5y Overall Survival Research Articles

Impact of molecular classification on prognosis in children and adolescents with spinal ependymoma: Results from the HIT-MED database

Abstract Background Ependymomas of the spinal cord are rare among children and adolescents, and the individual risk of disease progression is difficult to predict. This study aims at evaluating the prognostic impact of molecular typing of pediatric spinal cord ependymomas. Methods Eighty-three patients with spinal ependymomas ≤22 years registered in the HIT-MED database between 1992 and 2022 were included. Forty-seven tumors were analyzed by DNA methylation array profiling. In six cases, HOXB13 and MYCN proteins were detected as surrogate markers for specific methylation classes. Ten patients had NF2-related schwannomatosis. Results With a median follow-up time of 4.9 years (y), 5y- and 10y-overall survival (OS) were 100% and 86%, while 5y- and 10y-progression-free survival (PFS) were 65% and 54%. Myxopapillary ependymoma (SP-MPE, n=32, 63%) was the most common molecular type followed by spinal ependymoma (SP-EPN, n=17, 33%) and MYCN-amplified ependymoma (n=2, 4%). One case could not be molecularly classified, and one was reclassified as anaplastic pilocytic astrocytoma. 5y-PFS did not significantly differ between SP-MPE and SP-EPN (65% versus 78%, p=0.64). MYCN-amplification was associated with early relapses (<2.3y) in both cases and death in one patient. Patients with SP-MPE subtype B (n=9) showed a non-significant trend for better 5y-PFS compared to subtype A (n=18; 86% versus 56%, p=0.15). The extent of resection and WHO tumor grades significantly influenced PFS in a uni- and multivariate analysis. Conclusions Molecular typing of pediatric spinal ependymomas aids to identify very-high-risk MYCN-amplified ependymomas. Further insights into the molecular heterogeneity of spinal ependymomas are needed for future clinical decision-making.

The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study

BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and everolimus (EVE) are effective for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of different sequences of CDK4/6i and EVE are largely unknown. The study aimed to explore the efficacy of different sequences in China. Methods146 patients with HR+/HER2- MBC who received both CDK4/6i and EVE in salvage setting were collected. Objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were investigated. Results56 patients received CDK4/6i prior to EVE (Group A), 90 patients received CDK4/6i subsequent to EVE (Group B). The median PFS of CDK4/6i and EVE in Group A vs Group B were 8.4m and 2.5m vs 4.6m and 6.1m respectively. The total PFS of first-line and second-line endocrine therapy were not different between Group A and Group B [13.1m vs 17.7m (P = 0.330, HR = 0.738, 95%CI: 0.399–1.365)]. The 5y OS of patients in Group A or Group B were 62.0 % vs 57.4 %, P = 0.569. ConclusionsWe found that no matter CDK4/6i or EVE was used first, the survival were not significantly different between Group A and Group B. Both can be clinical options.

Local Control, Survival, and Toxicity Outcomes with High-Dose-Rate Peri-Operative Interventional Radiotherapy (Brachytherapy) in Head and Neck Cancers: A Systematic Review.

Background. Peri-operative interventional radiotherapy (POIRT) entails tumor resection, catheter implantation in the same surgery, and irradiation within the peri-operative period. It allows for maximal tumor burden reduction, better tumor bed identification, more flexible implant geometry, highly conformal irradiation, and treatment delay minimization. We reviewed the published local control, survival, toxicity, and quality of life (QOL) outcomes with POIRT for head and neck cancers (HNCs) in primary and re-irradiation settings. Materials and Methods. A systematic search of PubMed, Scopus, Science Direct, and other databases, supplemented by bibliography scanning and hand-searching, yielded 107 titles. Fifteen unique articles were eligible, five of which were merged with more updated studies. Of the ten remaining studies, four reported on primary POIRT, and seven reported on reirradiation POIRT. Given data heterogeneity, only qualitative synthesis was performed. Results. Primary POIRT in early tongue cancer results in 6-year recurrence-free (RFS) and overall survival (OS) of 92% for both; in advanced HNCs, the 9-year RFS and OS rates are 52% and 55%. Grade 1-2 toxicity is very common; grade 3-4 toxicity is rare, but grade 5 toxicity has been reported. POIRT re-irradiation for recurrent HNCs results in 5y RFS and OS rates of 37-55% and 17-50%; better outcomes are achieved with gross total resection (GTR). QOL data are lacking. Conclusions. Primary POIRT is safe and effective in early tongue cancers; its use in other HNC sites, especially in advanced disease, requires careful consideration. Re-irradiation POIRT is most effective and safe when combined with GTR; toxicity is significant and may be limited by careful case selection, implant planning and execution, use of smaller fraction sizes, and adherence to homogeneity constraints. Study Registration Number. PROSPERO Registry Number CRD42024548294.

Overall survival (OS) in a u.s. Asian population with stage IV NSCLC with EGFR mutations treated with first-line (1L) osimertinib (Osi) compared to earlier generation (Gen) of TKIs or sequential treatment (Tx).

e20597 Background: Osi, a 3rd-gen EGFR tyrosine kinase inhibitor (TKI), was approved as 1L tx for metastatic non-small-cell lung cancer (NSCLC) with EGFR mutations (ex19del or L858R) in 2018. This was based on the FLAURA trial, showing improved progression-free survival and OS of 1L osi compared to 1st-gen TKIs. Despite this, subgroup analyses revealed no OS difference in Asian or L858R patients (pts). Studies such as GioTag and UpSwinG showed better median OS in Asians with ex19del mutations on sequential afatinib and osi tx, prompting the question if sequencing of tx may also benefit L858R pts. We conducted this analysis of real-world outcomes in U.S. Asian pts with EGFR mutated NSCLC treated with 1L osi, 1st- or 2nd- gen TKIs (prior-TKIs-only), or sequential 1st- or 2nd- gen TKI followed by osi (sequential-TKI-osi). Methods: We conducted a single-institution IRB-approved retrospective study at NYU, including Asian pts diagnosed with stage IV NSCLC with EGFR ex19del or L858R, who received any gen of TKIs from 1/1/2010 to 1/13/2023. We compared 3-year (3y) OS based on tx and mutation subtypes, excluding pts with less than 3 years of follow-up. The analysis utilized the Cox proportional-hazards model to calculate hazard ratios (HR) and P values of OS. Survival curves were estimated using the Kaplan-Meier method. The log-rank tests were used to assess survival differences between tx groups. Additionally, a multivariable Cox proportional-hazards model explored the association between pts' survival time and multiple predictor variables. Results: We analyzed 139 cases: 103 (74%) females, 68 (49%) L858R, 113 (81%) never smokers, and age 31-96 years. The 3y OS analysis revealed no significant difference in the OS in L858R pts who received prior-TKIs-only (p = 0.83) or sequential-TKI-osi (p = 0.90), compared to 1L osi (median OS not reached in all three groups). However, in ex19del pts, prior-TKIs-only (HR 0.31, 95% CI 0.13-0.76) and sequential-TKI-osi (HR 0.30, 95% CI 0.11-0.85) txs showed superior OS compared to 1L osi, with a median OS of 24.7 mo in 1L osi and not reached in other two txs. Among all predictor variables (tx, age, sex, EGFR subtypes, and smoking status), only age had a significant but small impact on OS (HR 1.03, 95% CI 1.01-1.06). Conclusions: Our real-world analysis revealed that Asian stage IV NSCLC pts with L858R treated with 1L osi had a similar 3y OS compared to those treated with prior-TKIs-only and sequential-TKI-osi. Whereas, 1L osi was inferior to both txs in OS for ex19del pts. This finding may be unique and significant in Asian ex19del pts, though our analysis is limited by the small cohort of a retrospective study. Larger cohorts from retrospective studies or prospective trials are needed to investigate the response of Asian ex19del pts to 1L osi, while underling the need for novel tx options for L858R pts.

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.

Allogeneic hematopoietic stem cell transplantation from matched related donors for acute myeloid leukemia.

In patients with acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (HSCT) remains the priority treatment option as the most effective prevention of relapse. When an HLA-matched sibling is available, these transplants are preferred. We stratificated patients according to risk, disease state (an active disease, the 1st or 2nd complete remission ‒ CR1, CR2, which was achieved after the 1st or 2nd induction) and type of graft (from brother or sister). Finally, the overall survival (OS) of patients in individual groups was evaluated. The retrospective single-center study included 104 transplantations in 97 adult patients with AML who underwent HSCT from matched sibling donor in aperiod of 10 years between January 2011 and December 2020. 54 patients (55.7%) were alive as of the January 1, 2022. The median OS of the entire group, as well as the cohort with favorable (5y-OS 75.0%) and intermediate prognosis risk (5y‒OS 78.5%) was not reached. We found that patients, who required second induction therapy to achieve CR, had poorer OS after allogeneic HSCT, median 20.7 months (95% CI, 6.5-35.5) than those who achieved CR after first induction, median not reached (95% CI, 63.5‒63.5, p=0.0048). Statistically significant effect on OS shows transplantation in CR2 (HR 6.76, CI 95% 2.19‒20.80, p=0.0009), In addition, this parameter influenced OS more than achieving CR up to the 2nd induction course (HR 2.44, CI 95% 1.17‒5.11; p=0.0180) or entry to transplantation without CR (HR 2.81, CI 95% 1.09‒7.26; p=0.0326). The results presented in the work show the high efficiency of HSCT in each risk group. The number of induction therapies required to achieve CR is agood prognostic factor. The gender of asibling has no impact on OS (Tab. 11, Fig. 7, Ref. 18). Text in PDF www.elis.sk Keywords: acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, overall survival, remission status, donor tender.

FLT3 Ligand Kinetic Profile Predicts Response to Treatment and Event-Free Survival (EFS) in Adults with High-Risk MDS/CMML Receiving CPX-351: A GFM Study

Background: Our group recently reported, in a prospective multicentre phase 2 study of 31 patients with higher-risk (HR)-MDS or CMML receiving CPX-351 as first-line induction treatment 87% of overall responses (including 64.5% of CR/ CR according to ELN2017 criteria), and 93.5% of the patients could be bridged to transplant (GFM-CPX MDS trial, Peterlin et al. Lancet Haematol 2023). We had also previously reported, in AML, that the soluble forms of FLT3 ligand (FL) and IL6 could be prognostic factors of refractoriness to chemotherapy and overall survival (OS) (Peterlin et al. Cancer Medicine, 2021). A secondary objective of the GFM-CPX MDS trial was to assess the prognostic value of these two cytokines in HR-MDS/CMML receiving CPX-351. Methods: All patients included in the GFM-CPX MDS trial (clinicaltrials.gov#NCT04273802), induction chemotherapy with CPX-351 (44 mg Daunorubicin/100 mg Aracytine/m 2 on days 1, 3, and 5) also consented for the present biological FLAM-MDS sub-study. Using a new cytokine multiplex assay from Milliplex (MILLIPLEX®), FL levels (expressed in pg/mL) were evaluated on Day (D) 1, D8, D15 and D22 of the first cycle of induction; IL-6 (expressed in pg/mL) and CRP (known to be correlated with IL6, expressed in mg/L, normal value 0-5) levels were evaluated on D1 and D22 only. Patients who failed to achieve response (CR or CRi or MLFS, ELN2017 criteria) after the first induction cycle could receive a second one. The impact on CR/CRi rate after one cycle of CPX-351, OS and EFS of FL, IL-6 and CRP dosages and their kinetic profile during this first cycle were studied. Results: Dosages could be performed in 28 of the 31 patients included ( Table 1). Overall response (CR+CRi+MLFS) after cycle 1 was achieved in 24 (87%, MLFS n=7, CR+CRi n=17) patients; 3/4 non-responders received a second induction (1 achieved CR). Allograft was performed in 26/28 (93%). With a median follow-up of 18 months for surviving patients, 1y and 18-month OS were 79% and 75%, respectively. 1y and 18-month EFS were both 76%, respectively. Achieving CR/CRi versus MLFS/non-response was associated with better 1-y EFS (71% (52-96) vs 27% (10-72), p=0.009) but not 1-y OS (82% (66-100) vs 73% (51-100), p=0.8). Median (range) FL levels were 4.5 [0- 33.5] on D1, 74.1 [4.1-296.6] at D8, 326.6 [47.4-678] at D15 and 381.3 [4.4-800.1] at D22. As in AML (Peterlin et al, 2021), patients could be categorized according to three FLc kinetic profiles: i) sustained increase from D 1 to 22 (FLI group n=17, 61% of the cohort), ii) increase from D 1 to 15, then decrease on D 22 (FLD group, n=9, 32% of the cohort) and iii) persistent low levels (&amp;lt;100 pg/mL from D 1 to 22, FLL group, n=2, 7% of the cohort). Median (range) IL6 levels were 11 (0-587.8) on D1 and 179.8 (0-531) on D22. Increase of IL6 levels between D1 and D22 was observed in 19 patients (68%) and decrease in 7, while 2 patients had no IL6 detectable at either times. Finally, median (range) CRP levels were 2.3 (0-108) on D1 and 40.5 (7.2-323) on D22. Increase of CRP level was observed in most patients between D1 and D22 (n=25, 96%). There was no correlation between IL6 and CRP levels on D1 (p=0.64) or D22 (p=0.48). CR/CR rates, 1-y OS and EFS were not correlated with FL levels (&amp;lt; vs &amp;gt; median) at the 4 time points considered. However, a FLD kinetic profile was significantly associated with higher CR/CRi rates (100% vs FLI 47% vs FLL 50%, p=0.002) and 1-y EFS (78% (55-100) vs FLI 47% (28-78) vs FLL: 0%, p=0.003), Figure 1). 1-y OS was similar between the 3 FL kinetic profile groups (FLD: 89% (71-100) vs FLI 76% (59-100) vs FLL 50% (13-100), p=0.7)). In multivariate analysis, taking into account age, gender, R-IPSS and the FL kinetic profile during cycle 1 of CPX-351, a FLD kinetic profile was the only factor associated with higher CR/CRi rate (OR: 24.2, 95%CI: 2.4-3278, p=0.004) and better EFS (OR: 21.91; 95%CI: 2.47-194.77, p=0.006). Levels and kinetic profiles of IL6 and CRP had no impact on CR/CRi rates, OS and EFS. Conclusion: As in AML, FL kinetic profile predicts response and survival in HR-MDS/CMML. A FLD kinetic profile was the only factor independently associated with higher CR/CRi rates and better EFS. These results have to be confirmed on larger cohorts. Other treatment approaches may be of interest in patient with a non FLD profile.

Characterization of Comparative Clinical Outcomes and Molecular Features of Black Patients with Acute Promyelocytic Leukemia (APL) Reveals Similar Survival and Distinct Genomic Profiles

Introduction: Although APL, a subtype of acute myeloid leukemia (AML), is an aggressive disease, its treatment was revolutionized with combination all- trans retinoic acid (ATRA) and arsenic trioxide (ATO), making APL a highly curable malignancy. Molecularly, APL is characterized by t(15;17) resulting in PML:: RARA gene fusion as disease-initiating event and by several recurrent gene mutations (eg, FLT3) identified in previous studies. In AML, prior studies have established inferior overall survival (OS) of Black versus White AML patients (pts) in both population-based analyses and clinical trials, found a negative prognostic impact of higher social deprivation (SDI), and characterized differences in frequencies and impact of disease-associated gene mutations. Herein, we compared OS of Black and White APL pts and evaluated genomic landscape of Black pts, which has not been comprehensively assessed to date. Methods: For nationwide population analysis, 2 sets of cancer registries were included in the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 829 adults diagnosed with de novo APL (confirmed by cytogenetic and/or molecular findings) in 1995-2019. To assess survival in the setting of clinical trials, we analyzed 249 pts treated on historic frontline Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology (Alliance) trials with or without inclusion of ATRA (CALGB 9191, 1992-1995; CALGB 9710, 1999-2005). For Alliance pts, neighborhood SDI was assigned based on pt-reported residence zip code and classified as low (1-25, n=33) or high deprivation (26-100, n=95). OS was analyzed separately for pts diagnosed before and after 2012 to account for treatment advances with ATRA/ATO. To assess molecular features, we performed integrated genomic profiling (paired tumor/normal whole-exome and transcriptome sequencing) on 31 Black APL Alliance pts (9/31 completed, with complete results to be presented at the Annual Meeting). Results: On a population level using SEER data, 3-year (3y) OS significantly improved from 65% for cases diagnosed in 1995-2012 to 75% in those diagnosed after 2012 (p=&amp;lt;0.001), concordant with ATRA/ATO use. Notably, OS of Black and White pts did not differ significantly before or after 2012. This held true in race-specific findings for median household income, Yost index and urban/rural status; none of which significantly associated with OS. Older age was the only parameter associated with OS (3y rates, 1995-2012: &amp;lt;40y, 79%; 40-59y, 71%; ≥60y, 44%; and 2012-2019: &amp;lt;40y, 92%; 40-59y, 80%; ≥60y, 56%). Again, OS of Black and White pts did not differ within age groups. Likewise, OS of Black and White APL pts treated in a relatively controlled setting of clinical trials was not significantly different. As in population-based findings, OS improved over time and with ATRA addition (3y OS rates, 1992-1995, 66%; 1999-2005, 85%), and older age was a strong negative OS predictor (p&amp;lt;0.001). When comparing OS of pts treated on clinical trials with population-based OS, trial pts had a longer 3y OS (84% vs 64%, p&amp;lt;0.001). Notably, pts with SDI &amp;gt;25 (n=95) had a worse OS than pts with SDI &amp;lt;25 (n=33, p=0.03). On a molecular level, preliminary results of whole-exome sequencing (finalized for 9/31 Black pts) showed frequent mutations in FLT3 (5/9 pts), a known APL-associated event, but also revealed several recurrent gene mutations not reported in prior APL sequencing efforts, which were almost exclusively based on White pts, including mutations in DPP6, GOLA6L, NLGN2 and SP8 (found in ≥2 pts). Intriguingly, CALR mutations were found in 3/9 pts. Mutations in FLT3 and CALR were mutually exclusive and found in 8/9 pts, with the remaining pt harboring a SORBS2 mutation. Conclusions: In contrast to most cancer types, including AML, there was no OS disparity with respect to race in APL pts, both in population-based analyses and in the setting of historic clinical trials. Older age and residence with high SDI (&amp;gt;25) were negative OS predictors. Molecularly, our pilot data reveal existence of ancestry-associated differences in driver mutations, suggesting that FLT3 and CALR mutations represent necessary proliferative signals in addition to PML:: RARA-driven differentiation arrest. Support: U10CA180821, U10CA180882, U24CA196171; Clinicaltrials.gov IDs: NCT00048958, NCT00899223, NCT00900224; https://acknowledgments.alliancefound.org

Clonal Hematopoiesis Is Associated with Severe Cytokine Release Syndrome in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Background: Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR-T therapy, inflammation pre- and post-CAR-T infusion is attributed in the development of toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with inflammatory disorders such as rheumatoid arthritis and graft-versus-host disease, as well as clonal cytopenias of undetermined significance. In the setting of CAR-T, others have reported an association between CH and both ICANS and treatment-associated myeloid neoplasms. Herein, we examined the prevalence of pre-CAR-T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between CH and CAR-T related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). Methods: This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR-T therapy from 2017 to 2022 at City of Hope and had available pre-CAR-T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected &amp;lt;30d of CAR-T infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH (Yes/No) and absolute neutrophil count (ANC) recovery at day +60 (Y/N), maximum grade CRS and ICANS, grade &amp;lt;2 vs 2+, and OS and PFS at 1y. Covariables considered were age at CAR-T, baseline ANC, sex, race, CAR-HEMATOTOX (Rejeski et al. 2021), bridging therapy (Y/N), and number of prior lines of therapy. ANC recovery was defined as grade 2 or better for 3 measurements without growth factor support &amp;gt;2 weeks. Those without ANC recovery and who started new treatment before day +60 were excluded from that analysis. Results: Overall, the median age was 64y (range 21y-85y); 37 (60%) had de novo diffuse large B-cell lymphoma, 17 (27%) had transformed follicular lymphoma, 2 (3%) had MM, 2 (3%) had mantle cell lymphoma, and the remaining patients had other transformed indolent lymphomas. Median prior lines of therapy was 3 (1-12), and only 6% had previously undergone autologous hematopoietic cell transplantation. Systemic bridging therapy prior to CAR-T was required in 27 (44%), and 8 (13%) received radiation as bridging. All received fludarabine and cyclophosphamide for lymphodepleting chemotherapy. Axicabtagene ciloleucel was the most common (76%) CAR-T product, followed by tisagenlecleucel in 16% of patients. Overall, 51 (82%) and 29 (47%) patients experienced CRS and ICANS, respectively. had delayed ANC recovery. One-year PFS was 50% and 1y OS was 73%. Clonal hematopoiesis: 15 (24%) patients had at least one pathogenic CH mutation; 4 (6.5%) had ≥2 CH mutations. Of the 28 CH mutations identified, the most common were DNMT3A (18%), CHEK2 (11%), PMS2 (7%) and ASXL1 (7%); 29% of mutations had VAFs &amp;gt;10%. Outcomes after CAR-T: Patients with CH were significantly more likely to develop grade ≥2 CRS (60% vs. 28%, p=0.03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p=0.027). Accounting for baseline ANC (which was unexpectedly higher among the CH cohort and associated with delayed ANC recovery, p=0.02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p=0.17). There was no association between CH and ICANS, nor with 1y PFS and OS. Conclusion: CH was frequent (24%) in this cohort of CAR-T recipients and was associated with a higher risk of ≥2 CRS after CAR-T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR-T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis Acknowledgements: Funding through the CoH Hematological Malignancies Program Pilot Project Award. The authors acknowledge the work provided by CoH Center for Informatics, notably Research Informatics, and the utilization of the POSEIDON platform and the Honest Broker process.

The Impact of DNMT3A Mutation on Survival of AML Patients Receiving Allogeneic Hematopoietic Cell Transplantation in First Remission Depends on the Karyotype and Co-Occurring Mutations: On Behalf of the EBMT Acute Leukemia Working Party

DNMT3A gene mutations are more frequent in cytogenetically normal acute myeloid leukemia (AML) and frequently associated with NPM1 mutation and internal tandem duplication (ITD) of the FLT3 gene. However, DNMT3A mutation is not included as a distinct prognostic group in the recent European Leukemia Net (ELN) 2022 genetic risk classification of AML. In the context of allogeneic hematopoietic cell transplantation (allo-HCT), the prognostic value of DNMT3A is still not well studied. We evaluated, through the European Society for Blood and Marrow Transplantation (EBMT) registry, the impact of DNMT3A mutation, according to the karyotype, and NPM1 and FLT3-ITD mutation status, on post-transplant outcomes in AML patients receiving allo-HCT in first complete remission (CR1). We identified a total of 1374 adult AML patients (51% female, median age 57 years; range 18-78 years) with ELN-2022 intermediate- or poor-risk cytogenetics and available DNMT3A, FLT3ITD and NPM1 mutation status, who underwent their first allo-HCT in CR1 between 2013 and 2021. Of these, 631 (46%) patients had DNMT3A mutation. Patients with mutant DNMT3A were more likely to be female (57% versus 46%, p&amp;lt;0.001), to have normal cytogenetics (75% versus 54%, p&amp;lt;0.001), FLT3-ITD co-mutation (50% vs 23%, p&amp;lt;0.001), NPM1 co-mutation (60% vs 21%, p&amp;lt;0.001), and to receive a myeloablative conditioning and in vivo T cell depletion. After a median follow-up of 2.3 years, the 2-year leukemia free survival (LFS) and overall survival (OS) were 62% and 69%, respectively. The subsequent analysis was split according to baseline karyotype (normal or abnormal). Among 870 patients with normal cytogenetics, 472 (54%) patients had DNMT3A mutation. The 2-year relapse incidence (RI), LFS and OS were 24%, 63% and 70% respectively, in patients with DNMT3A mutation compared to 18%, 69% and 74% in patients with wild type DNMT3A. Among these patients with normal karyotype, multivariable analyses (MVA) were done within the 4 groups of FLT3-ITD and NPM1 mutations. Within the group of 324 patients with both FLT3-ITD and NPM1 positives, 244 were triple-positive (75%), LFS and OS were not significantly different with and without DNMT3A mutation (2y LFS: 62% vs 63%, HR: 0.98, p=0.95; 2y OS: 70% vs 73%, HR: 1.17, p=0.58). Conversely, among 146 patients with NPM1 mutation without FLT3-ITD, LFS was significantly lower for 91 patients with DNMT3A mutation (2y LFS: 68% vs 87%, HR: 2.70, p=0.02) but OS was not significantly different (2y OS: 79% vs 87%, HR: 2, p=0.13). On the other hand, among 318 with wild type NPM1 and without FLT3-ITD, LFS and OS were not significantly different for 108 patients with DNMT3A mutation compared to 210 patients with wild type DNMT3A (2y LFS: 62% vs 67%, HR: 1, p=0.98; 2y OS: 65% vs 71%, HR: 1.02, p=0.94). Conversely, among 82 patients with FLT3-ITD and wild type NPM1, 2-year LFS and OS were 53% and 58% respectively, for 29 patients with DNMT3A mutation compared to 71% and 76% respectively, for 53 patients with wild type DNMT3A. The number of patients didn't allow to perform MVA in this group. Finally, among 504 patients with abnormal cytogenetics, 159 (31%) patients had DNMT3A mutation. On MVA, DNMT3A mutation did not significantly affect LFS or OS. Poor-risk cytogenetics was associated with worse LFS, OS and increased RI. Older age negatively affected LFS and OS. In conclusion, in AML patients allografted in CR1, the impact of DNMT3A mutation depends on the karyotype and co-occurring mutations. Our data suggest that DNMT3A mutation negatively affects post-transplant survival selectively in patients with normal karyotype and either NPM1 mutation without FLT3-ITD, or patients with normal karyotype, FLT3-ITD and wild type NPM1. DNMT3A mutation shows no impact on post-transplant outcomes in other settings.

TP53 Mutations Detected By Clinical Laboratory Mutation Analysis Predict for Inferior Clinical Outcomes in Patients with Newly-Diagnosed Aggressive B Cell Lymphomas, Including Those with High-Risk Features

Introduction While comprehensive genomic analyses have identified genetic subgroups of diffuse large B cell lymphoma (DLBCL) when retrospectively performed on tumor biopsies (bx) from patients (pts) subsequently treated with R-CHOP (PMID 29713087, 29641966), it is unclear if these or similar assays can be applied in clinical practice. We aimed to determine if mutations (mut) detected in bx from newly-diagnosed DLBCL/high grade B cell lymphoma (HGBL) pts by clinical laboratory mutation analysis (CLMA) could predict for clinical outcomes following receipt of first-line therapy. Methods Pts with newly-diagnosed DLBCL/HGBL from January 2018-June 2022 whose bx underwent CLMA at the Penn Center for Personalized Diagnostics and received standard-dose R-CHOP or R-EPOCH as first-line therapy were included. Exclusion criteria were death due to non-lymphoma causes during first-line therapy and follow-up &amp;lt;1y after diagnosis if in remission. Pathologic workup of bx was performed as per institutional standard. Therapy was given at the discretion of the treating physician. Data were censored on July 1, 2023. Results One hundred thirty-seven pts met inclusion criteria, 15 were subsequently excluded and 117/122 pt bx underwent successful performance of CLMA (96%) with a median turnaround time of 17 days. Baseline characteristics, including mut occurring in ≥10% of cases tested, as well as genetic subgroup classification by LymphGen 2.0 based on available molecular data, are listed in the Table. R-CHOP was received by 72% of pts and R-EPOCH 38% of pts. The overall response rate (ORR) was 84% (complete response rate [CRR] 69%), and with a median follow-up of 31.3 months, estimated (est) 2 year (y) progression free survival (PFS), est 2y overall survival (OS) and est median OS post-relapse were 70%, 83% and 21.4 months (mo), respectively. Univariate analysis (UVA) identified HGBL classification, MYC rearrangement (R) and TP53 mut as significantly predictive of progression at 2y; however, only TP53 mut remained predictive on multivariate analysis (MVA) (HR 2.3, 95% CI 1.1-4.8, P=0.03). Additionally, UVA identified International Prognostic Index (IPI) score ≥3, HGBL classification, MYC-R, MYC-BCL2 double hit lymphoma, TP53 mut and TNFRSF14 mut as significantly predictive of death at 2y; however, only HGBL classification (HR 5.0, 95% CI 1.1-22.7, P=0.04) and MYC-R (HR 4.4, 95% CI 1.0-18.0, P=0.04) remained predictive on MVA. Given that TP53 mut predicted for both progression and death at 2y, we further analyzed bx with this mut. Forty-seven TP53 mut were detected in 42 pt bx, and were characterized as missense (mis) in 34, frameshift (fs) in 5, nonsense (non) in 5 splice site (ss) in 2 and other in 1. Thirty-eight (81%) TP53 mut were deemed loss of function (LOF), either as a mis/non mut designated as non-functional and/or LOF through The TP53 Database (https://tp53.isb-cgc.org/) or a fs/ss mut (PMID 22955915). Characteristics of pts with and without TP53 mut are listed in the Table. Significantly lower rates of ORR (71% vs 90%, P=0.009), CRR (55% vs 77%, P=0.01), est 2y PFS (57% vs 77%, P=0.006), est 2y OS (70% vs 91%, P=0.001) and est median OS post-relapse (6.1 mo vs not yet reached, P=0.001) were achieved by pts with vs without any TP53 mut. Est 2y PFS was 70% vs 33% ( P=0.01) and 2y OS was 85% vs 43% ( P=0.001) for pts with any TP53 mut treated with R-CHOP vs R-EPOCH. Additional analysis incorporating LOF status for TP53 mut revealed that for pts with at least one TP53 LOF mut vs only TP53 non-LOF mut vs no TP53 mut, 2y PFS was 51% vs 86% vs 77% ( P=0.002) as depicted in the Figure and 2y OS was 64% vs 100% vs 91% ( P=0.0004), respectively. Finally, stratified log-rank demonstrated either inferior or a trend towards inferior 2y PFS for pts with vs without TP53 LOF mut harboring high-risk features, including IPI score ≥3 (42% vs 80%, P=0.009), HGBL histology (25% vs 70%, P=0.046), non-GCB cell of origin by Hans algorithm (52% vs 81%, P=0.01), MYC rearrangement (33% vs 48%, P=0.17), MYC-BCL2 double hit lymphoma (40% vs 67%, P=0.34) and EZB genetic subgroup (30% vs 81%, P=0.04). Conclusions TP53 mut identified through CLMA, specifically those resulting in LOF, predict for inferior clinical outcomes in pts with newly-diagnosed DLBCL/HGBL. Results of CLMA can be practically used to inform prognosis and/or identify pts for clinical trials investigating therapies targeting derangements caused by specificmut.

Is Interim PET a Useful and Used Tool in Classical Hodgkin Lymphoma? Results from a Retrospective Multicenter Italian Experience

INTRODUCTION Interim PET (iPET) scan after 2 cycles has been proved a useful tool in order to escalate treatment in the setting of advanced stage (AS) classical Hodgkin Lymphoma (cHL) treated with ABVD as first-line therapy. However, few data are known regarding the use of iPET and the adoption of intensification treatment strategies in real life. MATERIALS AND METHODS We conducted a retrospective, multicenter study in which we collected consecutive, newly diagnosed AS cHL patients (pts) treated between January 2010 and December 2018. Pts could be included if aged 18 to 80 years old, if treated with ABVD/ABVD-like schemes and if pre-treatment and interim PET scans were available. Primary endpoint was the frequence of intensification after a positive iPET. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) of pts undergoing iPET-based intensification strategies. iPET was defined as positive or negative based on the assessment by the local investigator. When available, Deauville Score (DS) was also collected. Continuous covariates were summarized as median, interquartile distance (IQR) and range, categorical variables were summarized as absolute and percentage frequencies. Survival functions were defined as the time between the date of iPET to the date of progression (PFS) or death for any cause (PFS/OS) or last clinic control (PFS/OS) for censored cases. The survival functions were computed by means of Kaplan-Meier method. Comparisons between groups were done using the log-rank test; the effect of covariates was estimated using the Cox proportional hazard regression model and was expressed as hazard ratio (HR), with 95%CI. All the p-values reported were two-sided. RESULTS Detailed characteristics of the 399 enrolled pts are listed in Table 1. iPET was positive in 68 pts (17%), of whom 17 (25%) were immediately shifted to intensified therapies: 8 escBEACOPP (eB), 8 chemo+ASCT (cA), 1 other salvage regimens (oSR). DS was reported in 220 (55%) pts. In iPET-positive pts, DS was reported in 35/68 pts (51,4%): 25 were DS4 and 10 were DS5, respectively. Among the 51 iPET positive pts who didn't change treatment after iPET, 31 (61%) underwent a subsequent iPET after 4 cycles. iPET4 was positive in 17 pts (55%), of whom 12 (70%) were shifted to intensified treatments: 2 eB, 8 cA, 2 oSR. Overall, 29/68 iPET-positive pts (43%) were intensified either immediately after iPET or after a subsequent iPET4 positivity and the most commonly used intensification was cA (16/29 cases). After a median follow up of 6 years (0.2 - 12), 5-y PFS was 76% (95% CI 72 to 80%), and 5-y OS was 94% (95% CI 91 to 96%). In univariable analysis, iPET positivity (5y PFS 60% versus 80% for iPET negative pts, p &amp;lt; 0.001), stage IV, age (continuous form) and not receiving radiotherapy were significantly associated with worse PFS; iPET positivity (5y OS 82% versus 96% in iPET-negative pts, p=0.003), stage IV, age ≥ 60, IPS, B symptoms, male gender and not receiving radiotherapy were significantly associated with worse OS. PFS and OS were similar (p=0.851 and 0.520, respectively) for iPET-positive pts undergoing or not undergoing immediate intensification (59% versus 61%, and 84% versus 81%, respectively) [Figure 1]. The 5-y PFS and OS were significantly different between pts with iPET negativity and iPET positivity, as reported above. Remarkably, among iPET+ pts, no treatment modification after iPET positivity (either after 2 or 4 cycles) was associated with worse 5-Y PFS and OS (72% and 82% respectively) if compared to PET negative pts. Moreover, there were no differences in terms of both PFS and OS for iPET pts who modified treatment after either iPET or iPET4. CONCLUSIONS In AS cHL pts undergoing ABVD first line treatment, iPET positivity is 17%, but few pts shifted to intensification strategies and most pts didn't change treatment and underwent to iPET4. iPET4 was positive in 17/31 pts, of whom 70% shifted to salvage treatments, mainly cA. iPET prognostic role was confirmed, since PFS and OS were strongly correlated with iPET status, but early intensification didn't provide any PFS and/or OS advantages. Due to the high prognostic role of iPET positivity, AS cHL pts might benefit from more intensive first line treatments that could reduce iPET positive cases (e.g. AVD combos with anti-PD1 or brentuximab vedotin) or from more efficacious second line therapies (e.g. Brentuximab Vedotin and/or anti-PD1 based combination strategies)

A Single Center Experience with Using Dose-Adjusted Repoch in Elderly Patients with Large B-Cell Lymphoma

Background: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the predominant regimen for treatment of aggressive large B-cell lymphomas (LBCL). In the CALGB 50303 trial, REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with similar efficacy but increased toxicity compared to RCHOP, however pts with higher risk disease by International Prognostic Index (IPI) had longer progression-free survival (PFS) with REPOCH therapy in the subgroup analysis ( J Clin Oncol, 2019). Providers may be hesitant to use REPOCH therapy in older, frail patients (pts) with high-risk LBCL due to concern for increased toxicity. One study demonstrated that empirically dose-reduced REPOCH (30-50% dose reduction by age group) was effective and well-tolerated in an elderly population ( Ann Hematol, 2018).A separate study showed significantly reduced neuropathy rates without compromised efficacy when vincristine doses in the REPOCH regimen were capped at 0.5 mg/d compared to 0.4 mg/m 2/d ( Leukemia &amp; Lymphoma, 2019). At our institution, vincristine doses are capped at 0.4 mg/d for all pts, and REPOCH dosing is not empirically dose-reduced based for age alone. The aim of this study is to provide additional insights on the safety and efficacy of REPOCH in elderly pts diagnosed with LBCL with a routine vincristine dose cap of 0.4 mg/day (“REPOCH 0.4”). Methods: In this single cohort study, pts with newly diagnosed LBCL that received dose-adjusted REPOCH 0.4 at a single institution from August 2015 to October 2020 were retrospectively reviewed. Pts were excluded if they received fewer than 2 cycles, had CNS disease, transferred to another facility during treatment, or were lost-to-follow-up. Primary endpoints included adverse effects (AEs), overall response rates (ORR) via Lugano staging at end of treatment, 2y PFS, and overall survival (OS). Survival endpoints were estimated via Kaplan-Meier survival analysis. Secondary endpoints included CNS relapse rates and percentage of pts electing for hospice during therapy. Outcomes were descriptively compared to the historical cohort (N=241) in the CALGB 50303 trial receiving R-REPOCH without a vincristine dose cap ( J Clin Oncol, 2019) . Results: Forty-six pts were eligible for analysis (“entire cohort”), 19 of whom were 70 years or older (“70+ cohort”, figure 1). Median age in the entire and 70+ cohort was 67 and 75 years respectively. In the entire cohort, 23.9% of pts were double-hit, 43.5% had a non-germinal center phenotype, and 78.3% had stage III-IV disease. The median number of REPOCH 0.4 cycles received in both the entire and 70+ cohort was 6. In the 70+ cohort, 57.9% of pts were escalated to a dose level (DL) of 2 or 3 with no pts escalated beyond DL 3. Fifty-eight percent of pts in the entire cohort received intrathecal CNS prophylaxis and all pts received pegfilgrastim support. Pts in the entire cohort were older and higher-risk in comparison to the historical cohort as evidenced by IPI risk and double-expressor status. In the entire cohort, REPOCH 0.4 was well-tolerated (figure 2) with grade 3+ neuropathy rates of only 2.2% (5.2% in the 70+ cohort). Febrile neutropenia (all grades) occurred in 19.5% and 15.8% of the entire cohort and 70+ cohort respectively. Only 1 patient in the 70+ cohort experienced acute ejection fraction (EF) decline during therapy. ORR (complete and partial response) in the entire and 70+ cohort were 80% and 74% respectively. Complete response (CR) rates in the entire and 70+ cohort were both 63%. 2y PFS in the entire cohort was 68.3% (median not reached), and the 2y OS in the entire cohort was 82.9% (median not reached) which compares favorably to the 2y OS of 86.5% in the historical cohort. Overall, only 7% of pts elected for hospice and only 4% experienced CNS relapse. Conclusion: Pts with LBCL 70+ years tolerated dose-adjusted REPOCH 0.4 mg/d similarly to the entire cohort of all ages indicating that empiric dose reduction for age alone isn't necessary. CR rates were similar (63%) with pts 70+ years compared to pts in the entire cohort of all ages. REPOCH 0.4 mg/d was observed to have numerically lower rates of grade 3 or higher neuropathy (2.2%) compared to vincristine 0.4 mg/m 2/d (8.4%, J Clin Oncol 2019) and vincristine 0.5 mg/d dosing strategies (4.5%, Leukemia &amp; Lymphoma 2019) . To our knowledge, this is the first report of outcomes with REPOCH using a vincristine dose cap of 0.4 mg/d.

Interaction between Presenting Features, Co-Occurring Mutations, MRD and Induction Treatment Influences Outcome in Adults with NPM1 Mutated AML - an Analysis of 1357 Patients in the UK NCRI AML17 and AML19 Studies

Background NPM1 mutated (mut) AML is considered favourable risk unless associated with FLT3 internal tandem duplication (ITD) or adverse karyotype. However many other genetic and clinical risk factors have been identified, including high white cell count (WCC), secondary disease, co-mutations and presence of a “triple hit” genotype ( NPM1mut, FLT3 ITD and DNMT3Amut). Although alternative classification systems have been proposed, few studies have been large enough to robustly evaluate clinical and molecular subgroups within NPM1mut, and none have incorporated the effects of measurable residual disease (MRD) status or treatment intensity. Therefore, clinical decision making remains challenging and inconsistent. Here, we performed comprehensive genotyping and molecular MRD assessment in two consecutive prospective randomised studies to clarify these issues. Methods NCRI AML17 (2009-2014) and AML19 (2015-2020) were large randomised trials for younger adults with newly diagnosed AML. Induction regimens included DA +/- etoposide (ADE) and FLAG-IDA, with or without Gemtuzumab. Patients underwent sequential MRD assessment by RT-qPCR, and diagnostic DNA samples were analysed by targeted NGS. Overall survival (OS) was calculated with the Kaplan-Meier method, while cumulative incidence of relapse (CIR) considered death as a competing risk. Relapse events included MRD relapse. All reported hazard/odds ratios are from multivariable analyses including age, prior haematological malignancy, prior chemo/radiotherapy, WCC (log transformed), cytogenetic risk and mutation profile ( FLT3 ITD, DNMT3A, PTPN11, N/KRAS, TET2, IDH1, IDH2, WT1, TP53 MDS-related genes). Results 1357 patients with NPM1mutAML were identified, 888 in AML17 and 469 in AML19. 1100 patients had DNA available for panel sequencing, and 981 underwent MRD monitoring of whom 737 had an evaluable post course 2 (PC2) peripheral blood (PB) sample. Morphological remission (CR+CRi) was achieved in 1264/1357 patients (93%) and PC2 PB MRD negativity in 594/737 (81%). We confirmed the adverse impact of PB PC2 MRD positivity: 3y CIR was 65% vs 29% in those MRD- (p&amp;lt;0.001), and 3yr OS was 40% vs 79% (p&amp;lt;0.001). For PB PC2 MRD+ patients, CIR was &amp;gt;50% in all subgroups. There was a lower rate of PC2 PB MRD negativity in patients with high presenting WCC (OR 1.14, p=0.05), FLT3 ITD (OR 2.58, p&amp;lt;0.001), DNMT3Amut (OR 2.2, p&amp;lt;0.001) and WT1mut (HR 2.04, p=0.02). There was no effect of FLT3 allelic ratio, while patients with both FLT3 ITD and DNMT3A mutations had the lowest rate of MRD- (64%, Figure A). Of the 594 PC2 MRD- patients, we observed higher 3y CIR in patients with high WCC (HR 1.14, p=0.01), DNMT3Amut (HR 1.83, p=0.001), WT1mut(HR 1.96, p=0.01) and IDH1mut (HR 1.9, p=0.002), and lower CIR in patients with N/KRASmut(HR 0.53, p=0.01). Although presence of FLT3 ITD alone was not associated with CIR (HR 0.88, p=0.7), patients with both FLT3 ITD and DNMT3A mutations had 3y CIR from MRD- of 40% (HR 1.74, p=0.03). MDS-related gene mutations had no impact on achieving MRD-, nor relapse from MRD-. Considering all patients, OS was poorer with increasing age (HR 1.03, p&amp;lt;0.001), WCC (HR 1.07, p&amp;lt;0.001), adverse karyotype (HR 2.48, p=0.01), FLT3 ITD (HR 1.34, p=0.01), DNMT3Amut (HR 1.56, p&amp;lt;0.001) and WT1mut(HR 1.71, p&amp;lt;0.001). 3y OS was 52% in patients with both FLT3 ITD and DNMT3Amut, 63% with FLT3 ITD only, 67% with DNMT3A only and 75% with neither. Considering MRD- patients, only age (HR 1.02, p=0.04), DNMT3Amut(HR 1.75, p=0.007) and WT1mut (HR 1.8, p=0.048) remained associated with OS. There was no benefit to CR1 allogeneic transplant in MRD- patients (HR 0.83, 95%CI 0.51-1.34, p=0.4), including in any subgroups (heterogeneity p=0.9). Compared with other treatments, FLAG-Ida increased MRD- (87% vs 79%, p=0.009), reduced relapse from MRD- (16% vs 34%, p&amp;lt;0.001) and improved 3y OS (79% vs 63%, HR 0.52, p&amp;lt;0.001). The OS benefit of FLAG-Ida was greatest in patients with at least one of the features associated with failure to achieve MRD- and relapse from MRD- (high WCC, triple hit or WT1mut, HR 0.39 95%CI 0.26-0.58, heterogeneity p&amp;lt;0.01). Conclusion The “triple hit” ( NPM1, DNMT3A and FLT3 ITD) genotype, WT1mut and high WCC were associated with poor outcomes, due to a lower probability of achieving MRD-, and a higher relapse risk from MRD- remission. Survival was improved for patients receiving intensified induction with FLAG-Ida including patients in these high-risk groups.

Outcomes of Allogeneic HSCT in Elderly Patients (70 years old and above) -a Canadian Experience

Introduction: Allogeneic hematopoietic cell transplant (alloHCT) in elderly patients is a challenge, as with increasing age, there is higher incidence of co-morbidities and pre-frail status. In our recent study on alloHCT in patients 60 years (y) or older, those who were 70y or more had worse outcome and high 2-y non-relapse mortality (NRM) of 53% (Al-Shaibani E et al. Ann Hematol, 2023, 102: 917-926). We therefore implemented a number of changes to improve outcomes in elderly patients undergoing alloHCT. In this study, we analyze transplant outcomes in patients ≥ 70 y, and compare the earlier cohort with the more recent cohort. Methods: This is a retrospective analysis of all consecutive patients 70y or older, who had an alloHCT from Jan 2015 to Dec 2022. We compared those who underwent an alloHCT from 2015-2019 (Cohort A, n=44) with those who had a transplant from 2020-2022 (Cohort B, n=40). The median age of the patients was 71y (range 70-76). The underlying diagnosis was mainly a myeloid malignancy (AML, MDS, MPN, CMML, n=82; lymphoid (ALL, TPLL, n=2). There were 54 males. Stages of disease at transplant were in CR1 (n=51), CR2 (n=4) or stable disease (n=15, MDS, MPN or CMML pts). All patients received RIC regimens for conditioning including Flu4/Bu2/TBI200 (n=73), Flu4/Treo30 (n=7) and Flu/Treo42 (n=3). The GVHD prophylaxis regimens used included ATG2/PTCy/CSA (n=32), ATG4.5/PTCy/CSA (n=35), ATG4.5/CSA/MTX (n=7), ATG2/CSA/MTX (n=3). The donors were either matched related (n=10), matched unrelated (including minor mismatch) (n=57) or haploidentical (n=16). Graft source was peripheral blood in all except one who received bone marrow. (Details in Table). The overall survival (OS), event free survival (EFS), NRM, cumulative incidence of relapse (CIR), incidence of acute and chronic GVHD, length of transplant hospitalization and the number of hospital re-admissions in first 6 months were assessed. The Kaplan Meier curves were plotted for OS and EFS for the overall sample, as well as stratified by the two eras (cohort A and B) and the differences assessed using log-rank tests. Cumulative incidence curves for NRM and CIR were generated, and differences assessed using Gray's K-sample. Results: For all patients transplanted in 2015-2022, the 1-year OS was 53%, the 1-year EFS was 45% and the 1-year NRM was 35%. The median number of days of transplant hospitalization for the whole population was 33.5 days (range 16 - 116). The incidence of grade I-II aGVHD was 32%, and grade III-IV aGVHD was 9.5%; mild to moderate cGVHD was 14% and severe cGVHD was 2%. The 1-year CIR was approximately 18%. Comparing the two cohorts A and B, the 1y OS was 45% vs 62% (p=0.10) respectively; the 1-year EFS was 37% vs 58% (p=0.07) respectively and the 1-year NRM was 45% vs 23% (p=0.04) respectively (Figures attached). The incidence of GVHD and CIR were similar in both cohorts, despite reducing the ATG dose in cohort B. Conclusions: Our study shows that there were statistically significant improvements in NRM and a trend towards improvement in the OS and EFS in the patients transplanted during 2020-2022 compared to patients undergoing alloHCT from 2015-2019. This improvement may be due to one or more changes implemented in recent years, although it is not possible to identify a single factor. These changes were (a) introduction of Frailty testing in all patients (Salas MQ et al. BMT. 2021; 56:60-69). (b) capping the CD34 cell dose in grafts (c) introduction of Treosulfan for selected indications (MDS/CMML) (Pasic I et al. Leuk Res 2023, 128: 107131). (d) Letermovir for CMV prophylaxis (e) reducing ATG dose for GVHD prophylaxis and (f) focus on diet, nutrition, exercise. While alloHCT should be offered to medically eligible elderly patients, there is a special need to minimize the risks that are part of age related vulnerabilities.

Interest of Cytoreductive Therapy before Allogenic Hematopoietic Stem Cell Transplantation in Childhood Myelodysplastic Syndromes: A Retrospective Study on Behalf of the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)

Background: Pediatric myelodysplastic syndromes (cMDS) are rare and biologically different from that seen in adults. In addition to a specific genomic landscape, they are characterized by the high frequency of hypoplastic forms, and the recurrent association with germline predispositions (Khoury et al. 2022; Locatelli et Strahm 2018). For most patients, allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option. In case of cMDS with increased blasts (cMDS-IB), pre-tranplant cytoreductive chemotherapy may be considered, but remains controversial (Strahm et al. 2011). Methods This multicenter retrospective study included all cMDS patients (&amp;lt;18y.o.) reported to the SFGM-TC registry who underwent an allo-HSCT between 2000 and 2020. Data have been obtained through ProMISe (internet-based system shared by all EBMT transplantation centers). All patients have given signed informed consent. Results Eighty-four cMDS patients from 17 centers were included. Median age at transplant was 10.2 years (IQR: 7.2, 14.2). Fifty-two percent of patients presented with increased blasts at diagnosis. Germline predispositions were known in 24% of patients. GATA 2 mutations were the most frequent (14%). Eighty-two percent of patients presented with hematologic cytogenetic abnormalities, including 64% of monosomy 7. Myeloablative conditioning was used in most of cases (91%). Busulfan/melphalan was the most frequent conditioning regimen (58%). HSCT were performed from sibling donors in 29% of the cases, matched unrelated donors (MUD) in 44%, umbilical cord blood (UCB) in 21% and haploidentical in 6%. Stem cell source was bone marrow in 68% of the cases. Considering the whole cohort, 5y overall survival (OS) and disease-free survival (DFS) were 67% (IC95% 57-78%) and 63% (IC95% 54-74%) respectively (Figure 1). Five years cumulative incidences of non-relapse mortality (NRM) and relapse were 26% (IC95% 17-35%) and 12% (IC95% 5.6-20%) respectively. Of the 21 cases of reported toxic death, 15 were related to acute GVH (aGVHD). Six months cumulative incidences of grade II-IV and III-IV acute graft vs host disease were 46 % and 24 % respectively. In univariate analysis, patients under 12 years (p=0,018) or who received a BuCyMel conditioning (p=0,004) or a graft from a MUD (p=0,030) had worst 5y OS and PFS. As expected, OS increased with time (p=0,014) reflecting improvements in supportive care and HSCT procedures (Figure 2A). These results were confirmed in multivariate analysis, except for MUD. Twenty-four patients received pre-transplant cytoreductive therapy, most often intensive chemotherapy (20/24). In the overall population, pre-transplant cytoreduction was not associated with an improved survival. However, subgroup analysis of the 40 patients with cMDS-IB showed a significant improvement of the OS probability (HR 0.18 [0.04-0.83], p=0.014) in patients who received a pre-transplant cytoreductive therapy in univariate analysis (Figure 2B). Cytoreductive therapy did not appear to be associated with a reduced risk of relapse, but with a lower risk of NRM. Although not statistically significant, the incidence of aGVHD was higher in patients who did not receive any cytoreductive therapy (HR 0.60 [0.09-3.85]). Conclusion: This retrospective study reports the outcomes of 84 patients who underwent allo-HCT for childhoodMDS. This study seems to show a benefit associated with the pre-transplant cytoreduction therapy in the subgroup of patients with cMDS-IB, notably through a reduction of aGVHD and NRM occurrence. BuCyMel conditioning, currently recommended for cMDS-IB, appears here, to be associated with excess of toxic mortality. This study also confirms the high aGVH-related toxic mortality rates already reported in cMDS (Strahm et al. 2011). Recent retrospective data have shown a benefit of post-transplantation cyclophosphamide (PTCy) in GATA2 patients transplanted with sibling or matched unrelated donors (Nichols-Vinueza et al. 2022). Prospective data on the use of PTCy in cMDS are therefore needed. Acknowledgment: This research is funded by the non-profit organization Etoile de Martin/SFCE.

The Benefit of Allogeneic Transplant in 1 st Complete Remission in NPM1 Mutated AML with or without FLT3 ITD Is Restricted to Those Testing MRD Positive after Induction - an Analysis of the UK NCRI AML17 and AML19 Studies

Background While there is accumulating evidence that measurable residual disease (MRD) negative patients with intermediate risk AML may not benefit from allogeneic transplantation in 1 st complete remission (CR1-allo), many consider the presence of a FLT3 Internal Tandem Duplication (ITD) an indication for this procedure. However, the studies supporting this practice were mainly performed before the development of sensitive molecular MRD techniques (Schlenk NEJM 2008).The UK NCRI AML17 and AML19 trials studied, then incorporated, MRD by RT-qPCR into the management of patients with NPM1 mutated AML. Methods NCRI AML17 (April 2009 to December 2014) and AML19 (November 2015 to November 2020) were sequential prospective randomised trials for younger adults (18 - 60 years) with newly diagnosed AML. In AML17, decisions regarding CR1-allo were made using a validated risk score incorporating baseline factors and response to induction. In AML19, for patients with NPM1 mutated AML ( NPM1mut) the protocol recommended CR1-allo only in patients testing MRD positive in the peripheral blood (PB) post cycle 2 (PC2), regardless of other baseline risk factors such as FLT3 ITD, based on findings from AML17 (Ivey et al, NEJM 2016). Both trials were performed prior to the availability of midostaurin and FLT3 ITD MRD assays. Here we compare the outcomes of patients with NPM1mut in these trials and assess the benefit of CR1-allo according to FLT3 ITD and molecular MRD status. Time-to-event variables are analysed using the Kaplan-Meier method, and the impact of alloSCT assessed using time-dependent Cox regression and visualised with Simon-Makuch plots. Molecular relapses were included as relapse events, and alloSCT performed after molecular relapse was not considered as CR1. Results 737 patients with NPM1mutAML who achieved CR/CRi and had a valid PC2 PB MRD result were included in the analysis. 60/348 (17%) patients from AML17 and 83/389 (21%) from AML19 tested PB PC2 MRD positive. Overall, CR1-allo was performed in 20% of patients in AML17 and 25% in AML19. Of the MRD positive patients CR1-allo was performed in 16/60 (27%) in AML17 compared to 50/83 (60%) in AML19 where these patients were recommended for transplant. CR1-allo was performed in 18% and 16% of MRD negative patients in AML17 and AML19 respectively. In AML17, as previously reported (Ivey et al, NEJM 2016), patients who were MRD+ had poor outcomes, with 3-year cumulative incidence of relapse (CIR) of 84% and overall survival (OS) of 25%. These outcomes were improved in AML19, with 3y CIR 50% and 3y OS 51%. Across both trials, CR1-allo was associated with a significant survival benefit in MRD+ patients (3y OS 61% vs 24%, HR 0.42, 95%CI 0.26-0.69, p&amp;lt;0.001, Figure A). Patients who were MRD negative had excellent outcomes in both trials (3y CIR 33% and 24% and 3y OS 75% and 83% for AML17 and AML19 respectively). AlloSCT in CR1 provided no survival advantage for MRD- patients (HR 0.83, 95%CI 0.51-1.34, p=0.4). There were a total of 286 patients with NPM1mutFLT3 ITD mut AML with a PC2 PB MRD result across both trials. 81/286 (28%) were PB PC2 MRD+ of whom 32/81 (40%) received CR1-allo (28% in AML17 and 49% in AML19). Outcomes in these high-risk patients were improved in AML19, with 3y CIR 91% vs 68% and 3y OS 22% and 31% for AML17 and AML19 respectively. Those who received CR1-allo had improved outcomes (3y OS 45% vs 18%, HR 0.52, 95% CI 0.29-0.93, p=0.03) consistent with the overall MRD+ population. In the 70% of NPM1mutFLT3 ITD mut AML patients who achieved PB PC2 MRD-, outcomes were encouraging in both AML17 (3y CIR 37%, 3y OS 75%) and AML19 (3y CIR 27%, 3y OS 80%). CR1-allo was performed in 20% (19% in AML17, 21% in AML19), with no survival benefit for transplant (HR 0.80, 95% CI 0.37-1.72, p=0.6, Figure B). There remained no benefit when restricted to those with high (&amp;gt;0.5) FLT3 ITD allelic ratio (HR 0.63, 95% CI 0.2 - 2.23, p = 0.50) and there was also no evidence of an interaction between allelic ratio and benefit from transplant for MRD negative patients (p=0.86). Conclusion Molecular MRD can be used to stratify decision making concerning post remission therapy in patients with NPM1mut AML. Patients who achieve MRD negativity in the peripheral blood by the end of course 2 are at low risk of relapse and we found no evidence of benefit from allogeneic transplant in CR1, including in the subset with FLT3 ITD. This finding contrasts with MRD+ patients where there was a significant survival benefit for CR1 transplant.

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with Ph/BCR::ABL Negative B-Precursor Adult Lymphoblastic Leukemia (ALL): Preliminary Results of the GMALL Bold Trial

Older patients (pts) with newly diagnosed ALL are ineligible for unmodified pediatric-based therapies. Although results are improved with age-adapted, dose-reduced regimens including MRD-based treatment modification, there is much space for further improvement.Therefore, the GMALL study group developed a trial to evaluate Blinatumomab, a CD19 directed bi-specific T-cell engager, in sequence with chemotherapy in this patient population with high medical need (NCT 03480438). Importantly, Blinatumomab replaced three cycles of standard consolidation chemotherapy.Pts aged 56 - 76 years (yrs) with CD19-positive, Ph-neg B-precursor ALL wereeligible. The primary endpoint was complete hematologic remission (CR) afterinduction (1 cycle chemo, 1 cycle Blinatumomab) and the key secondary endpoint was molecular response (table 1). The efficacy population included pts treated with dose reduced and shortened induction I (IP1) and Blinatumomab 1 or early death (ED). Induction was followed by 3 further Blinatumomab cycles alternating with age adapted consolidation cycles (HDMTX/ASP, HDAC, reinduction and maintenance) according to GMALL protocols for older pts (Gökbuget et al, ASH 2021). The median age was 66 (56-76) yrs. 21% had pro-B-ALL and 79% c/preB subtype. 40% had comorbidities according to the Charlson Score; most frequent were diabetes (13%) myocardial infarction (10%) or vascular diseases (10%). 50 pts were evaluable for IP1: 76% achieved CR/CRu and 2 pts (4%) died due to infections. 33% (N=11) had a molecular response and 18% MolCR (table 1). 47 pts were evaluable for the primary endpoint after Blinatumomab 1: CR/CRu was observed in 85%; 2 experienced ED (4%; those mentioned above; no additional ED). 88% of the CR pts had a molecular response (82% MolCR). The median follow-up is 757 (61-1584) days. Overall Survival (OS) after 1 and 3 yrs was 80% and 67% for the efficacy population (figure 1). The resp results for the total population were 82% and 65%. The 3y OS was 69% for c/pre-B-ALL and 58% for pro-B-ALL (p&amp;gt;.05). 3y OS was 81% for pts aged 55-65 yrs and 53% for those older than 65 yrs (p=.025). Only three pts received an allogeneic stem cell transplantation in CR1. 6 pts relapsed, 2 pt developed a secondary malignancy (Colon Ca, MDS) and 3 pts died in CR (1 HLH, 1 arterial disease, 1 Covid19). EFS was 60% at 3 yrs. We compared the results with those of the current GMALL standard therapy for older pts with B-precursor ALL (N=186) (Gökbuget et al, ASH 2022). Patient characteristics were similar. CR rates after induction were 85% vs 78% for BOLD vs standard (p&amp;gt;.05). Molecular CR rates in pts with hematologic CR were 82% vs 55% (p=.006). OS at 3 yrs was 67% and 49% (p=0.08) and Remission Duration (RD) was 83% vs 58% (p=0.055). Overall tolerability and efficacy of the regimen was very promising with a high hematologic and molecular response rate; mortality in induction and consolidation was low. In comparison with the current standard therapy the MRD response rates were significantly better. OS and RD was superior despite the omission of several chemotherapy cycles in contrast to other trials with unmodified chemotherapy but additional cycles of Blinatumomab. An ongoing randomized trial (NCT04994717) compares an even more dose reduced combination of Blina and chemotherapy with standard of care. This is an independent academic trial initiated by the GMALL Study Group which received free supply of Blinatumomab and financial support by Amgen.

Longitudinal Blood Count Analysis Reveals That Poor Graft Function after Pediatric Hematopoietic Cell Transplantation Is a Common Complication Associated with Poor Outcome

Background Poor graft function (PGF) is an important complication of allogeneic hematopoietic cell transplantation (allo-HCT), predisposing to infections, bleeding complications and mortality. The reported incidence and outcome of PGF differ between studies, which may partially be explained by differences in patient cohorts and HCT strategies. Pediatric HCT differs from the adults setting in several aspects, such as the underlying disease and use of relatively young donors, including cord blood. To date, however, information on the incidence and outcome of PGF in pediatric HCT recipients is limited. Aim To determine the incidence, risk factors and outcome of poor graft function in pediatric HCT recipients. Methods Longitudinal blood count and transfusion data from 63.219 measurements were retrieved from the Utrecht Patient Oriented Database (ten Berg et al., Clin Chem Lab Med, 2007) to investigate PGF in pediatric recipients of a first HCT. Patients with less than 5 measurements within the first 30 days or 10 measurements within the first 100 days post-HCT were excluded. In line with published definitions, PGF was defined as cytopenia and/or transfusion dependence for 3 consecutive days after day 28 in ≥2 lineages simultaneously, and patients with relapse, grade III-IV GvHD and/or rejection were excluded (Müskens et al., Blood Reviews, 2023). Cytopenias were defined as thrombocytes &amp;lt;20x10 9/L, neutrophils &amp;lt;0.5x10 9/L and hemoglobin &amp;lt;7 g/dL (Kong et al., Biol Blood Marrow Transplant, 2013). Individual and cohort-wide reconstitution patterns of thrombocytes, neutrophils, and hemoglobin after HCT were analyzed and used to identify patients with PGF. Cumulative incidence and survival analyses were conducted using the {survival} R package. Probability of overall survival (OS) and event-free survival (EFS), defined as retransplantation-free, stem-cell-boost free survival, were calculated using the Kaplan-Meier estimate and compared at one year using the log-rank test. Risk factors for PGF and EFS were assessed in univariable and multivariable Cox proportional hazard models. Results Among 348 pediatric recipients who met the inclusion criteria, we identified 53 patients that fulfilled the criteria for PGF, resulting in a cumulative incidence of 0.15 (95% confidence interval (CI): 0.11-0.18). Risk factors for PGF included HCT for hematological disease (p = 0.03) and from an HLA-mismatched donor (p &amp;lt; 0.01). No difference in PGF incidence was observed between recipients of cord blood and bone marrow donors. The one-year OS (1Y OS) of patients in the PGF group was 71% (95% CI: 59-85%), compared to 91% (95% CI: 87-94%) in the good graft function (GGF) group (p &amp;lt; 0.0001, Figure 1A). Infectious disease was the cause of death in 47% in the PGF group, compared to 27% in the GGF group (p = 0.21). The 1Y EFS was 53% (95% CI: 41-68%) in the PGF group, compared to 90% (95% CI: 86-93%) in the GGF group (p &amp;lt; 0.0001, Figure 1B). Conclusion PGF is a common complication in pediatric HCT recipients. No difference in PGF incidence was observed between bone marrow and cord blood grafts. Both patient-specific (underlying disease) and donor-specific (HLA-matching) may contribute to its pathophysiology. PGF patients show a marked reduction in overall and event-free survival, highlighting the need for therapeutic strategies to prevent and/or treat PGF after HCT.

Real-world clinical outcomes in a U.S. Asian population with stage IV NSCLC treated with osimertinib (Osi) stratified by EGFR subtype.

e21128 Background: EGFR mutations are observed in 40-50% of Asian populations with NSCLC compared to 10-15% in Caucasian populations, with EGFR exon 19 deletion (ex19del) and exon 21 L858R as the most common activating mutations. The FLAURA trial demonstrated PFS and OS benefit of osi, a 3rd generation tyrosine kinase inhibitor (TKI), compared to earlier generation TKIs with a median PFS (mPFS) of 19 months (mos) and overall survival (OS) of 38.6 mos. Subgroup analysis, however, suggested this survival benefit was not seen in Asian patients (pts) or in pts with the L858R mutation. Further analysis of the 322 Asian pts enrolled at Asian sites demonstrated a mPFS of 16.5 mos (HR 0.54, p &lt; 0.0001) with osi compared to 11.0 mos with SOC EGFR TKI, but no difference on two-year OS (2y OS) (HR 0.65, 95% CI 0.42-1.02). We evaluated the 2y OS in Asian pts treated in the U.S. with stage IV NSCLC with first-line (1L) osi. We further explored the 2y OS of Asian pts who received an earlier generation EGFR TKI prior to osi. Methods: We conducted a single institution IRB-approved retrospective study of Asian pts treated at NYU Perlmutter Cancer Center with stage IV NSCLC with EGFR ex19del or L858R mutations treated with osi from 1/1/2010 – 2/1/2021. 2y OS was compared based on EGFR mutations and receipt of 1L osi vs an earlier generation EGFR TKI prior to osi (TKI-pretreated). Log-rank test was used to calculate the P values of Kaplan-Meier curves subgroups. Cox proportional-hazards model was used to investigate the association between the survival time of pts and multiple predictor variables including age, sex, EGFR subtypes (L858R or ex19del) and smoking status. Results: Of 117 total cases: 85 (73%) were female, 32 (36%) were male. 57 (49%) had ex19del and 60 (51%) had L858R. 94 (80%) were nonsmokers. Age range at diagnosis with stage IV disease was 31-96 years. The analysis revealed no significant difference in 2y OS observed between the 1L osi vs. TKI-pretreated groups (HR 1.90, 95%CI 0.93-3.89). However, the subgroup analysis showed that the 2y OS was inferior in the 1L osi group compared to the TKI-pretreated group in pts with ex19del (HR 2.99, 95%CI 1.12 -7.96), but not in those with L858R (HR 1.29, 95%CI 0.43-3.86). No significant effect on 2y OS was observed from age (p = 0.19), sex (p = 0.50), EGFR subtype (p = 0.19) or smoking status (p = 0.67). Conclusions: In accordance with the FLAURA data, our real-world analysis revealed that Asian pts treated with 1L osi was comparable to pts treated with 1st- or 2nd- generation TKIs. Furthermore, our data showed that the use of 1L osi had a lower 2y OS in Asian pts with ex19del compared to those pre-treated with TKIs, but this was not the case with L858R. Although small numbers, the results suggest that ex19del and L858R should be considered differently when considering 1L treatment options and further investigation into alternative options, such as combination therapies, warrants exploration.