Tyrosine kinase inhibitors are recommended as maintenance therapy following allogeneic stem cell transplantation (HSCT) for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), but optimal medication, dose, and duration remain a subject of ongoing study. We provide the final analysis of a prospective randomized trial comparing prophylactic and minimal residual disease (MRD)-triggered imatinib maintenance. The two patient cohorts did not differ significantly in terms of cumulative incidence of relapse (CIR; 14% vs. 18%), non-relapse mortality (NRM; 12% vs. 11%), leukemia-free survival (LFS) 64% vs. 69%, and overall survival (OS) at 10 years (68% vs. 71%). Endpoints were assessed every 6 weeks within the trial from 4 weeks after SCT until EOS at week 55 and after that according to local standards. In summary, this provides a framework for MRD-based treatment of patients for maintenance after HSCT with excellent long-term outcome after 10 years in both groups.

BACKGROUND:Fluoropyrimidines + angiogenesis inhibitor or dose-reduced doublets are used for (frail) elderly patients with metastatic colorectal cancer (mCRC). This non-comparative trial evaluated two 1st line regimens for patients not eligible for full-dose combinations. METHODS:This open-label, multicenter, phase II study randomized untreated mCRC patients ≥ 70 years ± frailty 1:1 to dose reduced mFOLFOX7 in Arm A or aflibercept (4 mg/kg) plus dose reduced mLV5FU2 in Arm B. Primary endpoint was the 6-months PFS rate (PFS@6), secondary endpoints included safety, overall survival (OS), overall response rate (ORR), patient reported outcomes and overall treatment utility (OTU). FINDINGS:The full analysis population comprised 120 patients (62 Arm A, 58 Arm B; 63% male), with a median age of 78.5 years. 82% frail patients were included. PFS@6 was 68% [95%CI 56%;80%] in Arm A and 46% [32%;59%] in Arm B. Median PFS was 7.9 and 5.5 months, median OS was 20.4 and 19.0 months and ORR was 47% and 22% in Arm A and B, respectively. At 3 months, 52% in Arm A and 35% in Arm B had a good OTU. Most frequent grade ≥ 3 AEs in Arm B were hypertension (41%) and proteinuria (10%). More patients in arm B had treatment-related SAEs grade ≥ 3 (17% in arm B and 5% in arm A). INTERPRETATION:Both regimens were feasible in this (frail) elderly population. Dose-reduced mFOLFOX7 and, to a lesser extent, 5-FU/aflibercept showed good PFS and 3-month OTU. Although most patients were regarded frail, survival rates were promising, most likely due to effective further-line treatments.

Currently there is no established prognostic scoring system for patients with chronic myeloid leukemia (CML) in blast phase (BP). This study aimed to identify prognostic factors of CML-BP in a large cohort of prospectively and retrospectively collected patients and to develop a readily available prognostic scoring system at the onset of BP to enable future comparison between different trials and series. The analyses were based on 275 patients from thirteen countries, collected within the European LeukemiaNet Blast Phase Registry with a median observation time of 45 months and a median OS of 18.9 months. A Cox proportional hazards model for overall survival (OS) was employed, missing values were imputed. The study identified six independent prognostic factors: blast percentage, platelet count, age (all at onset of CML-BP), immunophenotype of BP, extramedullary disease, and previous history of CML. The low-risk group, encompassing 14% of patients, had a median OS of 97 months, the intermediate-risk group (59% of patients) of 22 months, and the high-risk group (27% of patients) of 9 months. Cross-validation demonstrated a good performance of the score, although external validation is strongly recommended. Despite the inherent limitations of registry data, the findings offer robust insights into prognostic factors for CML-BP.

The phase 3 ENESTPath study investigated treatment-free remission (TFR) rates in patients with chronic Philadelphia chromosome-positive (Ph+) and/or BCR::ABL1+ chronic myeloid leukemia who had not achieved deep molecular response (DMR) after >2 years of imatinib treatment and were switched to nilotinib 300 mg twice daily (BID). After 24 months of treatment, patients with a stable DMR were randomized to either enter the TFR phase (Arm 1) or continue nilotinib consolidation for an additional 12 months and then enter the TFR phase if in stable DMR (Arm 2). The primary endpoint was the proportion of patients who remained in TFR (≥MR4.0 [BCR::ABL1IS ≤ 0.01

BACKGROUND:Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespectively of sex. However, differences relating to safety and efficacy in the treatment of mCRC between male and female patients are of growing interest. METHODS:The randomized FIRE-3 study compared first-line treatment with folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) plus cetuximab to FOLFIRI plus bevacizumab in patients with RAS wildtype (RAS WT) mCRC. The present analysis focusses on the impact of sex and primary tumor (PT) sidedness on outcome parameters. RESULTS:Of 352 patients with RAS WT tumors, 249 (71 %) were male and 103 (29 %) female. In male patients with left-sided RAS/BRAF WT tumors, a significant benefit from cetuximab was noted with regard to ORR (OR 1.15; P = 0.035) and OS (0.66; P = 0.010), while in right-sided patients cetuximab improved ORR (OR 2.92) and had no significant effect on PFS or OS. In female patients with left-sided, RAS/BRAF WT PT, a comparable effect of cetuximab versus bevacizumab was observed with regard to ORR (OR 1.05; P > 0.999), while a numerical OS benefit was noted in the cetuximab-arm (HR 0.78; P = 0.385). By contrast, in female patients with right-sided PT, a clearly detrimental effect of cetuximab-based therapy was observed for ORR (OR 0.44; P = 0.617), PFS (HR 4.95; P = 0.005), and OS (HR 2.58; P = 0.080). In the bevacizumab arm, neutropenia grade ≥ 3 was more frequent in female versus male patients (30.6 % versus 18.3 %; P = 0.063). Otherwise, there was no significant difference of grade ≥ 3 adverse events between male and female patients. CONCLUSIONS:The exploratory analysis of FIRE-3 suggests that the efficacy of cetuximab combined with FOLFIRI in RAS wild-type mCRC is related to sex and primary tumor sidedness. The results support the inclusion of patient sex into the design of future trials.

INTRODUCTION:Molecular diagnostics play a pivotal role in guiding therapy for metastatic colorectal cancer (mCRC). Current guidelines recommend stratification based on biomarkers such as RAS, BRAF, and DNA mismatch-repair (MMR) status to select between anti-EGFR (epidermal growth factor receptor) and anti-VEGF (vascular endothelial growth factor) therapies. MATERIALS AND METHODS:This retrospective analysis evaluated the randomized FIRE-3 study that compared first-line treatment with FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in RAS wild-type patients. The present analysis included 199 patients with RAS/BRAF wild-type MMR proficient tumors. Next-generation sequencing (NGS) was successfully performed in all patients and allowed stratification into hyperselected (no predefined genetic alterations) or gene altered subgroups using the previously published approach of the PRESSING-studies. RESULTS:Hyperselection according to PRESSING-3 was associated with a survival benefit from anti-EGFR-based therapy compared to bevacizumab (38.5 months vs. 27.5 months; HR 0.68; 95 % CI, 0.44-1.05; P = 0.08). This benefit was observed in both, right- and left-sided tumors, (HR 0.58 and HR 0.70). Patients with gene alterations showed inferior survival compared to hyperselected patients across all subgroups. In this unfavorable subgroup, application of cetuximab and bevacizumab were associated with comparable OS (total cohort: HR 1.04; 95 % CI, 0.61-1.79). Again, this finding was independent of primary tumor sidedness (left-sided tumors: HR 1.10; 95 % CI, 0.59-2.07; right-sided tumors: HR 1.05; 95 % CI, 0.31-3.55). CONCLUSION:Molecular hyperselection facilitated by next generation sequencing could replace primary tumor sidedness as a tool of decision making for optimal choice of targeted therapy in first-line treatment of RAS wild-type mCRC.

Primary endpoint treatment-change-free survival (TCFS), defined as time from randomization to death or initiation of a new disease-modifying treatment in the phase 2 DELTA trial. AML, acute myeloid leukemia; EPAG, eltrombopag; HMA, hypomethylating agents; IC, intensive chemotherapy.

PURPOSE:Consensus molecular subtypes (CMSs) of metastatic colorectal cancer (mCRC) are debatable biomarkers. An individual patient data (IPD) meta-analysis was performed to test for impact on objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS), and treatment interaction. METHODS:IPD (RAS wild-type [WT] tumors treated per protocol [fluorouracil/capecitabine, irinotecan/oxaliplatin, anti-vascular endothelial growth factor {VEGF}/anti-epidermal growth factor receptor {EGFR} antibodies] and with evaluable CMSs) were collected from five trials identified in PubMed, Embase, Medline, Cochrane Library, and proceedings of ASCO/European Society for Medical Oncology: FIRE1 (no identifier), FIRE3 (ClinicalTrials.gov identifier: NCT00433927), XELAVIRI (ClinicalTrials.gov identifier: NCT01249638), PanaMa (ClinicalTrials.gov identifier: NCT01991873), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116). The one-step IPD meta-analysis approach assessed data taking the clustering of patients in the studies into account (ORR: generalized estimating equations models; PFS/OS: Cox models). RESULTS:Seven hundred ninety patients were included: CMS1, n = 77 (9.7%); CMS2, n = 345 (43.7%); CMS3, n = 74 (9.4%); and CMS4, n = 294 (37.2%). Between-study heterogeneity was negligible (variance < 1 × 10-6). Compared with CMS1, CMS2 and CMS4 tumors had numerically higher odds ratios (OR) for ORR (CMS2: OR, 1.668 [95% CI, 0.982 to 2.836]; P = .059; CMS4: OR, 1.369 [95% CI, 0.874 to 2.146]; P = .170), and longer PFS (CMS2: hazard ratios [HR], 0.64 [95% CI, 0.48 to 0.85]; P = .002; CMS4: HR, 0.67 [95% CI, 0.50 to 0.91]; P = .009) and OS (CMS2: HR, 0.59 [95% CI, 0.43 to 0.80]; P < .001; CMS4: HR, 0.67 [95% CI, 0.49 to 0.92]; P = .01). The use of anti-EGFR versus anti-VEGF antibodies meaningfully improved PFS (HR, 0.67 [95% CI, 0.46 to 0.97]; P = .03) and OS (HR, 0.49 [95% CI, 0.33 to 0.72]; P < .001) in CMS4 tumors and was consistently observed for CMS4 RAS/BRAF WT (HR, 0.55 [95% CI, 0.37 to 0.83]; P = .004) or microsatellite stable status (HR, 0.52 [95% CI, 0.32 to 0.86]; P = .01). The interaction test of antibody treatment with CMSs was significant for PFS (P < .001) and OS (P < .001) in all patients and for OS in patients with RAS/BRAF WT tumors (P = .02). CONCLUSION:CMS4 might be an additional biomarker of anti-EGFR treatment efficacy in RAS (and BRAF) WT mCRC.

Background: Primary tumor sidedness (PTS) with discrimination of left-sided (LC) and right-sided tumors (RC) guides patient selection for targeted first-line therapy in RAS wild-type (RAS-WT) metastatic colorectal cancer (mCRC). This study assessed the hypothesis whether considering PTS with additional clinical parameters better predicts the treatment benefit of targeted first-line treatment. Methods: In FIRE-3, first-line treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI) plus cetuximab (FOLFIRI/Cet) was compared to FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC and unresectable metastasis. We evaluated whether combining PTS with number of metastatic sites (NOM), liver-limited disease status (LLD), age, sex, or carcinoembryonic antigen level (CEA) better predicts treatment benefit regarding overall survival (OS). Here, Cox regression models with second-order interactions were applied. Further, the results were validated by policy learning and Lasso regression analysis. Findings: Among 400 RAS-WT mCRC patients, combining PTS with LLD status in a Cox regression model outperformed PTS alone for predicted treatment benefit (P = 0.005; c-index=0.603). Significant OS benefit from FOLFIRI/Cet over FOLFIRI/Bev was observed in LC/non-LLD patients (HR=0.62; 95 %-confidence interval [CI]= 0.46-0.82; P = 0.002), but mitigated in LC/LLD patients (HR=0.83; 95 %-CI=0.53-1.29; P = 0.400). In RC/nonLLD patients, FOLFIRI/Bev demonstrated a significant OS advantage over FOLFIRI/Cet (HR=2.09; 95 %-CI=1.20-3.63; P = 0.010). However, RC/LLD patients showed potential benefit from FOLFIRI/Cet, though not statistically significant (HR=0.59; 95 %-CI=0.25-1.39; P = 0.218). Interpretation: Incorporating PTS and LLD status might improve selection of targeted first-line treatment in RAS-WT mCRC patients. FOLFIRI/Cet appears to be particularly beneficial for LC/non-LLD patients with mitigated benefit in patients with LC/LLD. In contrast, FOLFIRI/Bev is significantly favoured over FOLFIRI/Cet in patients with RC/non-LLD. Notably, RC/LLD patients may still benefit from anti-EGFR therapy despite right-sided primary tumor. These results are hypothesis-generating and warrant further validation.

In 2022, the European LeukemiaNet (ELN) risk stratification for patients with AML has been updated. We aimed to validate the prognostic value of the 2022 ELN classification (ELN22) evaluating 1,570 newly diagnosed AML patients (median age, 56 years) treated with cytarabine-based intensive chemotherapy regimens. As compared to the 2017 ELN classification (ELN17), allocating 595 (38%), 413 (26%) and 562 (36%) patients to the favorable, intermediate and adverse risk category, ELN22 risk was favorable, intermediate, and adverse in 575 (37%), 410 (26%), and 585 (37%) patients, respectively. Risk group allocation was revised in 340 patients (22%). Most patients were re-classified into ELN22 intermediate or ELN22 adverse risk group. The allocation of patients according to the ELN22 risk categories resulted in a significantly distinct event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS). As compared to ELN17, reallocation according to the ELN22 recommendations resulted in a significantly improved prognostic discrimination for OS (3-year area under the curve (AUC) 0.71 vs. 0.67). In patients with ELN22 favorable risk AML, co-occurring MR gene mutations did not significantly impact outcome. Within the ELN22 adverse risk group, we observed marked survival differences across mutational groups (5-year OS rate of 21% and 3% in patients with myelodysplasia-related (MR) gene mutations and TP53-mutated patients, respectively). In patients harboring MR gene mutations, EZH2-, STAG2- and ZRSR2-mutated patients showed an intermediate-like OS. In patients with secondary AML and those who underwent allogeneic HCT, EFS and OS significantly differed between ELN22 risk groups, while prognostic abilities of ELN17 and ELN22 classifications were similar. In conclusion, the ELN22 risk stratification improves prognostic discrimination in a large cohort of intensively treated AML patients. Given the heterogeneous outcome in patients with MR gene alterations, ranging between those of intermediate and adverse risk patients, we suggest reevaluation of risk allocation in these patients.

BACKGROUND:Metastatic recurrence of colorectal cancer (mCRC) after adjuvant therapy may differ biologically from recurrence in untreated mCRC. We examined first-line treatment outcomes of patients within the phase III CALGB/SWOG 80405 (CALGB 80405) and FIRE-3 trials according to previous exposure to oxaliplatin-based adjuvant treatment. METHODS:Patients from CALGB 80405 primary analysis (N = 1131) and FIRE-3 intent-to-treat population (N = 592) treated with FOLFIRI who previously received either oxaliplatin-based adjuvant therapy or no adjuvant therapy were identified. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared using the log-rank test. Adjusted Cox regression models were used to compare outcomes according to biologic agent and prior adjuvant treatment. RESULTS:A total of 800 patients were included in the analysis. There were no significant differences in OS and PFS based on adjuvant treatment. Among patients who received adjuvant oxaliplatin-based chemotherapy (N = 123), median PFS was 11.5 months for FOLFIRI-bevacizumab (bev) and 10.1 months for FOLFIRI-cetuximab (cet) (adjusted HR [95 %CI] = 0.81 [0.56, 1.18], p = 0.27). Median OS in the same group was 41.0 months for bev- vs 28.5 months for cet-treated patients (adjusted HR 95 %CI] = 0.78 [0.51, 1.20], p = 0.26). No significant interaction between treatment arm and prior adjuvant treatment was identified. CONCLUSIONS:No statistically significant difference in either OS or PFS by biologic agent was found in this unplanned subset analysis of two large, randomized phase III trials. However, further investigation is warranted to evaluate possible survival differences in larger patient cohorts.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

13 Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .

Introduction: Currently, six tyrosine kinase inhibitors (TKIs) are approved for chronic phase chronic myeloid leukemia (CML). Unfortunately, treatment sequence has never been tested prospectively, and, therefore, it remains unclear which TKI should be chosen, especially after first-line treatment with more potent second generation (2G)-TKIs. The original goal of the “Bosutinib Dose Optimization Study” (BODO) study was to evaluate whether a bosutinib step-in dosing regimen decreases gastrointestinal (GI) toxicity while maintaining optimal efficacy in patients (pts) with CML after failure or intolerance to 2G-TKIs. Despite its premature study end, it thereby contains one of the largest cohorts of 2nd generation TKI treatment after failure/intolerance of a 2G-TKI in first line. Methods: This is a sub-analysis of the BODO trial (NCT03205267), a multicenter, open-label single arm phase II study testing tolerability and efficacy of 2nd and 3rd line bosutinib step-in dosing in chronic phase CML pts intolerant and/or refractory to previous imatinib and/or nilotinib, and/or dasatinib therapy. Bosutinib was commenced with 300 mg QD and was (in the absence of > grade 1 toxicities) dose-increased by increments of 100 mg daily dosing every 14 days up to a maximum dose of 500 mg QD. 127 pts were planned to be recruited. However, due to slow recruitment, the trial had to be stopped prematurely after inclusion of 57 pts. For this analysis, we focused on the 45 patients treated with either nilotinib (n=23) or dasatinib (n=22) as first-line therapy. Cumulative incidence curves of response to bosutinib were calculated and compared using Gray's test. Results: 45 pts (n=28 males; median age 51 years, range: 19 - 77) were included in the analysis. The ECOG status was 0 (n=36, 80%) or 1 (n=9, 20%). Prior to study inclusion, a median daily dose of 600 mg nilotinib (range: 300 - 800) and 100 mg of dasatinib (range: 57 - 200) had been administered. The median duration of previous nilotinib and dasatinib therapy was 20.0 months (range: 23 days - 8.0 years) and 16.6 months (range: 3.7 - 34.3 months, p = 0.184), respectively. 18 (40%) pts were intolerant, 17 resistant (38%), and 10 (22%) both intolerant and resistant to previous TKI treatment. 17 (38%) pts entered the study in molecular response (at least major molecular remission (MMR) at screening). The odds of being in MMR at screening were higher in patients with longer pretreatment duration (OR = 1.9; CI: 1.1, 3.7; p = 0.038 per additional year of pretreatment). The corresponding probabilities of MMR were 40% (CI: 26, 54%), 58% (CI: 42, 71%), 68% (CI: 51, 80%) at 3, 6, and 12 months, and 79% (CI: 62, 89%) at 18 and 24 months, respectively. Median time to MMR was 4.9 months. MMR probabilities by pretreatment did not differ between nilotinib and dasatinib (p=0.788). 3 out of 4 intolerant pts without MMR at baseline reached MMR or a better molecular response level with bosutinib. 24 pts refractory to previous therapy (16 resistant; 8 both resistant and intolerant) were lacking baseline MMR, of which 16 pts achieved MMR or better (1 pt with MR4.5, 2 with MR4 and 13 with MMR). In the 24 refractory pts without MMR at baseline, the cumulative MMR and MR4 rates by 1 year were 48% (CI: 26, 68%) and 10% (CI: 2, 27%), respectively. One patient reached MR4.5 after 15.2 months of bosutinib therapy. Response to bosutinib was not significantly different in patients pretreated with either dasatinib or nilotinib. 33 pts received bosutinib for at least 6 months and also had a 6-months molecular response evaluation. At 6 months, median dose levels of bosutinib were not significantly different between responders and non-responders. No disease progressions were reported during the study and follow up. All pts had ≥1 any grade treatment emergent adverse event (TEAE), occuring a median of 15 days after starting bosutinib (range: 1 - 225 days). Cumulative probability of grade 3/4 TEAEs, and serious adverse events by 1 year was 69% (53, 81%) and 26% (CI: 13, 40%), respectively. The most common TEAE was diarrhea with a cumulative probability of 63% (CI: 47, 76%) by 1 month. Conclusion: Despite of the limitations of a single-arm study with incomplete recruitment, bosutinib was able to induce optimal responses in two thirds of pts previously resistant to 2G-TKIs while GI toxicity rarely led to treatment discontinuation. We conclude that bosutinib is a safe option after intolerance/failure of a 2G-TKI in first-line.

3529 Background: CMS were associated with prognostic relevance in RAS WT mCRC, while their role as predictive biomarker is debatable. We aimed to assess the predictive impact of CMS on treatment with anti-EGFR vs. anti-VEGF antibodies vs. cytotoxic treatment alone in a pooled analysis. Methods: Available CMS data (called by predictedCMS method) of the randomized controlled trials FIRE-1 (FUFIRI vs. mIrOx); FIRE-3 (FOLFIRI+ cetuximab vs. bevacizumab), XELAVIRI (sequential vs. initially combined FOLFIRI+bevacizumab) and PanaMa (FOLFOX+panitumumab followed by FU/FA +/- panitumumab) of RAS WT mCRC were included. Non-evaluable CMS were excluded. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Uni- and multivariate Cox regression analysis (including all baseline characteristics) was used to calculate hazard ratio (HR) and 95% confidence interval (95% CI). Results: 1147 tumors had available CMS data and 746 (65.0%) were RAS wild-type (WT): CMS1, n=89; CMS2, n=346; CMS3, n=71; CMS4, n=240. CMS were significant prognostic biomarkers in terms of PFS (median months, CMS1, 6.7; CMS2, 11.1; CMS3, 8.1; CMS4, 10.0, P<0.001) and OS (median months: CMS1, 14.8; CMS2, 28.7; CMS3, 19.5; CMS4, 26.5; P<0.001). CMS remained significant in a multivariate backward elimination Cox regression analysis including all baseline characteristic variables and BRAF status with regard to PFS ( P=0.03) and OS ( P=0.04) Interaction of CMS and treatment was significant regarding OS ( P<0.001) and PFS ( P=0.001). The longest OS was observed using anti-VEGF antibodies in CMS1 and anti-EGFR antibodies in CMS2 or CMS4 RAS WT tumors (Table). Conclusions: CMS were confirmed as prognostic biomarkers and might contain predictive information for the choice of anti-EGFR or anti-VEGF antibodies in RAS WT mCRC. Prospective validation remains mandatory. [Table: see text]

In newly diagnosed acute myeloid leukemia (AML), immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pretherapeutic risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed AML undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based first-line therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months; P=0.42) nor in the TriNetX cohort (7.5 vs. 7.2 months; P=0.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed AML might be a safe option for selected patients, provided that close clinical monitoring is performed.

3550 Background: Doublet chemotherapy plus bevacizumab is a well-established standard of care in the first-line treatment of RAS-mutant (RASmut) metastatic colorectal cancer (mCRC). The FIRE-3 trial was the first randomized study to compare FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC. Since this trial initially included patients irrespective of RAS mutation status, the present analysis performs an updated evaluation of therapeutic efficacy of targeted therapy with bevacizumab versus cetuximab in RASmut mCRC. Methods: FIRE-3 trial included 752 patients. Initially, pyrosequencing (PSeq) was used to identify RAS mutations. In a subsequent investigation next-generation sequencing (NGS) was applied in 373 available tumors. A 5% mutant allele cutoff was used for both PSeq and NGS both of which were done centrally. Results: Of the 224 RASmut and BRAF wild-type patients, 187 were identified by polymerase chain reaction (PCR) and PSeq, 122 by NGS. 86 tumors were PCR positive and NGS positive (PCR+/NGS+), 36 tumors PCR negative and NGS positive (PCR-/NGS+). In the overall RASmut cohort of 224 patients, no overall survival (OS) benefit was observed when cetuximab was compared to bevacizumab (20.3 months vs 21.1 months; HR 1.028; 95% CI, 0.547-1.583; P=.842). This effect was observed independent of sidedness of primary tumors (PT) for left-sided (21.5 months vs 22.1 months; HR 1.054; 95% CI, 0.763-1.456) and right-sided PT (19.2 months vs 19.5 months; HR 0.931; 95% CI, 0.547-1.583). Conclusions: While cetuximab notably is not effective in RASmut mCRC, this randomized comparison does not provide an indication for superior efficacy of bevacizumab in the first-line treatment of this patient group. Trial identification number: NCT00433927 [clinicaltrials.gov]

BackgroundCancer is the second most common cause of death in Germany, and treatment in certified cancer networks is recommended to ensure high-quality care. This study sought to (1) determine the percentage of all primary tumors that might potentially have been treated in certified cancer networks and (2) assess the development and current state of quality-assured cancer care for all cancer patients from a locally defined region in Upper Franconia, Germany.MethodsThis study was a population-centered retrospective cohort analysis based on data from the Bavarian Cancer Registry (2017-2023). First, we determined all potentially available cancer network certifications and calculated the percentage of cancer care that could potentially have been conducted in certified cancer networks. Second, we considered the certification status of the involved healthcare providers and analyzed whether or not cancer care was actually carried out in certified cancer networks.ResultsOverall, 90.1% (62,119/68,973) of all primary tumors, from a total of 63,372 patients, might potentially have been treated in certified cancer networks. The percentage of patients actually receiving care in certified cancer center networks was 40.7% for initial diagnosis, 59.0% for surgery, 53.2% for chemotherapy, and 50.7% for radiotherapy; the weighted mean was 50.3%. The results thus ranged between 46.9% (2023) and 52.8% (2022). The highest proportions of patients who received quality-assured treatment in certified cancer center networks were determined for breast cancer (79.5%), colon cancer (73.1%), and lymphoma (60.1%); in contrast, the lowest results were shown for lung cancer (2.7%), anal cancer (0.0%), and mesothelioma (0.0%). Female patients as well as younger patients were significantly more likely to receive care in certified care networks compared with their counterparts. In addition, we did not find a clear trend whether patients in different tumor stages were more or less likely to receive care in certified care networks.ConclusionsWe found meaningful differences in the proportion of patients who received quality-assured treatment in certified cancer center networks. Following this, patients should receive comprehensive information about receiving care in certified cancer center networks and consider longer travel distances, especially for those cancer types without locally available certified cancer networks.

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity and has increased incidence in the elderly. Approximately 40% of pts with DLBCL are >70 yrs old. In older/frail pts with untreated DLBCL, the attenuated chemotherapy regimen R-miniCHOP is the standard of care with a 2-yr overall survival (OS) of approximately 60% (Peyrade 2011). BTK inhibition added to R-CHOP improved OS in pts <60 yrs, but not in older pts where tolerability was limited (Younes 2019). A BTK inhibitor with a more favorable safety profile may improve survival also in elderly pts. Acalabrutinib is a second-generation BTK-inhibitor with promising data in combination with R-CHOP in pts with DLBCL up to 80 yrs (Davies ASH 2022). ARCHED/GLA 2022-1 is an investigator-initiated, randomized, open-label, phase 3 trial to evaluate the addition of acalabrutinib to R-miniCHOP in pts with untreated DLBCL aged >80 yrs or 61-80 yrs old and unfit for full-dose R-CHOP. Patients are randomized to receive either R-miniCHOP (control, C) or R-miniCHOP + Acalabrutinib (A). Stratification is based on age, ADL score and IPI. The primary endpoint is progression free survival. Methods This is a safety analysis based on the per protocol quarterly evaluation of serious adverse events (SAE) of the first year of recruitment. Recruitment started in June 2023. All pts randomized until 01/07/2024 were included. Baseline characteristics, SAE incidence and severity were analyzed. Adverse events of special interest (AESI) were reported as SAE. Results At data cut off 57 pts had been randomized (C: 28, A: 29). Median age was 83 yrs (range 66-94), 68% pts were >80 yrs old and 63% male. ECOG status was 0-1 in 67% and ADL score <6 in 28%. Extranodal disease was present in 77%, and 72% had an IPI score ≥3. Baseline characteristics were balanced between arms. A total of 44 SAE were reported in 29 pts (C: 18 events [13 pts; 46%]; A: 26 events [16 pts; 55%]). Fifteen (34%) of them were grade 1-2 (C: 6 events [5 pts; 18%]; A: 9 events [5 pts; 17%]). Twenty (45%) were grade 3 (C: 7 events [6 pts; 21%]; A: 13 events [9 pts; 31%]). One pt in arm C and one in arm A had one grade 4 SAE each. Four deaths (grade 5 SAE) occurred in arm C (14%, one lymphoma-related, one heart failure and two unknown cause) vs three (10%, one due to vascular causes and two unknown cause) in arm A. The most common SAE were infections. In arm C, 4 pts (14%) had one grade 2 and four grade 3 infections, and 5 pts (17%) in arm A had one grade 2 and five grade 3 infections. Cardiac events accounted for 10 SAE. Specifically, in two pts (7%) in arm C one heart failure grade 5, one grade 2 and one grade 3 hypertensive crisis occurred. Six pts (20%) in arm A had five grade 1-2 (three asymptomatic ventricular extrasystoles [AESI], one asymptomatic non-sustained ventricular tachycardia [AESI], and one angina pectoris) and two grade 3 (one atrial fibrillation and one heart failure). Three pts had bleeding SAE, two in arm C (hemoptysis and melena, both grade 1) and one in arm A (grade 3 rectal bleeding). Conclusion Acalabrutinib with R-miniCHOP resulted in increased but manageable toxicity. Rates of serious infections and bleeding were similar between groups. One third of all SAE reported were grade 1-2. More cardiologic SAE were reported in the experimental arm, mostly asymptomatic grade 1-2 AESI. Importantly, no increased rate of treatment emergent deaths was seen with acalabrutinib + R-miniCHOP in this frail, high-risk population. Thus, acalabrutinib with R-miniCHOP has the potential to improve outcomes in older/frail adults with untreated DLBCL. ARCHED is an academic study of the German Lymphoma Alliance and is funded by AstraZeneca GmbH. The trial is approved in the EU and is recruiting in Germany. (EU-CTN: 2022-501187-18-00, NCT05820841).