Unfit Pts Research Articles

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.

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.

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.

Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Drs. Yifan Zhai and Jie Jin are co-corresponding authors. Introduction Investigational lisaftoclax, a novel BCL-2 inhibitor, has shown antileukemic activities in pts with CLL. For the first time, we present the safety, pharmacokinetics (PK), and efficacy of lisaftoclax alone or combined with azacitidine (AZA) or homoharringtonine (HHT), in adults with AML, MDS, or other myeloid neoplasms. Methods In part one, lisaftoclax was administered orally once daily at an assigned dose (200, 400, 600, or 800 mg) to pts with R/R AML using a “3+3” dose escalation design. In part two, pts with R/R AML, mixed-phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), or chronic myelomonocytic leukemia (CMML) were enrolled in Cohorts A, B, and C; pts with higher-risk MDS (blast cells > 5%; IPSS-R > 3.5) were enrolled in Cohort D; and older (≥ 75 yrs)/unfit pts with TN AML were enrolled in Cohort E. Lisaftoclax was administered orally once daily in either 28- or 14-day cycles (MDS only), depending on the assigned dose level. A daily ramp-up schedule was used to prevent tumor lysis syndrome (TLS).In part two, select lisaftoclax doses were combined with low-dose HHT (1 mg daily on days [d] 1-14; Cohort A) or standard-dose HHT (2 mg/m 2 daily on d1-7; Cohort B) or AZA (75 mg/m 2 daily on d1-7; Cohorts C, D, and E). Dose-limiting toxicity (DLT) was assessed during the first cycle. Results As of July 19, 2023, 115 pts were enrolled, including 89 with AML (64 R/R; 25 TN older/unfit), 22 MDS (7 R/R; 15 TN), 2 MPAL, 1 CMML, and 1 BPDCN. The median (range) age was 62.0 (18-81) years, and 66 (57.4%) were male. A total of 13 pts received lisaftoclax monotherapy, and 102 received combination regimens. DLTs (pneumonia, respiratory failure, and heart failure) were observed in 1 pt in Cohort C, and no TLS was reported. Treatment-emergent adverse events (TEAEs) were observed in all 13 (100%) pts who received lisaftoclax monotherapy, of whom all experienced grade (Gr) 3/4 AEs and 4 (30.8%) experienced serious AEs (SAEs). Common TEAEs (> 30%) included leukopenia, neutropenia, lymphopenia, thrombocytopenia, anemia, diarrhea, hypokalemia, hypocalcemia, and hypomagnesemia. Similarly, TEAEs were reported in 12 (85.7%) pts treated with lisaftoclax combined with HHT, with Gr 3/4 AEs occurring in 12 (85.7%) and SAEs in 2 (14.3%). Common TEAEs (> 30%) included leukopenia, neutropenia, thrombocytopenia, hypokalemia, hypocalcemia, and pneumonia. TEAEs were also observed in 75 (100%) evaluable pts treated with lisaftoclax combined with AZA, with Gr 3/4 AEs occurring in 55 (73.3%) and SAEs in 18 (24.0%). Common TEAEs (> 30%) included leukopenia, neutropenia, thrombocytopenia, anemia, and diarrhea. A total of 40.0% (46/115) of pts discontinued the study because of progressive disease (45.7% [21/46]), lack of clinical benefit (8.7% [4/46]), AEs (17.4% [8/46]), withdrawal (26.1% [12/46], including 4 for transplantation), and investigator's decision (2.2% [1/46]). Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 to 800 mg. Compared to lisaftoclax alone, no significant difference was observed in the PK profile of lisaftoclax when combined with AZA or HHT. In part one, the overall response rate (ORR) and composite remission rate (CRc [complete remission (CR) + CR with incomplete blood count recovery (CRi)]) were each 8.3% (1/12). Lisaftoclax 600 mg was administered for further optimization of the combination regimens, and 800 mg was also explored. In Cohort E (n = 21), among TN AML pts treated with lisaftoclax, ORR and CRc were 71.4% and 47.6%, respectively, and the median (range) time to CR/CRi/MLFS was 1.05 (95% CI, 0.99-NR) months. In Cohort C (n = 36), ORR and CRc were 75.0% and 44.4%, respectively, and the median (range) time to CR/CRi/MLFS was 1.25 (95% CI, 1.02-2.17) months; and median (range) progression-free survival was 10.22 (95% CI, 6.34-NR) months, with a median (range) follow-up time of 3.25 (95% CI, 0.79-14.29) months. In Cohort B, ORR or CRc was 75.0%. In Cohort D, ORR was 70.0% and CR/marrow CR was 60.0% (Table 1). Conclusions Lisaftoclax showed favorable tolerability as monotherapy and when combined with AZA or HHT, exhibiting encouraging clinical efficacy among pts with R/R AML or MDS and older/unfit pts with TN AML. This ongoing trial continues to enroll pts. Internal study (CT.gov) identifier: APG2575AC101 (NCT04501120).

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.

Selinexor in Combination with Venetoclax and Azacitidine for Newly Diagnosed (ND) Unfit Acute Myeloid Leukemia (AML): A Multicenter, Open-Label Prospective Study

Introduction: Acute myeloid leukemia (AML) predominantly affects the elderly, with a median age at diagnosis around 68 years (Bhansali, 2023). Due to existing or potential comorbidities and frailty, many patients are unable to undergo conventional intensive chemotherapy at the time of diagnosis. The combination of venetoclax with azacytidine has shown improved clinical response rates of 64% with a median overall survival of 14.7 months (DiNardo, 2020). However, subgroup data demonstrated no significant benefits in the Chinese population, in pts with poor risk, or in those with TP53 mutations. Therefore, managing AML in elderly or unfit pts remains a significant challenge. Selinexor has shown promising tolerability and clinical activity in AML through various phase 1/2 trials. The triple regimen of selinexor, venetoclax, and azacytidine (SAV) has demonstrated favorable results in AML pts with severe co-morbidities in real-world settings. To further evaluate its efficacy and safety, we have designed a prospective study (NCT05736965) to assess the SAV regimen for ND AML pts who are ineligible for intensive therapy. Methods: To report the efficacy and safety of ND AML pts ineligible for intensive chemotherapy, treated with a triple regimen from 6 sites. The study enrolled pts who were unfit for intensive chemotherapy, ≥75 years, had significant comorbidities, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥3, organ dysfunction, or had abandoned intensive chemotherapy. The primary study objectives were the complete response (CR)/complete response with incomplete count recovery (CRi) rate and overall response rate (ORR). Responses were assessed according to the ELN2022 criteria. Pts received the following treatment regimen: Selinexor 60mg on days 3, 10, and 17; Azacitidine 75mg/m2 on days 1-3, 8-9, and 15-16; Venetoclax 100mg on day 1, 200mg on day 2, and 400mg on days 3 to 14. Each treatment cycle lasted for 28 days. Pts who achieved CR, CRh, or CRi, as per the center's treatment guidelines, were eligible for transplantation at any time point. Remaining pts continued to receive the SAV regimen until disease progression or intolerable toxicity. Results: From March 2023 to the data cutoff on June 10, 2023, a total of 20 pts were enrolled in the study, of which 16 had de novo or therapy-related AML, and 4 had secondary AML with a history of myelodysplastic syndrome. Table 1 displays the baseline characteristics and responses of the newly diagnosed AML pts. The median age of the 20 pts was 64 years (range: 28-80), and the majority of them had high-risk disease: 12/20 (60%) had intermediate-risk, and 8/20 (40%) had adverse-risk according to the ELN 2022 criteria. Additionally, 4/20 (20%) of the pts had therapy-related AML, 6/20 (30%) were aged ≥75 years, 12/20 (60%) had ≥2 high-risk molecular mutations, and a significant proportion had high blast counts. All pts completed at least 1 cycle of treatment (range: 1-4). Specifically, 1patient completed 4 cycles, 2pts completed 3 cycles, and 7pts completed 2 cycles. The remaining 10pts have just completed their first cycle of treatment and evaluation. With the exception of one patient with disease progression (PD), all other pts are still undergoing treatment. As the treatment duration extends, the depth of remission in pts may further deepen. The CR/CRi rates and ORR across the ELN 2022 risk groups for all pts, intermediate-risk group, and adverse-risk group were as follows: 80% (16/20) and 90% (18/20), 75% (9/12) and 91.7% (11/12), 87.5% (7/8) and 87.5% (7/8), respectively. In comparison, the VIALE-A data showed a CR/CRi rate of 52.9% for adverse-risk pts, indicating a higher remission rate observed in this study. As of now, 3 pts were MRD-negative. The reported adverse events of grade 3 or higher occurring in ≥10% of pts in the triple regimen were thrombocytopenia (35%), neutropenia (35%), and infections (15%). The most frequently reported adverse events of Grade 1-2 included anemia, nausea, fatigue, anorexia, and hyponatremia. All adverse events could be managed and improved through dose adjustments and supportive treatment. Conclusions: The SAV regimen has been found to be safe and effective, with encouraging complete response (CR) rates in newly diagnosed AML pts, especially in adverse risk patients. Further trial enrollment and correlative analysis are currently underway to thoroughly observe the efficacy and safety of the SAV regimen.

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.

Venetoclax in Combination with Hypomethylating Agents or Low-Dose Cytarabine for Relapsed/Refractory Acute Myeloid Leukemia: A Retrospective Single-Centre Experience

Background. Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical condition with an overall dismal outcome owing to the lack of standardized, effective treatment approaches. The only curative option for R/R AML patients (pts) is allogeneic hematopoietic stem cell transplantation (HSCT), that can be exploited in a minority of otherwise eligible pts due to poor efficacy and high toxicity of salvage regimens used to induce leukemia remission as bridge-to-transplant. Recently, a number of targeted agents with relatively favorable toxicity profiles have been explored in clinical trials for R/R AML pts. Since its first accelerated approval by the Food and Drugs Administration in 2018, the Bcl-2 inhibitor venetoclax (VEN), in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), has steadily become the standard therapeutic approach for newly diagnosed AML in elderly or unfit pts, while its role in R/R disease is not well defined yet. Aim. To gain insights into the potential effectiveness of VEN-based regimens in patients with R/R AML. Patients. We retrospectively analyzed the clinical outcomes of 67 R/R AML pts treated at our Institution with venetoclax-based regimens on an off-label basis, between March 2018 and April 2022. Fifty-eight pts (87%) carried a de-novo AML diagnosis, 6 pts (9%) had AML secondary to myelodysplastic syndrome and 3 pts (4%) had therapy-related AML. Median age was 58y (33-74y); 30 pts (45%) were aged >60, while 7 pts (10%) were aged >70y at VEN initiation. Thirty-eight pts (56%) were treated for first (n=32) or second relapse (n=6); last complete remission (CR) duration was <6 mo in 18 pts, 6-12 mo in 16 pts and >12 m (12-56) o in 4 patients; 11 pts (16%) had relapsed after HSCT; remaining 18 pts (27%) were treated for primary refractory disease. All pts received conventional immunophenotypic and cytogenetic characterization and at least NPM1, FLT3, CBFB/MYH11 and RUNX1/RUNX1T1 mutation/rearrangement detection. Next-generation sequencing (NGS) data were available for 56 pts (83%); specifically, 40 pts (primary refractory, n=18; relapsed, n=22) had NGS analysis carried out on bone marrow samples shortly before VEN initiation, while in 16 pts NGS was carried out on baseline diagnostic specimens. VEN partner drug was azacitidine in 45 pts (68%), LDAC in 15 (22%) and decitabine in 7 (10%). Thirty-nine pts (58%) were treated with an intention-to-transplant (ITT). Median follow-up duration was 11.8 mts (1.1 - 44). Results. Overall, we report a composite complete response (CCR) rate of 55% (n=37); 10 of complete responders (27%) had incomplete peripheral counts recovery. Minimal residual disease (MRD) negativity was achieved in 21/37 pts (56%). All CR invariably occurred during the first 8 weeks of treatment. Although it did not reach significance level (p=0.065), there was considerable variation in CCR rate among treatment settings: relapsed pts, 66%; primary refractory, 50%; post-HSCT relapse, 27%. Conventional risk stratification parameters (age, leukocyte counts, ELN 2017 risk category, NPM1/FLT3 mutational status, secondary disease, last CR duration) were poorly predictive of CR probability. A positive trend towards higher CCR rate, although not statistically significant, was found for NPM1 (CCR rate: 57%) and IDH1/2 mutation (66%) while FLT3/Ras pathway mutations were detrimental (23%). Median overall survival (OS) but not event-free survival (EFS), differed significantly among settings: relapsed pts, 11.9 mo; refractory, 8.6 mo; post-HSCT, 6.7 mo. (p=0.030). Stratifying pts based on NPM1 and FLT3-ITD status resulted in markedly different EFS: NPM1mut/FLT3-ITDneg, not reached; NPM1wt/FLT3any, 6.2 mo; NPM1mut, FLT3-ITDpos, 3.4 mo (p=0.031); as well as different OS: NPM1mut/FLT3-ITDneg, not reached; NPM1wt/FLT3any, 10.5 mo; NPM1mut, FLT3-ITDpos, 5.6 mo (p=0.003). Among the ITT population, HSCT actualization rate was 66%. Four pts are currently long-term survivors with follow-up exceeding 24 mo without receiving HSCT; notably, they all carried a NPM1mut/FLT3-ITDneg/Ras pathwayneg genotype. Conclusions: Overall, these findings suggest a role for venetoclax-based regimens in R/R AML patients and support the design of prospective studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Initiating First-Line (1L) Ibrutinib (Ibr) in Patients (pts) with Chronic Lymphocytic Leukemia (CLL) Improves Overall Survival (OS) Outcomes to Rates Approximating an Age-Matched Population of ≥65 Years

Background: CLL OS rates have improved over the last 20 years (y), starting with the use of chemotherapy and chemoimmunotherapy (CT/CIT), to the introduction of novel agents such as Ibr. Ibr has shown superiority to standard CT/CIT across a range of 1L pt populations with demonstrated OS improvements in multiple pivotal trials. Recently presented 8-y follow-up data from the first pivotal trial for Ibr demonstrated that more than half of 1L unfit pts remain progression-free. The ideal goal of any therapeutic regimen would be to cure patients of their disease, but the first step could be to provide enough effective therapeutic options to allow patients to live with their disease rather than die from it. Given the size of the program and the length of follow-up, Ibr is uniquely positioned to assess whether the initiation of 1L Ibr could essentially remove the survival hazard associated with CLL vs the general population. Aims: 1) To compare pooled OS of previously untreated CLL pts treated with Ibr to that of the available age-matched general population 2) To compare the pooled characteristics and OS results with Ibr vs CT/CIT across three phase 3 trials. Methods: Data were pooled from the RESONATE-2 (NCT01722487), ECOG1912 (NCT02048813), and iLLUMINATE (NCT02264574) clinical studies which evaluated Ibr alone and in combination with other agents in pts with previously untreated CLL/SLL. Individual trial descriptions and key eligibility criteria have been previously published. For the comparison of OS for Ibr-treated pts with that of the available age-matched population, an age-matched approach was applied to pooled Ibr-treated pts to include those who were ≥65 y at the time of initial CLL diagnosis. These pts were then compared to a simulated age-matched OS data cohort from the general population (CDC life table for total US population in 2019). Pooled OS data from Ibr-treated pts from the 3 Ibr studies were compared to OS data from CT/CIT-treated pts. OS was estimated using Kaplan-Meier methodology. Results: 603 pts with previously untreated CLL/SLL received Ibr treatment across the 3 pooled studies. Among those treated with Ibr, 58.7% received Ibr + rituximab, 22.6% received single agent Ibr, and 18.7% received Ibr + obinutuzumab; the median age was 63 y (range, 31‒89); among pts with available genetic data, 90% (482/538) were without del(17p)/TP53 mutation; median follow-up was 42 months (mo). To compare Ibr data to an age-matched general population, 201 pts age ≥65 y at initial diagnosis were pooled from the 3 Ibr studies; median time from initial diagnosis to randomization was 20 mo and the median follow-up from initial diagnosis was 7.6 y. OS estimate at 8-y for Ibr-treated pts aged ≥65 y from time of CLL diagnosis was 78% (95% CI, 71‒84) compared to 77% (95% CI, 70‒82) in the age-matched general population [HR, Ibr over general population, 0.97; 95% CI, 0.63‒1.51; p=0.90]; Figure 1. Pooled data from the 603 Ibr-treated pts were also compared to data from pts who received CT/CIT (N=424 pts) across the 3 pooled studies. Among pts who received CT/CIT, 41.3% received fludarabine + cyclophosphamide + rituximab; 31.4% received chlorambucil, and 27.4% received chlorambucil + obinutuzumab; the median age was 66.5 y (range, 28‒90); 91% (308/339) of pts with available genetic data were without del(17p)/TP53 mutation; median follow-up was 42 mo. OS estimates were significantly improved with Ibr: 3- and 5- y rates were 93% (95% CI, 91‒95) and 88% (95% CI, 83‒91), respectively, for pts who received Ibr and 85% (95% CI, 81‒89) and 75% (95% CI, 68‒81), respectively, for pts treated with CT/CIT [HR, Ibr over CT/CIT, 0.46; 95% CI, 0.33‒0.66); p<0.0001]; Figure 2. Conclusion: This pooled analysis suggests that initiating therapy with 1L Ibr improves OS vs traditional CT/CIT regardless of age or fitness. It is also the first demonstration to our knowledge that pts who initiate Ibr over an 8- y follow-up have similar survival estimates as age-matched pts in the general population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation

Introduction: Since non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) is influenced by the conditioning regimen, it is essential to precisely calculate its intensity for any patient. Therefore, the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) registry previously developed the Transplant Conditioning Intensity (TCI) score to define conditioning regimens based on the sum of the doses (weight scores) for every component of the pre-transplantation regimen. HCT patients (pts) were stratified by a 3-index scheme with a low [1-2], intermediate [2.5-3.5] or high [4-6] TCI-score. (Bone Marrow Transplantation 2020; 55:1114) When tested in a large registry dataset of acute myeloid leukemia (AML) pts >45 years of age, TCI grouping was highly predictive for early and 2-year NRM, and better compared with the classical 2-index reduced intensity conditioning/ myeloablative conditioning (RIC/MAC) classification. The aim of the current study was to validate using a distinct dataset, the ability of the original TCI classification scheme to predict post-HCT NRM. Methods: TCI score was applied to a timely distinct cohort reported to the EBMT as the one used to establish the TCI classification scheme. We tested the impact of TCI in predicting early (day 180) NRM (defined as any death without previous relapse) in 55-75 years of age AML first complete remission (CR-1) pts who were transplanted between 2018 and 2021. Included pts were allografted with peripheral blood stem cells (PBSC, 96.4%) or bone marrow (BM, 3.6%) from a matched sibling donor (MSD, 25%) or unrelated donor (UD, 75%). NRM at 2 years was a secondary endpoint. Results: 4,312 AML pts (median age 63.4, interquartile range 59.5-67.2) were assigned to a TCI category, as previously described. 49% of the pts received a low [1-2], 47% an intermediate [2.5-3.5] but only 4% of the pts received a high [4-6] TCI-score regimen. As expected, there was an inverse relationship between age, Karnofsky status and hematopoietic cell transplant-specific comorbidity index (HCT-CI) and TCI group (p<0.0001). Besides a higher prevalence of MSD transplantations in the high (40%) as compared to low (21.6%) and intermediate (26.4%) TCI-groups (p<0.0001), pts were well balanced within TCI groups regarding other transplant and patient characteristics. The day (d)100, d180 and 2-year NRM ranged from 4.8-12.5%, 8.9-17%, and 17.4-23.9% between low, intemediate and high TCI scores, respectively. In univariate analysis, TCI provided a highly significant risk stratification for early and 2-year NRM (p<0.0001 for all pairwise comparisons between groups) (Figure 1). In the multivariate Cox regression analysis adjusted for age, Karnofsky status, HCT-CI and other variables, there was a significant increase in risk of early NRM with each TCI group (Table 1). Compared to low TCI, pts receiving intermediate and high score TCI regimens had a significantly increased risk for d180 NRM (hazard ratio [HR] 1.34, 95% CI, 1.03-1.74, p=0.029 and HR 2.37, 1.39-4.06, p<0.002, respectively). The HRs for d180 NRM pts receiving a high TCI [4-6] score regimen was 1.77 (1.06-2.97, p=0.029) when compared to the intermediate TCI [2.5-3.5] group. As expected, early NRM was also significantly influenced by incremental age, Karnofsky status score <90 and HCT-CI >=3. TCI grouping was also significantly associated with overall NRM. Similar results were found when the analysis was restricted to pts aged between 55 and 65 years (N=2,640). There was good concordance between RIC/MAC and low/high TCI score grouping, whereas 49% of the MAC pts and 51% of the RIC pts were re-classified as having received a reduced toxicity conditioning regimen with a TCI score of 2.5-3.5. Conclusion: Here, we validated in an independent patient cohort, the recently proposed 3-group TCI score for its ability to predict early NRM in AML pts >55 years of age. TCI predicts early NRM independently of other known prognostic factors such as age, Karnofsky, or HCT-CI. Compared to the current RIC/MAC classification model, the TCI provides a finer and more precise tool which may be easily calculated for any patient to offer safer transplantation especially in older and unfit pts. TCI may be used as a new, well-defined, and standard terminology for conditioning intensity in registry databases, in the literature and in clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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]

Lower-intensity CPX-351 + venetoclax for patients with newly diagnosed AML who are unfit for intensive chemotherapy.

7031 Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients (pts) who are candidates for intensive chemotherapy (IC) and aged ≥1 year in the US and adults in Europe. However, the appropriate dosage of CPX-351 in pts unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit pts with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Pts who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Pts are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 pts enrolled by 9/15/2021, with a data cutoff of 12/2/2021: 4 pts in DEP at dose level 1 (CPX-351 20 units/m2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 pts in DEP at dose level 2 (CPX-351 40 units/m2 + VEN 400 mg), and a total of 20 pts in DEP and EP at dose level 1b (CPX-351 30 units/m2 + VEN 400 mg; established as the recommended phase 2 dose). Pts were unfit for IC based on age ≥75 y (n = 15) or health (ECOG PS of 2 to 3 and/or comorbidities [n = 16]). Median age was 74 y (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of pts were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) pts; no nonhematologic grade ≥3 TEAE was reported in &gt; 10% of pts. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n = 1), worsening lung infection (n = 1), and disease progression (n = 2). Median (IQR) recovery times were 30 d (22, 34.5) to neutrophils ≥500/μL and 21 d (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) evaluable pts. All 16 of these pts achieved remission (CR or CRi) after the first cycle. MRD negativity was achieved by 12/16 (75%) pts with CR or CRi, primarily after Cycle 1 (Cycle 1: n = 8; Cycle 2: n = 2; Cycle 3: n = 1; Cycle 4: n = 1). Survival data are not yet mature. Conclusions: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of pts. Clinical trial information: NCT04038437.

Combinatorial Anti-Tumor Activity in Animal Models of a Novel CD123 x CD3 Bispecific Dart® Molecule (MGD024) with Cytarabine, Venetoclax or Azacitidine Supports Combination Therapy in Acute Myeloid Leukemia

Combinatorial Anti-Tumor Activity in Animal Models of a Novel CD123 x CD3 Bispecific Dart® Molecule (MGD024) with Cytarabine, Venetoclax or Azacitidine Supports Combination Therapy in Acute Myeloid Leukemia

Clinical Characteristics and Outcomes of AML Patients Treated with Frontline CPX 351 or HMA/Venetoclax: A Single Institution's Experience

Introduction: Treatment options for newly diagnosed patients (pts) with acute myeloid leukemia (AML) have historically been limited. The combination of a hypomethylating agent and venetoclax (HMA/Ven) has emerged as standard of care treatment for elderly and/or unfit pts with newly diagnosed AML. Liposomal cytarabine/daunorubicin (CPX-351) has also become standard of care therapy for pts with AML with myelodysplasia related changes or therapy-related AML. Despite being an intensive regimen, CPX-351 may have a more favorable toxicity profile compared to other intensive regimens. As a result, CPX-351 may be offered to older fit pts who may not have been candidates for traditional induction regimens. As the landscape for frontline treatment options evolves, there are now overlapping pt populations who may be eligible for either frontline treatment option. A retrospective study that included clinical trial pts demonstrated similar response rates in pts treated with HMA/Ven and CPX-351 (Asghari Blood 2019). Similarly, a study of secondary AML pts receiving HMA/Ven and CPX-351 showed no difference in remission rate or survival (Salhotra Am J Hematol 2021). There remains a shortage of data describing clinical characteristics of pts selected for and treated with standard-of-care HMA/Ven and CPX-351. We present a study on our center's experience.Methods: The purpose of this study was to evaluate the clinical characteristics and outcomes of adult pts with newly diagnosed AML who were treated with either CPX-351 or HMA/Ven as initial therapy. Consecutive pts treated with either of these two induction therapies between August 2017 and June 2021 were evaluated retrospectively. Pts were eligible for response evaluation if they received at least 3 doses of CPX-351 or 28 days (1 cycle) of venetoclax (“response cohort”). All pts treated with CPX-351 or HMA/Ven were included in survival analysis (“survival cohort”). Response assessment is based on ELN-2017 criteria. Pt characteristics were described and compared using Fisher's Exact tests. Kaplan-Meier methods were used to summarize overall survival, and log-rank tests were used for the comparison of frontline therapies. Cox proportional-hazards regression estimated hazard ratio (HR), 95% confidence interval (CI), and interactions between frontline therapy and age at induction start.Results: A total of 79 pts were identified receiving frontline HMA/Ven or CPX-351; 61 pts (77%) were evaluable for response. Of the response cohort, 21 (34%) were treated with CPX-351 and 40 (66%) with HMA/Ven; pt characteristics are described in Table 1. CPX-351 pts were younger at start of induction (P<0.001); many pts in both treatment groups had unfavorable ELN risk scores at diagnosis (CPX 43%, HMA/Ven 41%; P>0.99). 33% and 23% of the HMA/Ven cohort achieved CR and CRi respectively; in the CPX-351 cohort 57% and 5% achieved CR and CRi respectively. A greater fraction of CPX-351 pts proceeded to allogeneic stem cell transplant than HMA/Ven pts (67% vs 23%; P<0.001). No differences were detected in achievement of MRD negativity by flow cytometry (P=0.51) or molecular profile (P=0.52).Median follow-up for all pts was 18.9 months; 42 deaths occurred. Differences in survival between the frontline therapies were not detected in the survival cohort (HR, 1.31; 95% CI, 0.67 to 2.57; P=0.43) nor the response cohort (HR, 0.97; 95% CI, 0.45 to 2.09; P=0.93); these results were unaffected by adjustments for age at induction, ELN risk score, and transplant status.8 pts who initially received CPX-351 and had refractory disease later went on to receive HMA/Ven reinduction; 2 achieved CRi, 2 MLFS, 3 Refractory and 1 Death in Aplasia. 1 pt who initially received HMA/Ven with refractory disease went on to receive CPX-351. This pt was refractory to CPX-351.Conclusion: HMA/Ven and CPX-351 are effective frontline treatment options with similar response rates and survival outcomes in newly diagnosed adults with AML. Pts treated with CPX-351 were younger and more likely to proceed with allogeneic transplantation, in line with standard practice. Though there was heterogeneity in pt populations, age did not appear to affect outcomes. As the landscape for standard-of-care upfront treatment for AML continues to evolve, further studies are warranted to determine optimal therapy selection and sequencing. [Display omitted] DisclosuresArnall: Novo Nordisk: Speakers Bureau. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Avalos: JUNO: Membership on an entity's Board of Directors or advisory committees. Copelan: Amgen: Consultancy. Grunwald: Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Janssen: Research Funding; PRIME: Other; Karius: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Blueprint Medicines: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; Med Learning Group: Other; Sierra Oncology: Consultancy; MDEdge: Other; PER: Other; Trovagene: Consultancy; Stemline: Consultancy.

First Prospective Data on Minimal Residual Disease (MRD) Outcomes after Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study

First Prospective Data on Minimal Residual Disease (MRD) Outcomes after Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults

A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for BCR-ABL1-Positive ALL in Adults

Therapy-Related Acute Myeloid Leukemia (t-AML) and the Advantage of Intensive Chemotherapy: Real-Life Analysis from Two Regional French Centers

Rational: Patients with t-AML are those previously treated for primary malignancy and are categorized with poor prognosis. t-AML treatment options include intensive chemotherapy (IC), hypomethylating agents (HMA) or low dose cytarabine (LDC). However, survival remains poor and allogeneic hematopoietic cell transplantation (Allo-HCT) could lead to better outcomes. The aim of this analysis is to assess the outcome of all consecutive t-AML pts from two regional centers in France, based on treatment intensity, and to identify prognostic factors.Patients and Methods: between January 2006 and December 2019, 112 adult pts diagnosed with t-AML occurring after treatment of solid tumors (ST; n=72), hematologic malignancies (HM; n=34) or autoimmune diseases (AID; n=6). Pts received chemotherapy and/or radiotherapy or high dose chemotherapy followed by autologous hematopoietic cell transplantation (Auto-HCT) in some. All eligible t-AML pts received intensive chemotherapy (IC, n=55) with the combination of anthracycline and cytarabine in 48 pts and CPX-351 in 7 pts. Unfit pts received non-IC (9 LDC, 24 HMA). The third study group (24 pts) received best supportive care (BSC). Fifteen pts underwent HSCT in first CR.Statistical analysis: We performed a descriptive analysis of the baseline characteristics and each treatment group was compared with a Kruskal-Wallis test and a Pearson's Chi-square test. Survival curves (Kaplan-Meier method) were compared with a log-rank test. Univariate and multivariate analyses on survival, relapse and NRM were done using Cox regression, Gray test, Fine & Gray regression. The bilateral level of significance was set at 5%. All analyses and graphics were made under the R program (v3.5.1). A pair-matched control analysis with de novo AML was performed only on pts who received IC matched for age, cytogenetics and ELN 2010 classification.Results: A total of 112 t-AML pts were identified, 56 were males (50%) with a median age of 68 yrs (19-87) at t-AML diagnosis. Before t-AML, 72 pts had ST (64.5%), 34 HM (30.5%) and 6 AID (5%). Forty-six pts (41%) received chemotherapy alone for their primary cancer, 17 (15%) radiotherapy alone, 49 (44%) radio chemotherapy, 17 (15%) auto-HCT and 6 (5%) long-term methotrexate for AID. Median interval from treatment of previous ST or HM to t-AML diagnosis was 4.7 years in ST, 6.6 years in HM and 21 years in AID (p=0.03). At t-AML diagnosis, 42% of pts presented an unfavorable karyotype and 44% an unfavorable ELN 2010 classification. Regarding molecular alterations, FLT3-ITD, FLT3-TKD, NPM1 and IDH1/2 mutations were observed in 6.9, 2.3, 11.5 and 2.3% of pts respectively. MECOM1 was overexpressed in 25.5% of cases. Among treated pts (n=88), 43 pts (49%) achieved CR: 4 from 33 (12%) in non-IC pts (3 in HMA and 1 in LDC) and 39 from 55 (71%) in IC pts. Fifteen pts (17%) underwent Allo-HCT with a median interval between AML diagnosis and Allo-HCT of 4.7 mo (2.6-17.5). The best response after transplantation was CR in 10 pts; at the last follow up, 4 pts are alive (3 in CR and 1 in relapse) and 11 died (5 from relapse, 5 from TRM causes and 1 from another subsequent malignancy). Overall, with a median follow up of 5.5 mo (0-144), the median OS and DFS were 9 mo (5.9-13.5) and 6.3 mo (5.3-10.3) respectively (Figure). There was a significant difference between the 3 treatment groups concerning OS (p<0.001) and DFS (p<0.001) with a significant difference in OS between IC and non-IC groups (p=0.02). In the 88 treated t-AML pts, with a median follow up of 8.2 mo (0.3-144), the median OS was 13.5 mo (10.3-19.6) and the median DFS was 8.2 mo (7-13.7). Multivariate analysis for total and treated populations showed no impact of all variables related to previous malignancies except for auto-HCT pre-t-AML (significant negative impact on OS, DFS, NRM), WBC at t-AML diagnosis (negative impact on OS, DFS) and chemotherapy (positive in total population on OS, DFS, NRM and negative impact of IC on OS and NRM in treated pts) . In IC treated pts, we showed, in a pair-matched analysis with de novo AML, no difference in term of OS and DFS due to a significant higher CI of NRM (p=0.045) at 24 mo (40% in t-AML versus 27.4% for de novo AML) and a lower CI of relapse (NS) at 24 mo (33% in t-AML versus 47.6% for de novo AML).Conclusion: The prognosis of t-AML remains poor and our study showed the advantage of using intensive chemotherapy whenever possible and, in comparison with de-novo AML, a higher NRM and a lower incidence relapse. [Display omitted] DisclosuresNicolini: Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

Mode of Progression after First Line Treatment Correlates with Outcome of Chronic Lymphocytic Leukemia (CLL)

Mode of Progression after First Line Treatment Correlates with Outcome of Chronic Lymphocytic Leukemia (CLL)

Safety of Obinutuzumab Alone or Combined with Chemotherapy in Previously Untreated (Fit or Unfit) or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients: Results from the Primary Analysis of the Phase 3b GREEN Study

Safety of Obinutuzumab Alone or Combined with Chemotherapy in Previously Untreated (Fit or Unfit) or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients: Results from the Primary Analysis of the Phase 3b GREEN Study