they previously received mediastinal radiation) and those with active central nervous system involvement of AML, unstable cardiac disease or other severe concurrent disease will be excluded. The primary endpoints of Parts 1 and 2 will be to determine the maximum tolerated dose of TAZ and of PALB in combination with CPX-351, respectively. Secondary endpoints for Parts 1 and 2 include preliminary assessment of efficacy. Correlative studies to evaluate the on-target effect of TAZ on H3K27me3 and DNA-damage and of PALB on cell cycling will be performed at protocol-specified time points. If these two 2-drug combinations prove to be safe, we will amend the protocol to add Part 3 which will evaluate the safety of the 3-drug combination of pre-treatment with PALB followed by co-treatment with TAZ and CPX-351.

SIE/Sies/GITMO Criteria in Elderly Patients with Acute Myeloid Leukemia (AML): Useful Also in the New Drug Era? a Multicentric Real-Life Study By the Hematological Network Rete Ematologica Lombarda (REL)

Introduction: In elderly acute myeloid leukemia (AML) patients (pts) the debate about the use of intensive chemotherapy (iC) as opposed to non-intensive therapy (niT) or best supportive care (BSC) is a hot topic, particularly after the introduction of venetoclax (VEN) use. Age, comorbidities, functional impairment, therapy benefits and risks, pts preferences, and AML features influence this choice. The SIE/SIES/GITMO (“fitness”) criteria (Ferrara, 2013) are a valuable and comprehensive tool, but a revalidation is needed in the light of the new treatment options. Methods: Within the Rete Ematologica Lombarda (REL), we evaluated 1) the concordance between “fitness” of pts, and the type of treatment they actually received, 2) the overall survival (OS) according to the “fitness”, to the prognostic European Leukemianet (ELN17) stratification and to the treatment received, and 3) the presence of other parameters, as Charlsons Comorbidity Index (CCI), potentially useful in therapy decision. Pts were classified as fit to iC (FIT), unfit to iC (UNFIT), or unfit even to niT (FRAIL), as defined by the SIE/SIES/GITMO criteria. Results: From Jan 20 to Dec 22, 503 AML pts (53% de-novo), with a median age of 76 years (y) (range, 65-93) were diagnosed consecutively at 11 Hematology Units. According to “fitness” criteria, 25% of pts were FIT, 61% UNFIT, and 14% FRAIL (Table1). Median age was significantly lower in FIT pts (70 y), as compared to UNFIT (78 y) and FRAIL (79 y) (p <0.0001). Overall, the concordance between “fitness criteria” and the treatment actually received by pts was 75.9% (71% in FIT, 76% in UNFIT and 84% in FRAIL). After a median follow-up of 12 months (m), median OS of the whole population was 7.4 m. Median OS of FIT, UNFIT and FRAIL pts was 13.7, 7.2 and 1.4m, respectively (p <0.0001, Fig 1a). According to physicians' decision, 18% of pts received iC, 55% niT, mainly hypomethylating agents (HMA: azacytidine or decitabine) + VEN, and 27% BSC. Median OS was 17m, 10.2m, 1.4m in iC, niT and BSC pts, respectively (p<0.0001, Fig 1b). According to ELN17, evaluable in 73% of pts, 19% were favorable (fav), 20% intermediate (int) and 61% adverse (adv), without differences into “fitness” groups. Median OS was significantly worse in ELN adv than in ELN fav and int (p: 0.001 and p: 0.002, respectively, Fig 1c). In FIT pts, median OS was 17m with iC and 11.4m with niT (VEN-HMA) (p: 0.3). The use of iC was associated with younger age (median age: 69 in iC vs 73 y in niT, p<0.0001), lower CCI (CCI< 2: 88.5% in iC vs 64% in niT, p: 0.0032) and not significantly with better ELN risk (ELN adv 49% in iC pts vs 70% in niT, p: 0.07). The use of iC or niT did not affect remission rate (64% vs 71%) nor OS in different ELN risk groups. In UNFIT pts, median OS was 14m with niT and 3.8m with BSC pts (p<0.0001). The use of niT compared to BSC was associated with younger age (median 77 vs 81 y; p<0.0001), not adv ELN risk (41% vs 7%, p: 0.0001), lower ECOG performance status (PS) and CCI (PS<2: 81% vs 65%, p: 0.0001; CCI<2: 66% vs 50%, p: 0.038). In UNFIT pts treated with VEN-HMA median OS was 11m vs 7.3m with HMA only (p: 0.019). The use of VEN-HMA rather than HMA only was associated with younger age (median: 76 vs 80 y; p: 0.0045), better PS and CCI (PS<2: 94% vs 84%, p: 0.026; CCI<2: 68% vs 50%, p: 0.008). ELN risk distribution was similar. In non-adv risk pts, OS was 17m with VEN-HMA, significantly better compared to HMA only (7m) (p: 0.03) as well as to adv risk pts treated with VEN-HMA (p: 0.0017). Age >82y, number of comorbidities, lack of caregiver were the most frequent reasons for the physician's preference for HMA therapy over VEN-HMA. InFRAIL pts, median OS was 2.9 m with niT and 1.1m with BSC pts (p: 0.04). The use of niT was associated with a relatively better PS and younger age (<73 y). At multivariable analysis, ELN fav and iC favorably affected survival, whereas a FRAIL fitness status, PS>2, and CCI>2 proved to be independent adverse prognostic factors. Conclusion: Fitness stratification of SIE/SIES/GITMO correlated to pts's survival and were useful in the decision-making approach of treatment also in the new drugs era. Within the “fitness” categories, age, CCI and particularly ELN risk, had an impact on the choice of the type of induction therapy, in FIT pts (iC vs niT) without changing the outcome, while in UNFIT pts an under-treatment worsened OS. These preliminary data should be implemented with a longer follow-up and a larger sample size.

Venetoclax Plus Azacitadine for Middle Aged and Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase 2 Trial

Background: “7+3” induction is the standard regimen in newly diagnosed young patients (pts) with acute myeloid leukemia (AML) fit for intensive chemotherapy with 60-80% complete remission rate. However, middle aged and elderly pts may experience more severe complications during induction therapy and overall survival is shorter than that of younger pts. Recently, venetoclax with azacitadine as induction therapy was approved as the first line therapy for pts with aged more than 75 years or unfit pts with composite complete remission (CRc) of 60-70%. We hypothesize that venetoclax with azacitadine as induction therapy in fit middle aged and elderly pts may have similar CRc rate and less complications. This study aims to evaluate the safety and efficacy of venetoclax plus azacitadine as induction therapy in fit middle aged and elderly newly diagnosed AML pts. Methods: This is an interim analysis of an ongoing phase 2 clinical trial (NCT05471700) of a planned 40 untreated AML pts aged 45-65 who were fit for intensive chemotherapy according to Ferrara Criteria. In cycle 1, pts received azacitadine 75mg/m2/day on d1-7 and venetoclax escalated from 100mg to 200mg to 400mg until 28-day cycle was finished. For pts with FLT3-ITD positive, sorafenib was optional administered at a dose of 400mg twice daily. Bone marrow assessments were performed on d28. Pts who achieved CRc (defined as complete remission[CR] and CR with incomplete hematologic recovery[CRi]) with intermediate or adverse risk groups received 1 or 2 cycles of consolidation with venetoclax plus azacitadine or center-specific cytarabine-based consolidation. Allogeneic stem cell transplantation (HSCT) was performed if a donor was available. Pts in favorable risk gruop received 3 to 4 cycles of center-specific intermediate or high dose cytarabine-base consolidation. Non-responders or pts who achieved partial remission received 1 more cycle of venetoclax plus azacitadine. Who could not get CRc after 2 cycles of induction would be withdrawn from the study. The primary objective is to determine the CRc rate. The secondary objective is safety, MRD negative rate, duration of remission (DOR), the rate of allo-HSCT, event free survival (EFS), and overall survival (OS). The endpoint is to show that venetoclax plus azacitadine is not inferior to “3+7” induction in fit pts with newly diagnosed AML aged 45-65. Results: From 10/9/2022 to 6/30/2023, a total of 32 pts was enrolled to this study, comprising 18 males and 14 females. There were 27 (84%) pts with de novo AML, 2(6%) pts were secondary AML, 3 pts (9.4%) were therapy-related AML. Median age was 58 years (range, 45-64 years). There were 2(6%), 14(44%) and 16(50%) pts were in the favorable, intermediate and adverse risk group, respectively. The baseline patient characteristics are summarized in Table 1. Outcome data were updated as of June 30, 2023, for a median follow-up of 2.2(0.2-8.8) months. Among 27 evaluable pts, 21(77.8%) achieved CRc with 11(40.8%) in CR and 10(37.0%) in CRi, 2(7.4%) achieved PR in cycle1, while 23(85.2%) achieved CRc with 14(51.9%) in CR and 9(33.3%) in CRi, 4(14.8%) got induction failure after 2 cycles(Figure 1). A total of 16 (61.5%) pts got MRD negative among the pts with CRc after cycle1, and 17 (65.4%) after cycle2. CRc rate after 2 cycles in ELN2017 favorable, intermediate, adverse risk group was 100%, 83.3% and 85.0%, respectively, and MRD negative rate was 100%, 88.9% and 55.6%, respectively. The regimen was well tolerated. No mortality occurred during induction therapy. The most common non-hematological grade 3/4 AE were febrile neutropenia (n=13, 40.6%)，followed by pneumonia (n=3, 9.4%).Sepsis occurred in 1 (3.1%) pt. With a median follow-up of 2.2(0.2-8.8) months, the median remission duration, EFS and OS have not been reached. Conclusions: Preliminary results indicate that venetoclax plus azacitadine as an induction regimen for fit middle aged and elderly pts with newly diagnosed AML is promising with high CRc and low toxicity. Recruitment of adults with newly diagnosed aged 45-65 AML pts for this trial is ongoing.

The FOxTROT platform: Clinical trials and exploratory research for personalization of neoadjuvant (NA) therapy in locally advanced colon cancer (LACC)—ISRCTN83842641.

TPS3636 Background: The FOxTROT1 trial demonstrated a significant reduction in 2-year (yr) recurrence with 6 weeks (wks) of oxaliplatin and fluoropyrimidine (OxFp) NA chemotherapy (NAC) in patients (pts) with LACC, establishing NAC as a new therapeutic option. The ongoing FOxTROT platform will refine and personalize NA therapy in LACC. FOxTROT2 is testing NAC in older pts and those with frailty, who are poorly represented in clinical trials. FOxTROT3 is assessing intensified NAC with modified FOLFOXIRI (mFOLFOXIRI; 5-fluorouracil, oxaliplatin, irinotecan) in fit pts. The FOxTROT platform will also test targeted treatments with established safety and efficacy in defined molecular subgroups. FOxTROT4 is investigating the efficacy and safety of NA encorafenib and cetuximab in BRAF-mutant pMMR LACC. Other arms in setup are shown in Table. Methods: FOxTROT platform trials are international, multicenter, open-label, phase II/III RCTs. Pts with resectable, cT3-4 N0-2 M0, biopsy-proven colon adenocarcinoma are eligible for recruitment. Pts whose age or frailty precludes mFOLFOXIRI can be considered for FOxTROT2. Pts suitable for mFOLFOXIRI can be considered for FOxTROT3. BRAF-mutant pMMR pts can be considered for FOxTROT4. Pts are randomized 2:1 between intervention and control arms. FOxTROT2 randomizes between 6 wks OxFp NAC (choice of 100% or 80% dose) vs proceeding straight to surgery. Adjuvant chemotherapy (AC) is per physician choice. Primary outcome is 3-yr DFS. 759 pts will be recruited over 5 yrs. FOxTROT3: 6 wks mFOLFOXIRI NAC vs 6 wks OxFp NAC. All pts receive AC but physicians may de-escalate mFOLFOXIRI to OxFp. Hierarchical co-primary endpoints: tumor regression grade (TRG) (blinded central assessment) and 3-yr DFS. 873 pts over 5 yrs. FOxTROT4: 6 wks NA encorafenib and cetuximab vs 6 wks OxFp NAC. AC is per physician choice. Primary outcome: TRG. 45 pts over 3 yrs. Secondary outcomes include: histopathological endpoints, downstaging, minimal residual disease by ctDNA, safety, toxicity, OS, surgical outcomes and patient-reported outcomes; and DFS in FOxTROT4. The FOxTROT platform opened 7th Feb 2022, funded by Yorkshire Cancer Research. At submission, 50 pts had been randomized at 23 centers. Trial design and management is conducted in partnership with patient representatives. A program of translational and radiomics research is running in parallel. International recruitment in France and India will commence in 2023 with additional international partners joining from 2024. Clinical trial information: ISRCTN83842641 . [Table: see text]

Fibroblast growth factor receptor 3 (FGFR3) alterations in PROOF 302: A phase III trial of infigratinib (BGJ398) as adjuvant therapy in patients (pts) with invasive urothelial carcinoma (UC).

4511 Background: Radical surgery with or without (neo)adjuvant cisplatin-based chemotherapy [(N)AC] is standard in fit pts with muscle invasive UC of bladder (UBC) or upper tract (UTUC). However, recurrence rates are high, underscoring the need for novel therapies. Since up to 70% of UTUC and 20% of UBC tumors were reported to harbor FGFR3 alterations, targeting this pathway is a rational approach. Infigratinib is a selective FGFR1–3 inhibitor with efficacy in advanced UC with FGFR3 alterations [Pal et al. 2018]. PROOF 302 investigated the efficacy and safety of adjuvant infigratinib vs placebo in pts with high-risk invasive UC. Methods: PROOF 302 was a global, randomized, double-blind, placebo-controlled, phase III trial for pts with high-risk invasive UTUC or UBC (≤15%) with FGFR3 alteration (i.e. mutation, gene fusion / translocation) with residual (≥ypT2 and/or ypN+) tumor after NAC, or pts ineligible for, or refusing, cisplatin-based AC, ≤120 days post-surgery. Pts were randomized 1:1 to infigratinib 125 mg or placebo daily on days 1–21 every 28 days for up to 52 weeks or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: investigator-assessed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: QOL, pharmacokinetics, genomic analysis of tumor and cfDNA. Assessment of genomic alterations was pursued using descriptive statistics. Results: We present the results of the genomic analysis of radical surgery tissues from pts screened for the trial using the FoundationOne platform. Out of 617 pts screened, 188 (30.5%) had alterations in FGFR 1-4 genes: 102/237 (43%) in UTUC, 85/369 (23%) in MIBC and 1/11 (9%) with unknown tumor origin. Of these 188 pts, median age 74 (32-90 years), 76% were male, 55% had UTUC, 44% had UBC. Genomic alterations are shown. In UTUC, FGFR3 had 56% single-nucleotide variations (SNV) and insertions/deletions (INDELS), 40% amplifications and 70% structural variants (SV). In UBC, FGFR3 had 44% SNV and INDELS, 60% amplifications and 30% SV. Conclusions: FGFR3 alterations were seen in only 19% of all pts screened for PROOF-302, a trial that was enriched for UTUC: 71/237 (30%) of UTUC and 48/369 (13%) of UBC. The trial was stopped early by the sponsor, but the genomic analysis provides insights into the prevalence of FGFR3 alterations; assessment of correlations with the primary/secondary endpoints is ongoing. The nature and frequency of co-occurring alterations in tissue samples is being investigated to help inform combination therapy strategies and putative resistance mechanisms. Clinical trial information: NCT04197986 . [Table: see text]

Integration between Geriatric Oncology and Palliative Care: A Single Center Experience for Hospitalized Older Patients with Cancer

Comprehensive Geriatric Assessment (CGA) is utilized to plan social and health care of the elderly and to complete the diagnostic-therapeutic choice of oncologist also considering early integration with palliative care. Cancer patients (pts) hospitalized aged ≥70 years were screened by the G8 questionnaire to define if necessary CGA. CGA identified: fit, unfit and frail pts. We screened 95 pts by G8 and 93 (98%) were at risk. Pts at risk, evaluated by CGA resulted: 3 fit, 45 unfit and 45 frail. 3 fit pts received standard medical or surgical therapy. 41 unfit pts (91%) received personalized care and 4 pts got worse quickly and died. The median age was 76 and median score IADL/ADL (Instrumental/Activities Daily Living) was 5. Malnutrition was present in 31% and MMSE (Mini-Mental State Examination) was normal in 62%. Among these 45 pts, 32 died with a median survival of 120 days: 14 at home, 13 in hospice and 5 during hospitalization. Among 45 frail pts, 3 received personalized care and 42 received the Best Supportive Care. The median age was 81 and the median score IADL/ADL was 2. Malnutrition was present in 55%, and MMSE was normal in 22%. Among these 45 pts 40 died with a median survival of 36 days: 12 at home, 24 in hospice, and 4 during hospitalization. Unfit pts have a better functional, cognitive and nutritional status than frail pts. Early integration between geriatric oncology and palliative care represents the possibility of create a personalized care pathway especially for frail pts.

Management and Outcomes of Older Patients (Age ≥ 70 Years) with Advanced Soft Tissue Sarcoma and Role of Geriatric Assessment and Oncological Multidimensional Prognostic Index (Onco-MPI) in a Real-World Setting.

Background: Incidences of soft tissue sarcomas (STS) steadily increase with age. Yet, despite the high prevalence in advanced age, older patients (pts) are underrepresented in sarcoma clinical trials and evidence-based guidelines for chemotherapy are lacking. International oncological societies suggest using geriatric tools to evaluate older patients with cancer to optimise treatment indication. Comprehensive geriatric assessment (CGA) is a multidimensional assessment of older subjects, based on which pts can be classified as fit, vulnerable or frail. Onco-MPI (multidimensional prognostic index) is a CGA-based score which also considers tumour characteristics, classifying pts into three risk groups of death at one year: high-risk, intermediate-risk and low-risk. Methods: This is a single-centre retrospective study which aims at describing real-word management and outcomes of older pts with advanced stage STS and at assessing the ability of CGA and onco-MPI to predict survival in these pts. Consecutive pts with advanced stage STS aged 70 years or older and treated at the Istituto Oncologico Veneto from January 2009 to June 2020 were retrieved from a prospectively maintained database. Pts' demographics, CGA assessments and tumour characteristics were analysed. Statistical analysis was performed with R version 3.4.3 Results: Out of 101 pts, with a median age of 77 years, 76 received chemotherapy (75.3%), which was anthracycline-based for 46 pts (60.5%). Anthracyclines were used in a higher proportion in fit pts (58.9% fit vs. 45.1% vulnerable vs. 12.5% frail pts). Frail pts and pts in the onco-MPI high-risk group experienced a higher rate of chemotherapy-related toxicities. Median OS was 13.8 months (95% CI 11.3-17.7 months). According to CGA, the median OS was 19.53 months (95% CI 15.23-36.8) for fit pts, 12.83 months (95% CI 9.7-17.5) for vulnerable and 7.75 months (95% CI 2.73-30) for frail pts (p = 0.005). Onco-MPI confirmed a predictive value for 1-year survival with intermediate risk pts not reaching a median OS at 1 year, and high-risk pts having a median one-year OS of 11.5 months (95%CI 9.7-NA), p = 0.02. In multivariate analysis, onco-MPI and CGA were associated with survival (high risk onco-MPI: HR 5.5, 95%CI 1.25-24.7 p = 0.02; fitness at CGA HR 0.552 95% 0.314-0.973; p = 0.040) as well as chemotherapy use (HR 0.24, 95% CI 0.11-0.51, p < 0.005). Conclusions: Both CGA and onco-MPI retain prognostic value for survival in pts with metastatic STS. Pts frail/vulnerable at CGA and pts within the onco-MPI high risk category should be offered an oncogeriatric management approach in order to optimise treatment-related survival and reduce toxicity.

Updated Phase IIb Results of Venetoclax with FLAG-IDA in Relapsed or Refractory Acute Myeloid Leukemia

Background: Patients(pts) with relapsed or refractory (R/R) AML experience poor response rates and short durations of response. FLAG-IDA salvage therapy has previously demonstrated a composite remission rate (CRc) of 21% with median OS (mOS) of 3.5 months (Roboz, JCO 2014). Combinations of BCL2 inhibition have proven to be synergistic with low intensity and intensive chemotherapy, with improved CRc and mOS rates. Venetoclax with FLAG-IDA demonstrated favorable response rates in the frontline and relapsed or refractory (R/R) setting, with overall response rate (ORR) of 97% and 70% in the Phase IIA (frontline) and Phase IIB (R/R) respectively (JCO 2021). Here we present updated results of the Phase IIb cohort. Methods: Pts >18 years of age with R/R AML, defined as lack of response after at least 1 cycle of induction or relapsed disease with any prior number of treatments but without prior receipt of venetoclax, with sustained organ function were eligible. Induction consisted of fludarabine (30mg/m2, D2-6), cytarabine (1.5g/m2 D2-6), idarubicin (6mg/m2, D4-5), and Filgrastim(D1-7). Venetoclax was administered D1-14 during induction and D1-7 for consolidation (100mg D1, 200mg D2, 400mg onwards for induction). Consolidation consisted of fludarabine(30mg/m2) and cytarabine (1.5g/m2) for D2-4. The primary objective was evaluation of ORR. Secondary objectives included overall survival (OS), CRc, and duration of response (DOR). Mutation analysis was performed using next-generation sequencing and measurable residual disease (MRD) detection was performed using flow cytometry (sensitivity 10-3-10-4). Results: Thirty-three R/R pts have been treated. Baseline characteristics are shown in Table 1. The median age was 47 (range 18 to 68). For 70% of pts, this regimen was Salvage 1. Thirty percent of pts underwent prior SCT. The majority of pts had ELN 2017 adverse risk disease (67%).Complex karyotype and TP53 mutations occurred in 19% and 21% of pts respectively. Among the 33 pts, 1 patient remains too early for response assessment. The ORR of the remaining 32 pts was 60% (19 pts), with CRc rate of 53% and 12 pts (71% of responders) achieving MRD negativity. ORR and CRc rates in salvage 1 pt were 65% and 61%. By ELN risk, ORR and CRc rates were 100% and 85% in favorable risk, 50%and 50% in intermediate risk, and 48% and 43% in adverse risk. ORR and CRc rates for TP53 wild-type vs TP53 mutant was 68% and 14%, vs 64% and 14%. The median number of cycles received was 2 (range 1-4) with a median number of cycles to best response of 1 (range 1-2). Among responding pts, 13 (68%) proceeded to allogeneic transplant, including two pts who transitioned to HMA + VEN and sorafenib maintenance, respectively prior to transplant. At a median follow up of 15.8 months, the OS and DOR were 27 (95% CI 22.3-26.3) months and NR (95% CI 22.4-NR) respectively. Six-month and 12-month survival was 69% and 60%, respectively. Of the 13 pts that proceeding with transplant, median DOR post-transplant has not been reached. OS in TP53 wild-type vs TP53 mutant was NR and 5.4 months with a 12-month OS of 68% and 17% respectively. Thirty-day and 60 day- mortality was 0% and 12%. Two deaths occurred within 60 days in pts with persistent leukemia (secondary to hemoptysis from known fungal pneumonia and disease). Conclusion: In a cohort of pts with R/R AML enriched for fit pts with adverse-risk disease, this intensive combination resulted in an ORR of 60% with a CRc of 53%. Seventy-one percent of CRc pts attained an MRD negative remission and 68% of responding pts proceeded to transplant. In conclusion, this regimen is associated with deep remissions and a high rate of transition to transplant inpatients with R/R AML, particularly in TP53 wild-type. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Conditioning Regimen Intensity and Donor Choice Do Not Impact Outcomes of Patients (pts) with Acute Myeloid Leukemia (AML) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) in First Complete Remission (CR1): An EBMT Analysis

Allo-HCT is a curative treatment for fit pts with intermediate and adverse risk AML who achieve CR1. The presence of minimal residual disease (MRD) before allo-HCT has been shown to increase risk of relapse and decrease survival. Here, we describe outcomes of pts with AML who received allo-HCT in CR1 and the impact of MRD before allo-HCT on outcomes. We identified 1032 pts with AML who received allo-HCT in CR1 between 2015 and 2020 from the EBMT registry. The median age was 53.6 (range, 18.1-82.5) years and 526 (51%) were male. Most (94%) pts had de novo AML. FLT3-ITD and NPM1 mutations were detected in 46% and 44% of pts, respectively and high-risk cytogenetics were present in 20%. >1 course of induction therapy was required by 18% of pts to achieve CR1 and 39% were MRD positive at time of allo-HCT. The median time from diagnosis to allo-HCT was 4.9 months. Of pts with FTL3-wild type (FLT3-wt) disease, 33% were MRD negative and 22% were MRD positive at time of allo-HCT. In pts with FTL3-ITD mutation, 29% were MRD negative and 17% were MRD positive at time of allo-HCT. Donor type was matched sibling donor (MSD) in 29% of pts (n=297), matched unrelated donor (MUD) in 47% (n=481), mismatched unrelated donor (MMUD 9/10) in 8% (n=88), or haploidentical donor (haplo) in 16% (n=166). HCT-specific comorbidity index (HCT-CI) was >3 in 22% of pts (n=190). Myeloablative conditioning (MAC) was administered to 45% of pts (n=470), while reduced intensity conditioning (RIC) was used in 55% (n=562). The most common conditioning regimen was fludarabine/busulfan in MSD (n=148, 50%), MUD (n=272, 57%) and MMUD (n=38, 43%) recipients, while thiotepa/fludarabine/busulfan was the most used in haplo-HCT (n=99, 60%). Total body irradiation (TBI) was given to only 8% of pts (n=84), mainly in haplo-HCT (n=29). Most (n=1002, 98%) pts received calcineurin inhibitors (CNI), tacrolimus or cyclosporine A, for graft-versus-host disease (GVHD) prophylaxis in addition to mycophenolate mofetil (43%) or methotrexate (38%). Post-transplant cyclophosphamide was used in 18% (n=191) of pts, with 71% (n=136) having received haplo-HCT, and anti-thymocyte globulin was given to 67% (n=689). The median follow-up was 24 months. At day 60, the cumulative incidence of neutrophil engraftment was 99%. The cumulative incidence of grade III-IV acute GVHD (aGVHD) was 9% at day 180. At 2 years, the cumulative incidence of extensive chronic GVHD (cGVHD) was 17%. At 2 years, relapse incidence (RI), NRM, overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) were 26%, 13%, 69%, 61%, and 48%, respectively. The main cause of death was primary disease in 55% of pts (n=157). Other causes of NRM were infections in 16% (n=45), and GVHD in 17% (n=47). In the multivariate analysis, compared to MSD, the use of MUD increased NRM (hazard ratio (HR) 1.86, p=0.02), GRFS (HR 1.28, p=0.039), aGVHD (HR 2.17, p<0.0001), and cGVHD (HR 1.36, p=0.044). The use of MMUD was associated with worse OS (HR 1.6, p=0.042) and higher risk of aGVHD (HR 2.11, p=0.003). Haplo-HCT was associated with higher incidence of aGVHD (HR 1.69, p=0.021) but lower risk of cGHVD (HR 0.63, p=0.033). Older age, lower performance status (PS), requiring >1 induction to achieve CR1, and FLT3-MRD positivity before allo-HCT were associated with worse LFS. Factors associated with lower OS were MMUD 9/10, older age, poor PS, >1 induction to achieve CR1, adverse cytogenetics, and FLT3-MRD positivity before transplant. In vivo TCD was associated with improved GRFS and lower risk of acute and cGVHD without increase of relapse. The use of RIC compared with MAC did not affect relapse, NRM or any other outcome. In conclusion, in pts with AML transplanted in CR1, those requiring >1 induction or with persistent FLT3-MRD positivity at time of allo-HCT had lower OS. Strategies to improve induction therapy, possibly through the addition of targeted agents, aiming to improve CR rates and deepening responses could potentially improve OS after allo-HCT. The use of RIC was associated with similar outcomes compared to MAC. This finding is particularly important for older pts or those with high HCT-CI scores unlikely to tolerate MAC. Survival after MSD allo-HCT is comparable to MUD and haplo, a finding that is in accordance with previous results for haplo and MUD as valid alternative donors in the absence of MSD. The use of MMUD was associated with lower OS compared to MSD and should be used as a last resort donor in this setting.

P907: CARFILZOMIB, DEXAMETHASONE, AND DARATUMUMAB (KDD) VS CARFILZOMIB AND DEXAMETHASONE (KD) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): FRAILTY SUBGROUP ANALYSIS OF THE CANDOR STUDY

Background: Frailty scores based on age, comorbidities, and functional status can help identify frail patients (pts) at risk of higher rates of treatment-related toxicity or poor outcomes. An analysis of carfilzomib-treated pts in ASPIRE, ENDEAVOR, and ARROW found that efficacy and safety of carfilzomib regimens is consistent regardless of frailty status (Facon Blood Adv 2020). Aims: To compare efficacy and safety across frailty subgroups in pts with RRMM treated with KdD vs Kd in the phase 3 CANDOR study. Methods: This post hoc analysis used a planned interim readout (June 15, 2020) of CANDOR (NCT03158688). Pts were categorized as fit, intermediate (int), or frail based on a frailty score of 0, 1, or ≥2. Scoring used an algorithm based on the International Myeloma Working Group (IMWG) frailty index: the final score is based on age (0 if ≤75 years, 1 if 76-80 years, 2 if >80 years), modified Charlson Comorbidity Index (CCI [Facon Blood Adv 2020]) (0 if CCI ≤1, 1 if CCI >1), and Eastern Cooperative Oncology Group performance status (ECOG PS) (0 if ECOG PS=0, 1 if ECOG PS=1, and 2 if ECOG PS=2). Progression-free survival (PFS) was summarized descriptively, with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazards model. Overall response rate (ORR) was summarized descriptively, with odds ratio (OR) and 95% CI estimated by Mantel-Haenszel method. Response and progression were assessed by the Onyx Response Computer Algorithm using IMWG criteria. Results: Frailty status was generally proportional between arms, with 27% and 35% classified as fit, 43% and 36% int, 25% and 27% frail, and 5% and 2% unknown for KdD and Kd, respectively. Although baseline characteristics of the overall population were generally balanced, more pts had prior transplant in the KdD vs Kd arm for int (65% vs 36%) and frail (41% vs 27%) subgroups, and in the frail subgroup fewer pts were lenalidomide exposed (37% vs 61%)/refractory (25% vs 46%) in the KdD vs Kd arm. Median duration of treatment for KdD vs Kd was 99 weeks (wks) vs 68 wks for fit pts, 82 wks vs 31 wks for int pts, and 51 wks vs 21 wks for frail pts. Median PFS in KdD vs Kd arms was not reached (NR) vs 17.6 months (HR 0.64, 95% CI 0.38–1.07) for fit, NR vs 11.1 months (HR 0.44, 95% CI 0.28–0.69) for int, and 18.5 vs 9.3 months (HR 0.66, 95% CI 0.38–1.14) for frail pts. ORR for KdD vs Kd arms was 89% vs 89% (OR 1.09, 95% CI 0.35–3.38) for fit pts, 87% vs 70% (OR 2.95, 95% CI 1.31–6.62) for int pts, and 75% vs 54% (OR 2.39, 95% CI 1.09–5.22) for frail pts (Figure). Any grade treatment-emergent adverse events (TEAEs) occurred in >95% of pts across arms and subgroups. Grade ≥3 TEAEs occurred in 87% (KdD) and 70% (Kd) of fit pts, 84% and 71% of int pts, and 91% and 90% of frail pts. Fatal TEAEs occurred in 4% and 2% of fit pts, 11% and 9% of int pts, and 16% and 8% of frail pts in the KdD and Kd arms. Carfilzomib was discontinued due to TEAEs in 25% vs 17% of fit pts, 22% vs 29% of int pts, and 35% vs 23% of frail pts. Among TEAEs of interest, acute renal failure occurred in 0 fit pts, 3% vs 14% of int pts, and 8% vs 5% of frail pts, and infusion reactions occurred in 16% vs 2% of fit pts, 13% vs 4% of int pts, and 14% vs 13% of frail pts in the KdD vs Kd arms (Table). Image:Summary/Conclusion: Consistent with previous findings of the efficacy and safety benefits of KdD, a PFS benefit with KdD vs Kd was observed across frailty subgroups, without increased toxicity. The clinically meaningful ORR benefit in the frail subgroup may help physicians evaluate treatment options in this challenging group.

PB1878: CROSS-TRIAL ANALYSIS OF FIXED-DURATION IBRUTINIB (I) PLUS VENETOCLAX (V) VS FLUDARABINE (F), CYCLOPHOSPHAMIDE (C), AND RITUXIMAB (R) AS FIRST-LINE TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Background: While continuous single-agent I or I-based therapies are superior to FCR, FCR remains an efficacious fixed-duration regimen for fit patients (pts) with previously untreated CLL. CAPTIVATE (PCYC-1142; NCT02910583) is a multicenter phase 2 study of first-line treatment with the all-oral, once-daily, chemotherapy-free regimen of I+V in fit pts with CLL. Primary analysis of the CAPTIVATE Fixed Duration (FD) cohort demonstrated deep, durable responses with fixed-duration I+V (Ghia et al, ASCO 2021). Aims: We performed a cross-trial analysis to evaluate outcomes with fixed-duration I+V relative to FCR using data from the FD cohort of the CAPTIVATE study and the FCR arm of the recent E1912 study (NCT02048813; Shanafelt et al. NEJM 2019;381:432-43). Methods: This cross-trial analysis included pts with previously untreated CLL or SLL aged ≤70 y who were treated with I+V in the FD cohort of CAPTIVATE or with FCR in E1912. As pts with del(17p) were not enrolled in E1912, pts with del(17p) from CAPTIVATE were excluded from the analysis. In CAPTIVATE, pts received three 28-d cycles of I, followed by 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). In E1912, pts received six 28-d cycles of FCR (F 25 mg/m2 on days 1-3; C 250 mg/m2 on days 1-3; R 50 mg/m2 on day 1 and 325 mg/m2 on day 2 in cycle 1, then 500 mg/m2 on day 1 in cycles 2-6). PFS and OS were estimated by Kaplan-Meier method. Adjusted treatment effects for PFS, OS, and ORR were estimated by inverse probability of treatment weighting (IPTW) using propensity score (PS) which balanced treatment groups for the following baseline prognostic factors: age, sex, ECOG performance status ≥1, CLL/SLL diagnosis, time from diagnosis, advanced Rai stage, absolute lymphocyte count, beta-2 microglobulin >3.5 mg/L, and high-risk genomic features (TP53 mutated, del[11q], unmutated IGHV). AEs were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Analysis included 136 pts without del(17p) treated with fixed-duration I+V in the CAPTIVATE FD cohort and 175 pts treated with FCR in E1912; baseline characteristics were generally well-balanced across groups, with notable differences in the proportions of pts aged ≥65 y and with baseline thrombocytopenia (Table). Median follow-up was 38.7 mo with I+V and 33.7 mo with FCR. After IPTW, PFS was improved with I+V relative to FCR (hazard ratio [HR] 0.42; 95% CI 0.25-0.71; log-rank P=0.0018; 36-mo PFS rate: 89% vs 70%), as was OS (HR 0.19; 95% CI 0.05-0.77; log-rank P=0.0084; 36-mo OS rate: 98% vs 90%). Results were generally similar in unadjusted analyses (Table). Adjusted ORRs were 96% for I+V and 85% for FCR (difference 11.2%; 95% CI 5.1–17.3; Chi-square P=0.0011). Median duration of treatment was 13.8 mo for I+V and 4.7 mo for FCR. Treatment was discontinued due to AEs in 5% and 21% of pts, respectively. Overall, grade ≥3 AEs occurred in 62% of pts with I+V and 90% with FCR. Grade ≥3 AEs in ≥5% of pts with I+V were neutropenia (36%), and with FCR were lymphopenia (67%), neutropenia (45%), leukopenia (41%), lymphocytosis (31%), anemia (18%), thrombocytopenia (18%), febrile neutropenia (16%), hypertension (6%), hyperglycemia (6%), and maculopapular rash (5%). EAIRs for grade ≥3 AEs and AEs of clinical interest of any grade were lower with I+V than with FCR (Table). Image:Summary/Conclusion: Results of this cross-trial analysis suggest superior PFS with fixed-duration I+V relative to FCR in first-line CLL. The safety profile with I+V appeared favorable relative to the safety profile of FCR, with lower AE rates and fewer discontinuations due to AEs.

Assessing eligibility for non-intensive chemotherapy (IC) randomized clinical trials (RCT) in patients (pts) with newly diagnosed (ND) AML from the Connect Myeloid Disease Registry.

7029 Background: Pts with AML in RCTs often do not reflect the population seen in clinical practice due to strict eligibility criteria. This study evaluated criteria from a recent RCT of non-IC against a broad cohort of real-world pts with AML from the Connect® Myeloid Disease Registry (NCT01688011). Methods: Pts were stratified into 3 groups based on the non-IC phase 3 VIALE-A trial eligibility criteria: 1) “eligible” pts who would have met all VIALE-A inclusion criteria; 2) “unfit” pts who would have been ineligible for VIALE-A due to ≥ 1 of the following: abnormal liver/kidney function, high ECOG, recent prior malignancy, comorbidities score ≥ 2 by ACE-27, hepatic grade ≥ 1, AIDS grade ≥ 1; 3) “fit” pts who would have been ineligible for VIALE-A because they would have qualified for IC (defined as: ≤ 74 y of age, low ECOG, no apparent cardiovascular/renal comorbidities, and did not meet any criteria in #2). Baseline characteristics were summarized by eligibility group. Overall survival (OS) by group was estimated using the Kaplan–Meier method. Induction regimens were categorized as IC (any regimens containing 7+3, MEC, CLAG, FLAG) or venetoclax (VEN)-based. Hazard ratios (HRs) for induction regimens among each group were estimated using Cox models adjusted for age, ELN risk, ECOG, frailty score, and comorbidity index. Results: Of 734 enrolled pts with AML (Dec 2021), most were male (61%) and white (84%); median age 71 y (range 55–97). Only 26% of pts (n = 192) were eligible for a non-IC RCT, 45% (n = 327) were ineligible due to unfitness, and 29% (n = 215) were ineligible due to overall fitness. The main reason for non-IC RCT ineligibility was high overall comorbidity grade (n = 265 [36%]). Fit pts intended to undergo transplant more often compared with unfit pts. Median OS for eligible, unfit, and fit pts were 14, 10, and 22 months, respectively. Among unfit pts, those receiving IC had significantly longer OS compared with pts receiving a VEN-based regimen (median OS 14 vs 6 months, respectively; HR: 0.51, 95% CI: 0.27–0.98, P = 0.042; Table). Eligible pts who received IC tended to have shorter median OS (13 months) vs pts who received VEN-based therapies (23 months; not sig.). Conclusions: The majority of pts with ND AML in the Registry would have been ineligible for a non-IC RCT due to being too fit or unfit. Pts ineligible for an RCT due to unfitness but who received IC maintained an OS benefit vs those receiving VEN-based therapies. This analysis suggests that non-IC RCTs may be excluding pts who appear unfit but can potentially tolerate IC and experience improved survival outcomes. Clinical trial information: NCT01688011. [Table: see text]

A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial

A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial