High-risk Pts Research Articles

Real-World Results of Autologous Stem Cell Transplantation in Newly Diagnosed Patients with Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

INTRODUCTION Autologous stem cell transplant (ASCT) remains an important option for eligible multiple myeloma (MM) patients (pts) as part of initial therapy. In Canada, fit younger pts are typically offered ASCT; selected centers offer tandem ASCT to high-risk (HR) pts; and current standard practice involves continuation of maintenance (maint) therapy until disease progression, which is facilitated by public funding for lenalidomide (len) in this setting. Using our national database, we examined the details and outcomes of ASCT performed as part of initial therapy in eligible Canadian MM pts. Methods The Canadian Myeloma Research Group database (CMRG-DB) contains both legacy and ongoing prospective data and can track and characterize real-world outcome of pts treated at 17 major Canadian institutions. All pts who received an ASCT as part of initial MM therapy between 01/Jan/2007 to 31/Dec/2021 were included. Progression-free survival (PFS) was calculated from the time of first ASCT until disease progression, death due to any cause or last follow up, whichever comes first, while overall survival (OS) was defined as the time from ASCT to the date of death or last follow up. Results 3821 pts underwent ASCT as frontline therapy and were included in the analysis. Median age was 61 (range 26-77) years, 15.2% had a creatinine > 177 umol/L and 18% had HR FISH [del17p, t(4;14) and t(14;16)] (FISH was unknown/missing in 50% of pts). The majority (82%) received bortezomib (btz)-based induction; this consisted of CyBorD in 72% with rates of ≥PR (≥VGPR) of 92% (60%). Only 1.6% received a proteasome inhibitor (PI) + len; rates of ≥PR (≥VGPR) were 96.5% (63.2%) in this subgroup. Median time to ASCT from start of induction was 5.6 months (mos). A second induction regimen, including len in 78.5%, was administered to 376 pts for suboptimal response/progression on first induction. The ≥PR (≥VGPR) rates in these 376 pts was 72.9% (35.4%) with a median time from start of second induction to ASCT of 4.2 mos. Tandem ASCT was performed in 314 pts, primarily in HR pts (64%). In HR FISH pts, the median PFS (mPFS) for single vs tandem ASCT was 25.1 vs 35.4 mos (p 0.018) and median OS (mOS) 91.5 vs 84.4 mos (p 0.048), respectively. For those without HR FISH, mPFS and mOS for single vs tandem ASCT were, respectively, 46.5 vs 33.8 mos (p <0.001) and 158.6 vs NYR (p <0.001). After ASCT, only 205 (5%) pts received consolidation that consisted of a PI + len in 93.2%. However, 2060 pts (53.9%) received post-ASCT maint (len +/- steroids in 63.1%, btz +/- steroids in 2.1 %, len + btz +/- steroids in 1.7%, other PI +/- steroids in 1.6%, len + other PI +/- steroids in 5.7 % and thalidomide +/- steroids in 8.5%). The mPFS and mOS for all pts was 35.4 mos (95% CI 33.7-37.3) and 125 mos (95% CI 120-138) from first ASCT. Table 1 summarizes the mPFS and mOS according to treatment. Those given a second induction regimen had significantly inferior outcomes (mPFS 27.9 vs 36.2 mos [p 0.001]; mOS 118 vs 126 mos [p 0.011]), although the use of maintenance led to comparable results regardless of number of induction regimens (mPFS 55.3 vs 51.1 mos [p 0.11]; mOS 158.6 vs not yet reached (NYR) [p 0.13]). Consolidation pts had a better mPFS (55.3 vs 34.4 mos [p 0.001]), but no significant gain in mOS (p 0.065). The mPFS and mOS were 48.8 vs 24.5 mos and 159 vs 105 mos for the maint vs non-maint cohorts, respectively, when all types of maint were included. For pts receiving len, btz or both (+/- steroids), the mPFS was 53.7 mos vs 48.2 mos vs 43.5 mos, respectively, while the mOS was 159 mos vs NYR vs 115 mos, respectively. Amongst pts receiving such maint, outcomes for pts with HR FISH were compared with those without HR FISH: mPFS was 36.6 mos vs 55.2 mos and the mOS was 97.4 mos vs 164.4 mos, respectively. CONCLUSIONS This large study demonstrates that the integration of btz and len into the transplant sequence produces a mOS of ≥10 yrs in most ASCT pts in the real-world setting. Our observations highlight the contribution of post-ASCT maint, particularly len given until progression, when used in multiple pt groups including those with and without HR, as well as those requiring a second induction regimen. Nevertheless, HR pts require additional strategies to optimize results. Further analyses to assess the relationship of pt characteristics, specific treatment details and outcomes are in progress. These results serve as Canadian benchmarks for comparison with newer approaches that combine immunotherapy with ASCT as initial therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Novel, Clinically Adaptable Comorbidity Assessment Tool for Non-Hodgkin Lymphoma (NHL), the Three-Factor Risk Estimate Scale (TRES): Analysis of 40,000 Older Adults Enrolled in SEER-Medicare

Introduction Comorbidities impact survival and tolerance of therapy in patients (pts) with NHL. Lack of a standardized measure and the complexity of available scores has hindered the formal assessment of comorbidities in pts with NHL. We previously developed an easy to use comorbidity score in pts with chronic lymphocytic leukemia (CLL), the CLL comorbidity index (CLL-CI; Gordon et al, CCR, 2021). The CLL-CI is scored by assessing medical conditions in vascular, endocrine and upper gastrointestinal categories. Scores range from 0 to 3. The CLL-CI has been validated in independent cohorts of pts with CLL (Rotbain et al, Blood Adv, 2022) but has not been evaluated in other NHL subtypes. We hypothesized that the CLL-CI would be associated with survival in NHL. As this study includes pts with other NHL subtypes, we now call the CLL-CI the three-factor risk estimate scale (TRES). Methods Our study included pts >65 years old diagnosed with NHL between 2008-2017, selected from the SEER-Medicare linked database. TRES score was evaluated in the 12 months preceding NHL diagnosis using ICD-9/10 diagnosis, procedure codes and prescription information from Medicare part A, B and D claims. If one or more medical conditions were present in each category 1 point was assigned for a maximum score of 3. Pts were classified to low (score 0), intermediate (score 1) and high (score 2-3) risk groups. Chi-square or t-test was used to compare pt characteristic distributions. Kaplan-Meier estimate and multivariable Cox regression with competing risk were used to test the association between mortality and TRES score. Results A total of 40,486 pts with median age 77 years (interquartile 71-83) were included. TRES score was low in 41%, intermediate in 37% and high in 22%. Older age, male sex, black race, Hispanic ethnicity, aggressive NHL subtype, no systemic therapy and living in a census tract with lower income or high school graduation rates were all significantly associated with increased TRES score. Being married and living in the West were associated with lower TRES score. Median follow up from NHL diagnosis was 33 months (interquartile, 13-60 months). Compared to low risk pts, higher TRES scores were associated with shorter overall survival (OS; Fig 1A). In multivariable models of OS, hazard ratios (HR) were 1.27 (95%CI 1.23-1.31) for intermediate and 1.68 (95%CI 1.62-1.74) for high risk pts. Male sex (HR 1.27, 95%CI 1.23-1.31), black race (HR 1.17, 95%CI 1.07-1.28), unmarried (HR 1.1, 95%CI 1.07-1.14), living in the South (HR 1.08, 95%CI 1.02-1.14), stage 4 (HR 1.58, 95%CI 1.50-1.67) and older age were independently associated with shorter OS. Living in a census tract with higher income (HR 0.86, 95%CI 0.81-0.90) or high school graduation rates (HR 0.85, 95%CI 0.81-0.90) and receiving chemoimmunotherapy (HR 0.38, 95%CI 0.36-0.40) were independently associated with longer OS. The most common NHL subtypes were CLL (N=11,406), large B cell (DLBCL; N=11,154), follicular (FL; N=5,087), marginal zone (N=3,647), mantle cell (N=1,565), peripheral T cell (N=1,136), cutaneous T cell (N=1,051) and lymphoplasmacytic (N=651). Higher TRES score was associated with shorter OS in all NHL subtypes (p<0.0001). For the most common NHL subtypes: the estimated 3-year OS was 80%, 72% and 61% in CLL; 58%, 47% and 37% in DLBCL; 85%, 75% and 66% in FL: low, intermediate and high TRES scores, respectively. The cause of death was reported and analyzed in 30,155 pts. The most common cause of death was NHL (23.6%, N=7,110). Compared to low risk, higher TRES scores were associated with increased lymphoma specific mortality (LSM; Figure 1B). In multivariable models, HR were 1.10 (95%CI 1.04-1.17) for intermediate and 1.24 (95%CI 1.17-1.33) for high risk pts. TRES score was significantly associated with LSM in the most common NHL subtypes; 3-year LSM rates in CLL were 6.4%, 8.1% and 10% (p=0.015); DLBCL 31.2%, 37.8% and 43.5% (p<0.001); and FL 8.8%, 14.2% and 17.4% (p<0.001) with low, intermediate and high TRES scores, respectively. Conclusion The TRES comorbidity score is a simple to use tool which can be rapidly assessed and is associated with OS and LSM in older adults with NHL-median OS is more than 5 years shorter in pts with a high TRES score. Assessment of the TRES score should be incorporated into the care of older adults with NHL. Future studies are planned to prospectively evaluate the TRES score as a predictive biomarker to guide the treatment of pts with NHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Non-Hodgkin Lymphoma (NHL), Comorbidity and Death Due to Other Cancers in 30,000 Older Adults from SEER-Medicare

Introduction: NHL is a heterogeneous disease which frequently occurs in older adults. Patients (pts) with NHL have an increased risk of non-NHL malignancies (NNM; Morton, JCO, 2010) and published guidelines emphasize the importance of standard of care cancer screening in this population (Hallek, Blood, 2018). Comorbidities are associated with a more aggressive clinical course and shorter survival in pts with NHL. We hypothesized that comorbidities, measured using the three-factor risk estimate scale (TRES; Gordon, CCR, 2021), would be associated with increased risk of death due to NNM. These findings could have important implications for cancer screening in comorbid pts with NHL. Methods: We included pts in SEER-Medicare with NHL (ICD-O-3/WHO recodes 25012, 33041 and 33042) diagnosed between 2008-2017. Medicare claims were available through 2019. All cases had a pathologically confirmed diagnosis of NHL, age at cancer diagnosis >65 years and continuous coverage in Medicare parts A, B and D with no HMO coverage for the 12 months preceding diagnosis and for 12 months, or death if sooner, after diagnosis. Pts were excluded who were diagnosed on death certificate or at autopsy. Other cancers were identified in SEER. Comorbidities were assessed using the TRES comorbidity score, previously known as CLL-CI (Gordon, CCR, 2021). This index evaluates endocrine, vascular and upper gastrointestinal organ systems, assigning pts to low, intermediate and high-risk groups based on overall survival. Chi-square or t-test was used to compare pt characteristic distributions. Kaplan-Meier estimate and multivariable Cox regression with competing risk were used to test the association between NNM and TRES score. Results: Our cohort consisted of 40,486 pts with NHL. Median age was 77 years, 49.5% were female, 91% were white, 3.3% Hispanic and 2.5% black. 51% were unmarried. 62% received treatment for NHL during the study period, the most common type of treatment was chemoimmunotherapy (31%). TRES score was low in 41%, intermediate in 37% and high in 22%. 23.6% had a cancer diagnosis prior to NHL and 10.4% after. The most common types of cancer preceding NHL diagnosis were prostate (29%), breast (16%), melanoma (9%), colorectum (6%), bladder (6%) and lung (5%). The most common cancer types after NHL diagnosis were colorectal (16%), head and neck (11%), lung (7%), bladder (5%), MDS/AML (5%) and melanoma (5%). Cause of death was reported and analyzed in 30,155 pts which were included in the primary analysis of NNM specific survival. After a median follow up of 33 months, a total of 14,473 deaths occurred, 48% of all subjects in whom cause of death was reported. The most common cause of death was NHL (49%, N=7,110) followed by NNM in 36% (N=5,183) and other causes in 15% (N=2,180). Compared to pts with a low TRES score, intermediate and high-risk scores were associated with an increase in NNM (p<0.001, Figure 1). In multivariable models, hazard ratios (HR) were 1.41 (95%CI 1.32-1.51) for intermediate and 1.94 (95%CI 1.80-2.08) in high risk pts. Other variables associated with non-NHL cancer mortality were NHL subtype, stage, age, gender, marital status and initial treatment type. The most common NHL subtypes were chronic lymphocytic leukemia (CLL N=8,368), diffuse large B cell lymphoma (DLBCL, N=8,292), follicular lymphoma (FL, N=3,870), marginal zone lymphoma (MZL, N=2,597), mantle cell lymphoma (MCL, N=1,208), peripheral T cell lymphoma (PTCL, N=851), cutaneous T cell lymphoma (N=773) and lymphoplasmacytic lymphoma (LPL, N=495). TRES score was associated with NNM in all NHL subtypes, except for PTCL (Table 1). In pts who died, the percent due to NNM by NHL subtype was 50% in CLL, 25% in DLBCL, 40% in FL, 50% in MZL, 18% in MCL, 21% in PTCL, 39% in CTCL and 74% in LPL. The most frequently cited causes of death from NNM were MDS/AML, colorectal, lung and head and neck cancers. Discussion: Other cancers are a common cause of death in older adults with NHL, particularly in pts with indolent B cell subtypes (range, 40%-74%), and comorbidities further increase the risk of death from NNM. This may be due to the combinatorial effects of NHL and comorbidity on immunologic and metabolic regulation. These results have important implications for the treatment of older adults with NHL and highlight the need for close monitoring and the development of adapted cancer screening guidelines in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mutations Associated with Progression in Follicular Lymphoma Predict Inferior Outcomes in Newly Diagnosed Patients (Alliance 151303)

Follicular lymphoma (FL) is a clinically heterogeneous B cell non-Hodgkin lymphoma (B-NHL) subtype. While some patients (pts) tolerate watch-and-wait for years, others require prompt treatment. Further, a subset of pts suffers progression of disease within 24 months (mo) of treatment initiation (POD24) and/or aggressive histologic transformation (tFL). No predictive model guides FL treatment, but the FLIPI stratifies pt outcomes using clinical parameters. The m7-FLIPI integrates FLIPI, performance status (PS), and mutations in EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11; however, it is not routinely used to guide treatment due to unproven generalizability and actionability to date. We conducted a clinicogenomic analysis of 343 pts with FL or tFL [enrolled on CALGB/Alliance trials 50402, 50701, or 50803 (n = 58); or real-world cohorts from WUSTL (n = 191), Cleveland Clinic (n = 77), and U Miami (n = 17)], applying a custom 2,611-gene sequencing panel to B-NHL specimens. We explored patterns of mutated genes in newly diagnosed FL (n = 231), relapsed (rel) FL (n = 65), and tFL (n = 47). We also asked whether specific genomic features were associated with clinical parameters and assessed the association of different mutations with pt outcomes. Median age was 60 years (range: 22-89); stage distribution was 23% early vs 77% advanced; FLIPI distribution was 34% low vs 34% intermediate vs 32% high. Progression-free and overall survival (PFS/OS) of pts in our cohort exhibited anticipated relationships with key parameters (e.g., histology: 48-mo OS 96% vs 69% for FL vs tFL). We applied the m7-FLIPI to our 231 newly diagnosed FL samples, observing weak prognostic impact [low vs high risk; HR for PFS 1.37 (95% CI 0.43-1.23), p = 0.2]. Given heterogeneous treatment histories of our pts compared to uniform pt treatment in the initial m7-FLIPI cohort, we tested for an interaction between m7-FLIPI and frontline treatment. We observed a strong interaction between m7-FLIPI risk stratification and receipt of cytotoxic chemotherapy (p < 0.01; Fig 1A). 48-mo PFS was 80% for pts with low risk m7-FLIPI receiving chemo-based frontline treatment, vs 50-55% for all three other pt subsets (high risk m7-FLIPI pts irrespective of chemo-status, and low risk m7-FLIPI pts receiving chemo-free treatment). This suggests that the prognostic value of the m7-FLIPI mutational pattern is impacted by pt treatment. To probe the links between the B-NHL genomic landscape and pathologic or clinical features, we compared the mutation burden (median number of mutations) across a range of B-NHL subsets. FL cohorts based on grade 1-2 vs 3A, early vs advanced stage, FLIPI, initial treatment vs observation, and POD24 vs no POD24 did not differ by mutation burden. However, mutation burden was significantly higher (p < 0.01) in tFL than rel FL, and in rel FL than newly diagnosed FL. Using a Cox proportional hazard penalized splines model, we did not find a significant relationship between mutation burden at FL diagnosis and PFS. CREBBP was the only gene in which mutations were significantly more common in FL than tFL (BH FDR q < 0.1), yet mutated CREBBP was associated with shorter frontline PFS in pts with FL (p < 0.05). Conversely, mutations in 23 other genes were more common in either rel FL or tFL compared to newly diagnosed FL (BH FDR q < 0.1), including 6 significantly mutated genes (SMGs; by MutSigCV): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We hypothesized that pts with newly diagnosed FL may be at high risk of poor outcomes if their pre-treatment tumors harbor mutations more common in progressive/transformed disease. We defined a 'mutations associated with progression' (MAP) signature as 2 or more mutations in these 7 genes (6 SMGs enriched in progressive/transformed disease and CREBBP). Applying univariate and multivariate Cox proportional hazard modeling (adjusting for FLIPI and PS), pts with newly diagnosed FL possessing a MAP signature had significantly shorter frontline PFS [multivariate HR for PFS 1.9 (95% CI 1.12-3.2), p < 0.05; median PFS 39 vs 89 mo, p < 0.05; Fig 1B]. In summary, our analyses highlight a set of MAPs that may offer unique insight into progression risk in FL, which may be more generalizable than the m7-FLIPI. Future studies are warranted to validate the poor prognosis associated with the presence of MAPs in pts with untreated FL, which could facilitate prospective studies of novel therapies in this subset of high risk pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bortezomib-Melphalan-Prednisone (VMP) Vs. Lenalidomide-Dexamethasone (Rd) in Transplant-Ineligible Real-Life Multiple Myeloma Patients: Updated Results of the Randomized Phase IV Real MM Trial

BACKGROUND. Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have represented standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) until the recent introduction of daratumumab (Dara) in the frontline setting. However, no prospective randomized trial has directly compared VMP with Rd. Moreover, real-life older NTE pts are underrepresented in clinical trials, and only few data on safety and efficacy in this population are available. AIMS. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicine Agency AIFA - Independent Research) to compare safety and efficacy of the two standard regimens, VMP vs Rd, in an unselected real-life population of NTE NDMM pts. METHODS. NDMM pts ineligible for transplant due to age ≥65 years or comorbidities were randomized 1:1 to: 9 VMP cycles (42-day cycles, V: 1.3 mg/m2, days (dd) 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1-4 and dd 1, 8, 22, and 29, cycles 5-9; M: 9 mg/m2, dd 1-4; P: 60 mg/m2, dd 1-4) vs continuous Rd (28-day cycles, R: 25 mg, dd 1-21; d: 40 mg, dd 1, 8, 15, and 22) according to standard practice. Pts gave written informed consent and were enrolled regardless of performance status, comorbidities, renal function, or baseline laboratory values. Pts were stratified according to the International Myeloma Working Group (IMWG) frailty score and cytogenetic risk by fluorescence in situ hybridization [high risk if positive for del(17p), t(14;16), or t(4;14)]. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Key secondary endpoints included response rates, overall survival (OS), and safety. RESULTS. At the data cut-off (July 4, 2022), 231 pts were randomly allocated to receive VMP (n=114) or Rd (n=117). Baseline characteristics were evenly balanced between the two arms: median age was 77 (IQR 73-80) and 76 years (IQR 73-79); 49% vs 50% of pts were frail; 17% vs 19% pts had high-risk cytogenetics, respectively. After a median follow-up of 19 months, the median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Figure - panel A). However, the HR was not constant over time: from 0.65 (95% CI 0.36-1.19, P=0.16) during the first year of treatment (suggesting a slight benefit of VMP vs Rd) to 1.37 (95% CI 0.65-2.86, P=0.40) after the first year of treatment (suggesting a slight benefit of continuous Rd therapy). The subgroup analysis according to cytogenetic risk showed a significant effect modification of the comparison VMP vs Rd in terms of PFS, with an HR=0.21 (95% CI 0.04-0.99) in the high-risk group vs an HR=1.24 (95% CI 0.70-2.18) in the standard-risk group (interaction P=0.036). No significant effect modification was observed in terms of age or frailty status. In the ITT population, the 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Figure - panel B). No safety concerns were reported. The most frequent grade (G)3-4 adverse events (AEs) with VMP were thrombocytopenia (15%) and neuropathy (7%), while neutropenia (23%), infections (12%), and dermatologic toxicities (9%) were the most frequent G3-4 AEs observed in the Rd arm. Sixty-six percent of pts in the VMP and 59% in the Rd arms had ≥1 dose reductions of any drug, including 35% of pts in the VMP arm switching to once-weekly V before cycle 5. CONCLUSION. We confirmed the efficacy of VMP and Rd in an older real-life population of NTE NDMM pts including ~50% of frail pts. VMP and Rd were equally effective in standard-risk pts and in all frailty subgroups in terms of PFS. However, high-risk pts benefited more from VMP (HR 0.21), suggesting that the doublet Rd is suboptimal in this subgroup. Safety data were consistent with those previously reported. Of note, only one third of real-life pts were able to receive full-dose VMP or Rd therapy according to their schedule. Despite the limited follow-up, the difference in terms of OS between the two arms may be explained by the poor outcomes of patients failing lenalidomide-based treatments. Importantly, following a recent amendment, as of July 2022, enrolled pts will be randomized to Dara-VMP vs Dara-Rd. Decision-making and treatment selection will be further supported by a future analysis of this addition of Dara, based on patient and disease characteristics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Richter's Syndrome (RS)

Background While venetoclax (VEN) in combination with rituximab is an effective combination for patients (pts) with R/R CLL, it requires 2 years (yrs) of treatment (tx) and intravenous infusions. Duvelisib (DUV) is an oral PI3K-δ/γ inhibitor (PI3Ki) approved for R/R CLL/SLL after 2 prior therapies, and preclinical data support the potential for synergy both in CLL (Patel et al., 2017) and in RS PDX models (Iannello et al., 2019). This ongoing phase I/II study is investigating an all-oral, MRD-guided, time-limited regimen of DUV + VEN. Here, we report updated outcomes, now with nearly 2 yrs median follow-up. Methods In this ongoing investigator-sponsored trial (NCT03534323), primary endpoints were DLTs, MTD, RP2D (phase 1) and best CR rate (phase 2). Key eligibility criteria for CLL pts: requiring tx by iwCLL criteria, ≥1 prior tx but no prior DUV or VEN, ECOG PS ≤2. For RS pts there was no restriction on # of prior tx, though no VEN was allowed within 1 yr. Pts receive a maximum of 12 cycles of combination DUV + VEN. Tx begins with a 7-day lead-in of DUV 25mg BID, and VEN initiation occurs on day 8. In phase 1, VEN was started at 10mg or 20mg inpatient (inpt) with weekly ramp-up outpatient (outpt) to 50mg, and then to a maximum dose of 100mg, 200mg, or 400mg using a 3+3 design. In phase 2, VEN is initiated at 10mg (outpt) or 20mg (inpt) with weekly ramp-up to 400mg daily. Pts with RS can undergo accelerated VEN ramp-up to 400mg over 5 days (inpt). After 12 cycles, pts with undetectable bone marrow MRD (BM-uMRD) can discontinue tx, with an option to reinitiate VEN at progression, and pts with detectable MRD continue VEN. Assessments: toxicities by CTCAE v5, efficacy by 2008 iwCLL criteria, MRD by central 8-color flow (10-4 sensitivity). Research funding and DUV were provided by Secura Bio. Results As of July 13, 2022, 43 pts were enrolled (n=35 CLL and n=8 RS). Median age: 69 yrs (range 50-79); 70% male. 70% unmutated IGHV. In all patients, 42% were TP53-aberrant (del(17p) or TP53 mut); 9% del(11q); 33% complex karyotype (≥ 3 abnormalities); 23% NOTCH1 mut. Median prior tx: 2 (range 1-6). 42% with prior BTKi tx (all ibrutinib). The RP2D of VEN in combination with DUV was 400mg daily. In the total population of 43 pts, all-grade all-causality heme tox included: neutropenia (64%; 57% Gr3/4), thrombocytopenia (43%; 19% Gr3/4), anemia (33%, 5% Gr3). Notable non-heme tox ≥ 20% included: diarrhea (40%; 7% Gr 3), nausea (40%, 2% Gr3), fatigue (40%, all Gr1/2), hypertension (36%, 7% Gr3), increased alkaline phosphatase (36%, all Gr1/2), headache (26%, all Gr1/2), increased AST/ALT (24%; 7% Gr3), and cough (26%, all Gr1/2). Other notable SAEs ≥ 5%: increased bilirubin (12%, 5% Gr3/4), severe infection (9% Gr3, 1 pt with Gr5 COVID-19 pneumonia). 3 pts had laboratory evidence of tumor lysis syndrome (TLS); 1 pt had clinical TLS with acute kidney injury after the 20 mg VEN dose during ramp-up that fully resolved, and the pt successfully resumed VEN monotherapy. One pt developed a Gr4 gastric perforation while on high-dose steroids to manage diarrhea and discontinued study tx. One pt with RS had Gr5 hepatic failure in the setting of biopsy-proven RS liver involvement. The median number of cycles was 13 (range 1-44). The best ORR in the pts with CLL (n=35) was 69% (43% CR/CRi, 26% PR; Figure 1A). 31% of pts with CLL achieved PB-uMRD and 31% BM-uMRD (Figure 1A). 9/35 pts (26%) achieved CR/CRi with BM-uMRD after 1 year of DUV+VEN and electively discontinued therapy in remission, including 4 pts with del(17p). In the pts with RS (n=8), 3 achieved a CR and 1 achieved a PR. In the 16 CLL pts with TP53-aberrancy, the best ORR was 50% (CR 44%, PR 6%). In 15 CLL pts with prior BTKi tx, the best ORR was 53% (CR/CRi 40%, PR 13%). Eleven pts remain on tx. Reasons for tx discontinuation include: achievement of BM-uMRD (n=12 CLL), electively moving on to allogeneic transplant (n=2 CLL, n=1 RS), PD (n=3 CLL, n=6 RS), unacceptable tox (n=4 CLL, n=1 RS), death due to COVID-19 pneumonia (n=1 CLL). The 2-year PFS for pts with CLL was 78% (95% CI: 63-96; Figure 1B) and the 2-year OS was 90% (95% CI: 80-100). Conclusion A time-limited, all oral regimen DUV + VEN is active in R/R CLL and RS, including in high-risk pts post-BTKi. Immune-mediated and infectious toxicities were observed, but were manageable for most patients. Our data support continued exploration of DUV + VEN in pts with R/R CLL and RS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax Consolidation Achieves Durable Off-Treatment Remissions in Patients with High Risk CLL Who Have Been on Ibrutinib More Than a Year

Background Patients (pts) receiving ibrutinib (ibr) for CLL rarely achieve complete remission (CR) with undetectable minimal residual disease (U-MRD). Therefore, indefinite ibr maintenance therapy (Rx) is standard of care. Long-term Rx with ibr results in a cumulative risk of Rx discontinuation due to progression or toxicity. The risk of progression is highest in pts with complex karyotype and/or del(17p); some series suggest increased risk in pts with del(11q) or persistently elevated β2-microglobulin. Venetoclax (ven) is synergistic with ibr. We hypothesized that adding ven to ibr in pts at high-risk for CLL progression, who had been on ibr for more than 12 months (mo) would achieve U-MRD and allow Rx discontinuation. Methods We designed a phase II, investigator-initiated, response-adapted clinical trial with the addition of ven to ibr in pts (pts) with one or more high-risk features for disease progression who had received at least 1y of ibr regardless of line of Rx. Pts had detectable disease at time of study entry without meeting IWCLL criteria for progression. High-risk was defined as presence of at least one of: del(17p) or TP53 mutation; complex karyotype; del(11q); or elevated β2-microglobulin. Ibr was continued at 140-420mg/d and standard initiation and escalation of ven was performed to the target dose of 400mg/d. Rx with combined ibr and ven continued for a maximum duration of 24, 28-day cycles (C). Pts had bone marrow (BM) evaluation for MRD by flow cytometry (sensitivity 10-4) and CT scan for re-staging every 6mo. Pts in CR with U-MRD on two consecutive evaluations, 6mo apart, stopped ven, but could continue ibr at physician discretion. Pts who were MRD+ post-C24 continued ibr maintenance. Results: We report the results of the first 45 pts enrolled. All patients have completed ven treatment. Median number of prior therapies was 1 (range 0-4). 22/45 patients were receiving ibr as initial Rx. 63% of pts had del(17p) and/or mutated TP53. On intent to treat analysis, 17/45 pts (38%) post-C6 and 26/45 (57%) post-C12 achieved U-MRD. Three patients stopped ven prior to C12 (ineligible, n=1, metastatic solid tumor, n=2). Six of 16 (38%) patients with MRD+ at C12, converted to U-MRD by the end of the study. Best cumulative rate of U-MRD in BM was 33/45 (73%), Figure 1A. There was no difference in U-MRD4 rates or PFS according in those with TP53 abnormalities vs those without. Three pts were in CR prior to ven. Of the remaining pts, 24/42 (57%) pts improved response to CR/CRi during ven treatment. Median follow-up is 37.5 mo for PFS and 40.3 mo for OS. Forty-one patients completed treatment per protocol. Of the 32 patients with U-MRD at the completion of Rx, 10 stopped ven prior to C24 per protocol (5 after C12 and 5 after C18) after achieving U-MRD CR on two consecutive response assessments. At completion of ven, 10/32 pts with U-MRD4 continued ibr at physician discretion (6/10 with del(17p)). Five patients have progressed (Figure 1B): 1 during combination therapy; 3 during ibr maintenance (2 of whom had U-MRD4 at completion of ven); 1 with Richter's Syndrome during observation after achieving U-MRD4 CR. No pt died during ven Rx. Two patients died after receiving treatment for other cancers (metastatic melanoma, AML) and one after coming off protocol to receive acalabrutinib. Blood MRD analysis was obtained q6 mo (Figure 1C) in pts with U-MRD at the EOT; 10/32 have had confirmed MRD re-emergence (8/22 who stopped ibrutinib and 2/10 who continued); 3 subsequently progressed. Treatment was well-tolerated. The most common AE was diarrhea in 47 pts, grade 1-2 in all but 1 pt. The most common grade 3-4 AE was neutropenia, seen in 20% pts (Grade 3 in 8 and grade 4 in 1 patient). No febrile neutropenia was seen. Three patients developed grade 3 infections (pneumonia, pyelonephritis, skin abscess). No patient stopped ven due to toxicity. Seventeen patients experienced at least one SAE, most commonly non-melanoma skin cancers (n=9). Conclusions: Consolidation ven added to ibr in pts with high-risk CLL was well-tolerated and achieved cumulative BM U-MRD4 rate of 73% ibr discontinuation in 49% of pts. Only 1/45 pts progressed during combination Rx. At a median of 12 mo post-ven follow up, most pts who attained BM U-MRD have ongoing U-MRD in blood. A second cohort restricted to 45 high-risk pts with TP53 abnormalities or complex karyotype is accruing and there are plans to also include patients treated with acalabrutinib. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease

Background While venetoclax (V) plus obinutuzumab (O) is a highly effective frontline CLL regimen, outcomes remain suboptimal for high-risk patients (pts). The efficacy of ibrutinib plus VO in such pts is encouraging, but cardiac and infectious toxicities (tox) are common. We hypothesized that a time-limited triplet with the more selective BTKi acalabrutinib (A) would be active and well-tolerated. We previously published results on an initial cohort unrestricted by genetic risk (Davids et al., 2021), and now report on a new cohort with enrollment restricted to high-risk pts, as well as longer follow-up on the initial cohort. Methods Treatment (tx)-naïve pts with CLL with any genetic risk profile were initially enrolled in this investigator-sponsored, phase 2 study (cohort 1), followed by a multi-center expansion restricted to previously untreated pts with TP53-aberrant CLL (cohort 2). A starts at 100 mg BID for 28 days, followed by 2 cycles of AO (O at standard dosing), and V starts on C4D1 at 20 mg, then 50 mg on C4D2, with weekly ramp-up thereafter to 400 mg QD (total 4 week V ramp-up). AVO continues C5-7 (6 total cycles of O), and AV continues C8-15. If the primary endpoint of undetectable bone marrow MRD (BM-uMRD) CR is reached at C16D1, pts can discontinue therapy (tx); all others continue AV through C24, with the option to discontinue if BM-uMRD at C25D1. Assessments: efficacy by 2018 iwCLL criteria, toxicities (tox) by CTCAE v5, MRD by central 8-color flow (10-4 sensitivity) and NGS clonoSEQ (up to 10-6 sensitivity, Adaptive). BH3 profiling work is ongoing, performed as previously described (Ryan J et al., 2016) on peripheral blood (PB) samples after 1 and 3 cycles. Association of BCL-2 dependence with clinical response was compared by an unpaired t-test. Results As of 13 July 2022, 68 pts were enrolled (cohort 1 all-comers: n=37, cohort 2 TP53-aberrant: n=31) in this ongoing study (NCT03580928), with median follow-up of 35 mos (range 2-45). In all 68 pts, median age 63 yrs (range 36-80); 25% ≥70 yrs; 66% male; 60% TP53-aberrant (del(17p) or mut); 24% complex karyotype (≥3 abnormalities); 74% unmutated IGHV. Of the 56 pts evaluable to date at C16D1, 43% (24/56) achieved the primary endpoint BM-uMRD CR. The best ORR is 98% (48% CR, 50% PR). At C16D1, MRD by flow: 86% PB-uMRD, 86% BM-uMRD (Fig 1A). In a subset of 49 pts with available samples, 59% were PB-uMRD by NGS at 10-5 sensitivity (at 10-6, 59% of pts had indeterminate results due to low cell counts). In the 29 pts with TP53-aberrant disease evaluable at C16D1, the best ORR is 100% (52% CR, 48% PR), and 45% (13/29) achieved BM-uMRD CR, MRD by flow: 86% PB-uMRD, 83% BM-uMRD (Fig 1A). There were no differences in response or MRD based on IGHV status. 79% (19/24) of pts in BM-uMRD CR electively discontinued tx after 15 cycles; median time off tx for these pts is 22.9 mos (range 1-30). 2 of the 19 pts who discontinued tx have had MRD only recurrence, and 1 had CLL disease progression; all 3 restarted tx with AV and achieved PR. 3 pts developed Richter's syndrome: 1 with DLBCL after 15 mos on study, and 2 with Hodgkin transformation (one 13 mos after completing study tx and one 12 mos into study tx; both achieved CR to Hodgkin-directed tx). 93% of all pts (63/68) remain progression-free. In all 68 pts, all-grade heme tox included: neutropenia (75%; 37% Gr3/4), thrombocytopenia (73%; 28% Gr3/4), anemia (49%, 3% Gr3). Non-heme tox: headache (78%, 1% Gr3), fatigue (76%, 1% Gr3), bruising (66%, all Gr1/2), nausea (49%, all Gr1/2), diarrhea (40%, 4% Gr3), infusion-related reaction (30%, 4% Gr3), hypertension (27%; 9% Gr3), increased ALT (27%, 1% Gr3), arthralgia (25%, all Gr1), and infection (6% Gr3; 1 case of Gr5 COVID-19 pneumonia). 2.9% (2/68) pts had afib. 14 pts (21%) required dose-reduction of either only A (4%), only V (9%), or both drugs (7%). BH3 profiling is ongoing, and initial data suggest that pts who later went on to achieve CR may have a greater increase in BCL-2 dependence at C4D1 than pts who achieved PR as best response (p=0.05, Fig 1B). Conclusion AVO is a highly active, well-tolerated triplet in a frontline CLL population enriched for high-risk disease, with 83% of TP53-aberrant pts achieving BM-uMRD after 15 mos of tx. Responses are durable, with 93% PFS in all pts at a median follow-up of nearly 3 yrs. Low rates of cardiac and infectious tox were observed. Our data support continued investigation of the MRD-guided, time-limited AVO triplet. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 4 years. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy. Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up is 48.8 months. Six pts came off study during 1st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. We evaluated baseline pt and disease characteristics (age, gender, IGHV mutation status, CLL FISH panel, complex karyotype, TP53 mutation, del(17p)/TP53 mutation) and rate of bone marrow U-MRD at 6 months, 12 months and at any time during the combined IBR+VEN treatment. At 6 months of combined therapy, presence of TP53 mutation was associated with a lower rate of bone marrow U-MRD (p=0.03); however, none of the aforementioned characteristics, including TP53 mutation were associated with marrow U-MRD responses at 12 months or with best MRD response at any time during the combined therapy. There was a trend towards lower U-MRD rate among pts with mutated IGHV vs. unmutated IGHV at 12 month (p=0.09) and as best response (p=0.09). The 4-year PFS is 94.5% (95% CI, 90.3%-98.9%) and 4-year OS is 96.6% (95% CI, 93.3%-99.9%). The 4-year PFS by TP53 aberrant status is shown in Figure 1. The 4-year PFS for pts with del(17p)/TP53 mutation (n=27) is 90.9% and for pts without del(17p)/TP53 mutation (n=93) is 95.5%. None of the aforementioned pt/disease characteristics were associated with PFS. Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median time of 23.9 months post Cycle 24, 11 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 11 pts with MRD recurrence, 10 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt had disease progression after 22 months of treatment-free interval and is currently receiving acalabrutinib. There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 4-year PFS of 94.5%. MRD responses and PFS were independent of baseline pt/disease characteristics. Continuation of combined therapy among marrow MRD+ pts during the second and the third year led to achievement of U-MRD in a subset of pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG-Concept Trial

Background: High-risk (HR) multiple myeloma (MM) patients (pts) have a significantly disadvantageous prognosis. Emerging data show that achievement of minimal residual disease (MRD) negativity is associated with better outcome in HR pts. Most recently, several clinical trials demonstrated that addition of monoclonal anti CD38 antibodies (i.e. isatuximab) significantly improve MRD negativity, response rate and survival when added to standard of care regimens. Carfilzomib (K), lenalidomide (R) and dexamethasone (d) is one of the most effective and tolerable regimens in newly diagnosed multiple myeloma (NDMM). The phase II CONCEPT trial (NCT03104842) investigates the quadruplet regimen isatuximab plus KRd (Isa-KRd) in HR NDMM in induction and consolidation including high-dose melphalan (HDM) for pts being transplant-eligible (TE). Here, we report for the first time the planned interim analysis (IA) of the primary endpoint MRD negativity after consolidation for TE-patients and the corresponding final analysis of transplant non-eligible (TNE) pts. Methods: 153 pts with HR NDMM were included into the open-label, academic, multicentre phase II clinical trial, an extension cohort of TE pts is currently recruiting. According to the trial design, 99 of 127 TE pts in study arm A (TE-ITT) were included in the intention-to-treat population (ITT) of the planned IA (TE-ITT-IA); results of the 26 TNE pts in study arm B (TNE-ITT) are finally reported. HR MM was defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 in combination with ISS 2 or 3 stage disease. Pts could be included after a maximum of 1 cycle of MM treatment. Pts received 6 cycles of Isa-KRd induction, followed by HDM for TE pts or 2 Isa-KRd cycles for TNE pts, 4 cycles Isa-KRd consolidation and Isa-KR maintenance. Primary endpoint is MRD negativity at end of consolidation measured by next-generation flow at the minimum sensitivity threshold of 10-5 (H0: MRD-neg-rate ≤ 50% (TE) and ≤ 30% (TNE), tested by one-sided binomial test), this planned IA reports on. Secondary endpoint is progression-free survival (PFS), tertiary endpoints include overall response rate (ORR) and safety. Results: 125 pts (99 TE-ITT-IA, 26 TNE-ITT) were included from August 2017 to April 2020 in the IA population in 17 German Centres. No bias arose in the reduction of the TE-ITT population to the TE-ITT-IA population. Based on inclusion criteria, all pts had cytogenetic HR disease including del17p in 55 pts (44.0%), t(4;14) in 48 (38.4%), t(14;16) in 19 (15.2%) and > 3 copies 1q21 in 45 pts (36.0%). 38 pts (30.4%) had ≥ 2 HR aberrations. 66 pts (52.8%) had ISS 2 and 58 (46.4%) ISS 3 disease. Median age (range) was 58 (35-73) years in the TE-ITT-IA and 74 (64-87) years in the TNE-ITT. The design of the study provides for the MRD-analysis to be performed on 93 patients in the TE-ITT-IA and 24 patients in the TNE-IA. At the end of consolidation, in the TE-ITT-IA population 67.7% (n=63) of pts were MRD negative, 3.2% (n=3) MRD positive, 24.7% (n=23) timepoint not reached, 4.3% (n=4) missing (4 pts not assessable, 2 did not start). In the TNE-ITT population 54.2% (n=13) of pts were MRD negative, 0% MRD positive, 45.8% (n=11) timepoint not reached. The primary endpoint was significantly reached in both study arms (p = 0.0004 for TE-ITT-IA and p=0.012 for TNE-ITT). ORR (best response to treatment) in the TE-ITT-IA was 94.9% (n=94) with 72.7% showing complete remission (CR) or better (n=72), 18.2% (n=18) very good partial remission (VGPR), 4% (n=4) partial remission (PR), 1% (n=1) progressive disease (PD) and 4% (n=4) timepoint not reached. In the TNE-ITT, 57.7% (n=15) showed CR or better 30.8% (n=8) VGPR, 3.8% (n=1) were unknown and 7.7% (n=2) timepoint not reached. Updated PFS data will be shown. Safety-population consists of 122 pts. In total, 85.2% (n=104) developed ≥ grade 3 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 64.8% (n=79) of pts. TEAEs leading to discontinuation of study treatment occurred in 5 pts. Conclusions: The CONCEPT trial is the first trial investigating Isa-KRd for HR NDMM in TE and TNE patients. Isa-KRd in induction and consolidation leads to high MRD negativity rates after consolidation in this difficult-to-treat population. Toxicity was consistent with expectations and no new safety signals occurred in this IA. In our view, our data underline the importance of optimized quadruplet treatment in NDMM, especially in HR disease.

Mucosal Associated Lymphoid Tissue Lymphoma in Thailand, a Nationwide Multicenter Registry and Prognostic Index; Results from the Thai Lymphoma Study Group (TLSG) Registry

Introduction: Marginal zone lymphoma (MZL) is the second most common lymphoma subtype in Thailand. Extranodal MZL or mucosal associated lymphoid tissue (MALT) lymphoma is the highest prevalent entity. Although gastric MALT lymphoma is the most common organ of this entity but for Thai population, ocular adnexa MALT lymphoma is the most common primary organ of MALT lymphoma. Objective: This study aimed to describe epidemiology of MALT lymphoma in Thai population and develop prognostic model for MALT lymphoma. Patients and methods: Patients (pts) diagnosed with MALT lymphoma were enrolled to the TLSG registry. Demographic data, treatment modalities, survival data were gathered. Univariate and multivariate analyses were done by Cox regression. To test the prognostic indices, Kruskal-Wallis test was performed. Kaplan Meier curves were plotted and log rank test was used to test the difference between risk groups. STATA® version 17 was performed for statistical analyses. Results: From January 2007 to March 2022, the TLSG has prospectively enrolled 8,404 lymphoma patients to the registry from 15 nationwide medical institutes; of these 670 patients (7.97%) were histologically diagnosed with MZL. Among MZL, MALT lymphoma was the most common entity with 501 pts (77.8%) followed by nodal MZL (117; 17.5%), and splenic MZL (52; 7.7%). Of these MALT lymphoma population, 457 pts with completed follow-up data were eligible for long-term survivals analyses. The three most common primary organs were ocular adnexa (225; 49.2%), gastric (59; 12.9%), and sinonasal (57; 12.5%). Median age at diagnosis was 59 (range;20-95). 162 pts (35.4%) of these were 65 years or older. For gender, male was slightly predominant (56.9%). High ECOG performance status (3-4) in 15 (3.5%). Extensive extranodal organs (>2) in 78 (17%). Advanced stage (III-IV) in 162 (35.4%). High lactate dehydrogenase (LDH) in 112 (24.5%). Presence of B-symptoms in 103 (22.5%). Regarding treatment, chemotherapy (CMT) only was administered in 27.5%, CMT + rituximab (R) 13.4%, CMT + radiation (RT) 11.6%, R+CMT+RT 2.2%, R monotherapy 0.4%, antibiotic eradication 6.6%. Locoregional therapy with RT 24.2% and surgical removal alone in 3.6%. Univariate analysis was performed and found that ECOG>3, age>65, number of extranodal organs>2, B-symptom, stage III-IV, and LDH were potential factors to be used for multivariate analysis. For multivariate analysis, ECOG>3, age>65, and number of extranodal organs >2 were found to be statistically significant affected survivals. These prognostic factors were used and tested for overall and progression-free survivals (OS and PFS, respectively). Patients without any risk factor were classified to be low-risk pts and pts with any of these risk factors were categorized to be high-risk pts. Five-year PFS and OS were significantly better in low-risk pts; vs 83.3% vs 66.1% (p=0.028) and 97.8% vs 76.7% (p<0.001) respectively. (Figures 1A, B) Conclusion: MZL is the second most prevalent lymphoma subtype in Thailand and MALT lymphoma is the most common entity. The prognostic index for MALT lymphoma showed that patients without any risk factor (ECOG>3, age>65, and number of extranodal organs >2) had statistically significant better PFS and OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dosage, Safety and Efficacy of Posaconazole As Primary Antifungal Prophylaxis in High-Risk Recipients of Allogeneic Stem Cell Transplantation

Introduction: The use of anti-mold prophylaxis with anti-aspergillus activity is recommended for patients (pts) undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with high risk of fungal infection (Maertens, J Antimicrob Chemother 2018). Yet, few data are available regarding the use of posaconazole. Methods: This retrospective study included all Allo-HSCT adult recipients having benefited from posaconazole therapy in our center as a primary anti-fungal prophylaxis for high-risk of fungal infection. The latter was defined as use of i)an alternative donor, ii)sequential conditioning regimen, iii)a regimen associated with severe mucositis, iv) post-transplant cyclophosphamide (PT-Cy) or v) previous allo-HSCT. Posaconazole was programmed to be initiated at day (D) 0 or D5/6 (in case of PT-Cy) and administered up to day 100. We report here on the residual concentration of posaconazole during the neutropenic phase then on the tolerance and efficacy of such prophylaxis in this cohort. Results: Seventy high-risk pts (males 63.3%, median age 54 years old, range 20-73) received Allo-HSCT between April 2020 and December 2021 for a myeloid (n=51), lymphoid (n=17) or non-malignant hematological (n=2) disease and received posaconazole as a primary prophylaxis. The Sorror score at transplant time was ≥ 3 for 24 pts (33.8%). Twenty-two patients had already received posaconazole as a primary prophylaxis before Allo-SCT including 26 during the neutropenic phase of their induction for AML or MDS, 3 for prolonged neutropenia, 2 during treatment with alemtuzumab for T-cell leukemia/lymphoma, and 1 during a previous AlloHCST. Four patients had also received other antifungal agentsbefore Allo-SCT (caspofongine (n=1), voriconazole (n=1) or liposomal amphotericin B (n=2)) because of a suspected mold infection which has been finally excluded. All pts had at least one high-risk criterion of fungal infection. These included the use of an alternative donor in 42 pts (haplo-identical donor n= 41, umbilical cord blood n=1), sequential conditioning regimen in 9, with PT-Cy in 57, second or third allo-HSCT in 8 and conditioning regimen associated with severe mucositis in 11 (TBI 8-12gy n=3, thiotepa-based n=8). All but one pts received posaconazole using the gastroresistant tablet form at a dose of 300mg/day. One patient received the drinkable suspension form at a dose of 200mg 3 times a day. Following prophylaxis initiation, serum posaconazole concentrations were available in 51 and 16 patients at medians of 9 and 39 days, respectively. A protective residual level of posaconazole (> 0.5mg/L) was achieved in 57% of the patients (n=29) at first assessment and 87.5% (n=12) at second evaluation. Posaconazole was stopped early due to related-toxicity in 9 cases (12.6%), including liver toxicity in 7 pts, QT prolongation in 1 and skin hyperesthesia in 1. Treatment was restarted without recurrence of toxicity in 2 cases. Posaconazole was stopped early in 2 patients due to non-related toxicity, including one veno-occlusive disease and one hepatic acute GVHD. Posaconazole was temporary discontinued in 4 patients due to a suspected fungal infection before being restarted. Most patients (n=59/70, 84.2%) did not present fungal infections while being under posaconazole therapy. Only 11 cases were documented with this complication (Table 1), including 8 invasive pulmonary aspergillosis (IPA; possible n=3; probable n=5), one possible invasive fungal infection and 2 mucormycoses (1 with possible IPA). Fungal infections occurred despite documentation of a protective residual level of posaconazole (> 0.5mg/L) in 5 of 6 evaluable patients. Of note, 9/11 patients had received PTCY as GVHD prophylaxis. Posaconazole was stopped (before D7 in 3) and other antifungal drugs started (voriconazole or liposomal amphotericin B) allowing to fungal infection cure in 5 pts. However, 7 pts died including 2 of an uncontrolled fungal infection. Conclusion: Posaconazole is a well-tolerated and efficient primary prophylaxis in recipients of Allo-HSCT at high-risk of fungal infection. As some fungal infections occured very early after D0 while prophylaxis started only a D5/6 after PTCY, our results suggests to propose posaconazole as early as the beginning of the conditionning together with dose monitoring. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary Results from a Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in centrosome amplification, often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. An investigator-initiated study using a 28-day continuous CFI-400945 dosing schedule at the Princess Margaret Cancer Center (PMCC) demonstrated clinical activity in AML [Murphy et al., 2020] and responses were seen in high-risk pts with adverse cytogenetics, including those with TP53 mutations. CFI-400945 was tolerated with clinically manageable toxicities and the dose limiting toxicity (DLT) was colitis. The recommended phase 2 dose was 96mg. A newer crystal form of CFI-400945 was introduced after the PMCC study. Consequently, the optimal dosing of CFI-400945, including as a combination agent, are not yet clinically defined and are the rationale for this study. Study Design and Methods: This study is a multi-part phase 1/2 study of CFI-400945 as a single agent and in combination with hypomethylating agents (HMA) (NCT04730258). For Part 1, pts with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Pts with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For Part 2, pts should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated pts who decline or are ineligible for intensive therapy may be included. The study uses a standard 3 + 3 design, and the dosing schedule is 21 days on and 7 days off (28-day cycle) - this is to potentially avoid the colitis seen in the study at PMCC. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose-limiting toxicities (DLTs) is <1 out of 6 at highest dose level at or below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: As of the 30Jun22 data cut off, 9 pts had been enrolled into the study. Four (44%) pts had AML, 2 (22%) had MDS, 3 (33%) had CMML. The median number of prior therapies was 2 (range 1-4), and 2 (22%) pts had received a stem cell transplant. Six (66%) were male and the median age was 69 (range 22-75). Three of 4 AML pts had unfavorable risk cytogenetics by ELN 2017 criteria, and 2 pts (1 each with MDS, CMML) with TP53 mutations. Five pts received 32mg and 4 pts 48mg. There have been no DLTs. There have been 8 (89%) SAEs with the following occurring in >2 pts (febrile neutropenia (6 pts), pneumonia (2 pts)). Common treatment emergent adverse events (TEAE) in > 2 pts were febrile neutropenia 6 pts (67%), hypokalemia 5pts (56%), anemia and hypomagnesemia 4 pts each (44%), hypophosphatemia, diarrhea, abdominal pain, nausea, vomiting, dyspnea, peripheral edema 3 pts each (33%). Thirty-three percent (20 events, 3 pts) of the grade 3 or greater TEAE's were considered related to CFI-400945. There have been no CR or PR per ELN response criteria observed to date, however, there were 2 (50%) SD per IWG criteria at the 48 mg dose level (1-MDS, 1-CMML). Pharmacokinetic (PK) evaluations indicated that the mean terminal-life ranged from 7 - 10 hours. Low accumulation was observed after 21 days of daily dosing (AR <2-fold). In general, exposure in this study is overlapped with that observed in the PMCC study. PD studies evaluating the effect of CFI-400945 on markers of mitosis, ploidy, and centriole function are ongoing. Conclusion: CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in Part 1. There have been no responses per ELN to date but there was SD in 2 pts (48 mg dose). Lack of DLTs suggest dose level is still suboptimal at time of submission. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose escalation continues in this study and updated data will be presented.

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed and Refractory Follicular Lymphoma: Analysis of Safety, Efficacy, and Minimal Residual Disease

Abstract 11889: Effectiveness of sST2-Guided Therapy in Patients With Heart Failure With Reduced Ejection Fraction

Introduction: Natriuretic peptide-guided therapy has not proven to be more sufficiently effective than usual care (UC) in patients with heart failure (HF). Soluble ST2 (sST2) has a number of advantages over natriuretic peptides. Hypothesis: sST2-guided therapy (sST2-GT) will be more effective than UC in patients with HFrEF. Methods: The prospective study included 76 patients (pts) with HFrEF, who were hospitalized due to acute decompensated HF. Pts with sST2 levels ≥ 37.8 ng/ml at the time of discharge constituted the high-risk cohort and were randomized into 2 groups: 19 pts in the sST2-GT and 18 patients in the UC. 39 pts with sST2 &lt; 37.8 ng/ml and NT-proBNP &lt; 1700 pg/ml were included in the low-risk cohort. The duration of the active treatment period was 6 months with monthly visits for therapy correction, the total follow-up period was up to 1 year. Therapy was carried out in accordance with clinical recommendations. In the sST2-GT group, therapy was also adjusted taking into account the concentration of sST2. The goal in this group was to reduce sST2 concentration by more than 30% or to less than 30 ng/ml. Measurement of sST2 (ASPECT-PLUS) concentration, echocardiography and registration combined endpoints (CEP) (HF decompensation (HFD) or cardiovascular mortality) were identified in all groups after 6 and 12 months. Results: Pts therapy in both high-risk groups was comparable, but pts in the sST2-GT group had a greater number of study clinic visits (7.1±2.3 vs 5.6±1.6 (p=0.024) compared with UC group. Pts sST2 concentration decreased in both high-risk groups, with the study goal achieved in 68,4% of pts in sST-GT group. Fewer CEP were registered In sST2-GT group pts compared to the UC group (for 6 months - 5 (0.26 / pt) vs 15 (0.83 / pt), p = 0.029 and 9 (0.47/pt) vs 22 (1.22/pt), p=0.035 over the entire follow-up) and it was practically similar low-risk cohort (0.46/patient). Fewer HFD were registered in the sST2-GT group compared to the UC group (for 6 months 4 (0.21 /pt) vs 13 (0.72 /pt), p &lt; 0.001 and 8 (0.42/pt) vs 19 (1.06/pt), p&lt;0.001 over entire follow-up), which was similar the low-risk group (0,31/pt). LV EF increased only in the sST2-GT group (from 29.2±6.2 up to 36.1±8.8, p=0.003 for 6 months). Conclusions: sST2-GT in high-risk pts with HFrEF is more effective than UC.

120 (PB-033) Poster - Pathogenic mutations in ethnic Lebanese Arab patients with high risk for hereditary breast cancer

Background: Breast cancer accounts for 35–40% of cancer in women in Lebanese and Arab countries with 50% of patients (pts) diagnosed before age 50. Prevalence of pathogenic BRCA variants in high-risk pts is 5.6–20% (Abulkhair and El Saghir 2021). 7 BRCA1 and 7 BRCA2 pathogenic variants were found in 5.6% of 250 pts with high hereditary risk breast cancer using amplicon sequencing and MLPA (El Saghir 2015; Poulet 2016). We report results of Next Generation Sequencing (NGS) on selected cases based on Manchester Score.

Prostate Brachytherapy Boost in the Elderly: Results of a Comparative Study

<h3>Purpose/Objective(s)</h3> To analyze the oncological outcome and toxicity profile in elderly (> 70 years) prostate cancer after high-dose rate brachytherapy (HDB) boost. <h3>Materials/Methods</h3> In this retrospective observational single institution study (Health-data-hub N°F20201008194116), patients with intermediate (IR) and high-risk (HR) prostate cancer underwent external beam radiation therapy (EBRT) followed by HDB boost with or without androgen deprivation therapy (ADT). The impact of patient age (≤ 70 y vs. > 70 y) was investigated. Oncological outcome focused on biochemical (BRFS), local (LRFS), regional (RRFS) and metastatic relapse-free survival (MRFS) as well as Disease-free (DFS), Cause-specific (CSS) and overall survival (OS). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were investigated. <h3>Results</h3> From 02/09 to 12/21, 519 pts received a HDB boost. Among them, 387 were analyzed (≤70y: 180 pts [47%] vs. >70y: 207 pts [53%]). Regarding NCCN classification, 98 pts (≤70y: 53 pts; >70y: 45 pts; p = NS) and 289 pts (≤70y: 127 pts; >70y: 162 pts; p = NS) were IR and HR pts respectively. Intensity modulated RT was used in 241 pts (62.6%) with pelvic irradiation in 336 pts (86.2%) for a median dose of 45.5 Gy [35 – 57.5] in 23 fractions [15 - 25]. HDB boost was performed under general/spinal anesthesia delivering a single fraction of 14 or 15 Gy for 307 pts (79.3%). ADT was used in 309 pts (≤70y: 133 pts; >70y: 176 pts; p = 0.009) for a median time of 17.1 months [3 - 41] (IR: 6 months; HR: 18.8 months). With a median follow-up (MFU) of 72.3 months [64.6 – 81.1] for the whole cohort, 5-y BRFS, 5-y LRFS, 5-y RRFS and 5-y MRFS were 88% [84 - 92], 97% [95 - 99], 99% [98 - 1], 95% [93 - 98] respectively with 5-y DFS, 5-y CSS and 5-y OS of 84% [80-88], 99% [97-100] and 94% [92 - 97]. With the same MFU of 60 months in both age groups, oncological outcome was not statically different except for the 5-y CSS (≤70y: 97% [94 - 100] vs. >70y: 100%; p=0.05). Late GU toxicity was observed in 124 pts (32.1%) with 9 G3 pts (7.2%). Late GI toxicity was observed in 41 pts (10.2%) with no G3. However, in a subgroup analysis comparing 70y< pts ≤80y vs. >80y pts, a significant difference was noticed in terms of late GU toxicity (29.7% vs. 61.9%; p = 0.006). <h3>Conclusion</h3> For IR and HR prostate cancers, HDB boost leads to high rates of disease control with less than 3% of late G3 GU/GI toxicities. For elderly pts (>70y), HDB boost remains warranted in order to achieve optimal oncological outcome mainly in HR pts, although competing comorbidity factors will significantly impact the OS. However, HDB boost should be carefully discussed in the super senior pts (> 80 y). Due to the increase in life expectancy, the management of prostate cancer in the elderly is a real challenge for patients, clinicians, health care providers and payers. Except for unfit men, elderly patients remain candidates for optimal curative treatment (i.e., regardless of age) after oncogeriatric assessment.

NRG RTOG 1005: A Phase III Trial of Hypo Fractionated Whole Breast Irradiation with Concurrent Boost vs. Conventional Whole Breast Irradiation Plus Sequential Boost Following Lumpectomy for High Risk Early-Stage Breast Cancer

<h3>Purpose/Objective(s)</h3> Randomized trials support a supplemental radiation dose (Boost) to the lumpectomy (L) cavity region after whole breast irradiation (WBI), providing a 20-30% relative reduction of in-breast recurrence (IBR); with the disadvantage that it extends treatment duration ⁓ 1 week. Hypofractionated WBI (H-WBI) in ≤ 3 weeks is used after L to deliver adjuvant WBI with acceptable toxicity and comparable IBR as conventional WBI (C-WBI) 50 Gy in 2 Gy fractions (F). NRG RTOG 1005 sought to determine whether a boost delivered concomitantly with H-WBI over 15 F is non-inferior for IBR compared to boost delivered sequentially after C-WBI in patients (pts) considered at High Risk of IBR. <h3>Materials/Methods</h3> Protocol-specified High Risk pts post L with stages 0, I & II breast cancer were randomized to C-WBI 50 Gy in 25 F or 42.7 Gy in 16 F plus sequential boost of 12 Gy in 6 F or 14 Gy in 7 F (Arm I) or H-WBI 40 Gy in 15 F plus concomitant boost of 8 Gy in 15 F of 0.53 Gy per day (Arm II). Radiation was target based 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT) and quality review (QA) was required. Stratification was by age (<50 vs ≥ 50), adjuvant chemotherapy (Y vs N), ER status (+ vs -) and histologic grade (1, 2 v 3). The primary endpoint is IBR. Assuming Arm I 5‐year IBR of 1.59%, 90% CI upper bound hazard ratio (HR) of 2.12 and 1‐sided significance level = 0.05, 2150 pts with at least 46 IBR events provide >80% power to conclude non‐inferiority. IBR was analyzed comparing the cause-specific hazards. Adverse Events (AE) were graded with NCI CTCAE v4. Physician-reported NRG-RTOG Global Cosmetic Score (GCS) was grouped as excellent/good vs fair/poor, and arms compared with chi-square. <h3>Results</h3> 2262 of 2354 randomized pts were eligible (Arm I n=1124; Arm II n=1138). Median age 55 years, 34% Stage II, 52% grade 3, 30% ER-, 17% close/+ margins consistent with a "High Risk" population. Radiation was 3DCRT 81%, IMRT 19%, and the QA was per protocol 81% and 88% on Arm I vs II, respectively. With a median follow-up of 7.3 years and 56 IBR events, the 5 and 7-year IBR were 2.0% and 2.2% on Arm I and 1.9% and 2.6% on Arm II. The non-inferiority comparison (Arm I reference level) resulted in a HR (90% CI): 1.32 (0.84, 2.05) and p = 0.039, thus meeting non-inferiority. No differences in AEs noted between arms, with low rates of ≥ grade 3 treatment-related AEs, 3.3% vs 3.5% for Arm I vs II, respectively (p=0.79). No difference in 3-year excellent/good cosmesis by arm: 86% for Arm I vs 84% Arm II (p=0.61). <h3>Conclusion</h3> Concomitant boost with H-WBI results in non-inferior IBR compared to sequential boost after C-WBI in high-risk cases and reduces overall treatment time. Using target based 3DCRT or IMRT, there are no differences in toxicity or cosmetic outcome for concomitant v sequential boost or the WBI fractionation regimen.

329P Duration of adjuvant therapy in stage III colon cancer: A real world multi-institutional US-based experience

Since the publication of IDEA, the duration of adjuvant chemotherapy (CTX) in stage III colon cancer (CC) has shifted to a risk-stratified approach as 3 months (mo) of CAPOX vs 6 mo was found to be non-inferior in patients (pts) with low risk (LR) (T1-T3/N0-N1). High risk (HiR) (T4 or N2) disease failed to show non-inferiority, however 3-year DFS differences were less than 2% and only .1% when pts received CAPOX. However in the US cohort, pts did not receive CAPOX, possibly due to capecitabine intolerance. Herein, we performed a real-world evaluation of CTX in US pts with stage III CC. A retrospective review of stage III CC pts treated from 2016-2022 from 5 US academic medical institutions was performed. Pts were stratified into 3mo vs 6mo of CTX, HiR vs LR, and CAPOX vs FOLFOX. 3-year DFS and adverse events were recorded. A total of 443 pts were included. In the overall population, no difference in 3-year DFS was observed in 3 vs 6 mo of CTX (69.3 vs 71.0%, hazard ratio [HR] = 1.26, 95% CI (0.74, 2.17), adjusted p [aP] = 0.40), numerically less than was observed in IDEA. HiR pts were observed to have detriment in 3-year DFS with 3mo vs. 6mo CTX (34.0% vs 62.9%, HR = 1.51, 95% CI (0.77, 2.99), aP=0.23). Grade 3 adverse events (AE) of nausea, diarrhea, and hand/foot syndrome from capecitabine were higher than reported in IDEA.Table: 329PDFS by treatment, duration and riskCTXN (Events)36 Months DFS6 mo FOLFOX255 (76)71.8%6 mo CAPOX54 (17)67.5%3 mo FOLFOX37 (9)68.8%3 mo CAPOX97 (16)69.4%HiR vs LR6 mo LR126 (23)82.3%6 mo HiR183 (70)62.9%3 mo LR102 (13)81.2%3 mo HiR32 (12)34.0% Open table in a new tab In this real-world experience we observed no DFS benefit in pts treated with 3 vs 6mo CTX. In HiR pts treated with 3mo CTX, we observed a lower 3-year DFS rate compared to 6mo of CTX. The findings were not statistically significant due to low number of events in this cohort and was significantly lower than reported in IDEA. AEs were more prevalent in US pts compared to non-US pts in IDEA, likely due to capecitabine intolerance. Our study is the first to assess 3mo vs 6mo capecitabine based adjuvant CTX in a risk stratified US population and suggests discrepancies in DFS and AEs compared to IDEA in US pts who received CAPOX.

P366: BLINATUMOMAB ADDED TO PREPHASE AND CONSOLIDATION THERAPY IN NEWLY DIAGNOSED PRECURSOR B-ALL IN ADULTS. A PHASE II HOVON TRIAL

Background: The bispecific antibody blinatumomab (blina) is approved for patients(pts) with relapsed/refractory precursor B-cell ALL (ALL). It has also shown to be highly effective in MRD+ pts in first line treatment. TABLE - Pt characteristics Total, N(%) 71(100%) Age(y), median(range) 53(18-70) Age (y), N(%) ≤40 22(31%) 40-60 29(41%) >60 20(28%) BM blasts (%), N(%) ≤50% 4(6%) >50% 62(87%) Unknown 5(7%) Karyotype, N(%) Ph+ 26/71(37%) KMT2A 2/67(3%) Complex 23/67(34%) Hypodiploidy 5/67(7%) Aims: To evaluate whether blina added in upfront therapy to prephase and after consolidation (cons)-1 would increase MRD negativity measured by qPCR or flowcytometry at a cut-off of <10-4 (primary endpoint). Secondary endpoints included CR, EFS, OS, adverse events and treatment-related mortality. Methods: Pts, 18-70 years(y) old, with newly diagnosed CD19+ ALL (incl. Ph+), were included. Treatment was based on a pediatric inspired protocol (HOVON 70, Rijneveld et al., 2011) with reduced doses of anthracyclines, MTX, etoposide and PEG-ASP for pts ≥40y old. Prephase consisted of 10 days steroids, from day 5 combined with 14 days blina in the standard step-up dosing schedule. After cons-1 and after intensification 2, two 4-week blina courses were added irrespective of MRD. The protocol was amended twice due to toxicity. First, in 2018 the first PEG-ASP administration was omitted. Second, in 2021 doxorubicin, dexamethasone and PEG-ASP were reduced during intensification 1. Rituximab (if CD20+), prophylactic ITs and imatinib (if Ph+) were standard. AlloHSCT was offered to intermediate and high-risk pts. Trial was registered with ClinicalTrials.gov, identifier NCT03541083. Results: Seventy-one pts were enrolled. Pt characteristics are presented (Table). Fifteen pts discontinued treatment before blina cons-1 due to refractory disease (n=8), toxicity (n=7) or death (n=2). In the total study population, 55/71 pts (77%) achieved CR after (blina) cons-1. Among pts still on treatment after cons-1, 55/56 (98%) pts achieved CR, 50/55 (91%) reached MRD negativity. After prephase, CR was already reached in 63% and MRD negativity in 53%. Blina related AEs in prephase were as expected (83% of pts had ≥1 AE and 10% had ≥1 SAE (hepatotoxicity 3 pts, pain lymph node 1, CRS 1, pneumonia 1, renal insufficiency 1)). CRS was observed in 35% of pts, 32% of whom experienced grade 3 and no grade ≥4. During prephase 5 pts discontinued blina; during blina cons-1, 4 pts stopped blina. With a median follow-up of 17,6 months, the estimated 2-y EFS was 64% standard error (SE) ± 7% (≤60y 71% SE ± 9% and >60y 47% SE ± 12%). Overall, 14 (20%) pts died. OS after 2y was 73% SE ± 7% (≤60y 82% SE ± 8% and >60y 52% SE ± 14%) (Figure 1). For pts with Ph+ ALL, 2-y EFS was 88% SE ± 6%and OS also 88% SE ± 7%. For Ph- ALL, 2-y EFS and OS were 53% SE ± 9% and 68% SE ± 9%, resp. Among pts who reached CR on protocol (n=60), 5 (8%) had relapse, 6 (10%) died and 6 (10%) discontinued treatment due to toxicity. Until now, 22 pts proceeded to alloHSCT and 11 with maintenance. Image:Summary/Conclusion: Blina can safely be added to prephase of an intensified pediatric schedule for newly diagnosed ALL up to 70y of age, albeit with dose reductions for PEG-ASP, doxorubicin and dexamethasone. The combination increases CR and MRD negativity rate. The early addition of blina resulted in very early achievement of MRD negativity with 53% after prephase and 91% after blina cons-1. Further reductions of chemotherapy should be explored (especially for Ph+) if these results are maintained with longer follow-up.