Terms Of Progression-free Survival Research Articles

The Age of Immune-therapy in Multiple Myeloma with a Collective Goal for a Cure

Since the year 2000, we have seen unprecedented improvement in newly diagnosed multiple myeloma in terms of progression-free survival and a doubling of overall survival in 2009 from 2.5 years to 5 years. Patients treated now expect a median survival of 7.5 years, while those receiving quadruplet therapy, stem cell transplant, and consolidation and maintenance therapy have an expected survival up to 11 years. Factors contributing to these improved outcomes include novel agents, antibodies, B-cell Maturation Agent-directed therapy, chimeric antigen receptor T-cells, bispecific antibodies, selective use of stem cell transplant, and supportive care measures such as bisphosphonates, prophylactic antimicrobials, cytokines, and intravenous immunoglobulins. Incorporation of these novel therapies in conjunction with increasing understanding of the genomic landscape of multiple myeloma and the evolving use of minimal residual disease negativity should persuade the oncology community to treat patients with high-risk smoldering multiple myeloma and guide treatment of early relapse in patients with newly diagnosed multiple myeloma. Here, we review early interventions within the context of genomic changes, minimal residual disease status, and strategies for treating high-risk smoldering multiple myeloma and standard and high-risk newly diagnosed multiple myeloma to improve progression-free survival, overall survival, and provide context for which patients may be considered cured.

Comparison of Treatment Outcome in EGFR Positive and Negative Patients with Non Small Cell Lung Cancer: A Longitudinal Study

Introduction: Lung cancer is one of the most common malignancies to occur worldwide. Two main subtypes of lung cancer include small cell lung cancer and Non Small Cell Lung Cancer (NSCLC). Patients with advanced stage NSCLC who achieve good response with Tyrosine Kinase Inhibitors (TKI) have been found to have Epidermal Growth Factor Receptor (EGFR) mutation. The first biomarker identified for targeted treatment in lung cancer was EGFR and patients of NSCLC with EGFR mutation have superior survival outcome when treated with targeted therapy as compared to conventional chemotherapy. Aim: To compare the outcome of targeted therapy to mutation to EGFR and conventional therapy in non mutant lung cancer patient of NSCLC. Materials and Methods: The present longitudinal study was conducted in the Department of TB and Respiratory Diseases, Jawaharlal Nehru Medical College and Hospital, Aligarh, Uttar Pradesh, India from July 2017 to November 2019 on a sample size of 80. Patients diagnosed with NSCLC and EGFR mutation status were included in the study. They were started on TKI if tumour was EGFR positive and on conventional chemotherapy (cisplatin plus paclitaxel) if no mutation was detected on histopathology. Among the study group, 35 patients were EGFR positive and started on geftinib (group I), 45 were EGFR negative and received platinum-based chemotherapy (group II). Outcomes were measured in terms of progression-free survival, Overall Survival (OS), and toxicities. Statistical analysis of data was done using Statistical Package for the Social Sciences (SPSS) version 20.0. Results: Among the study group, 35 patients were EGFR positive and started on geftinib (Group I), 45 were EGFR negative and received platinum-based chemotherapy (group II). The mean age of EGFR positive patients was 58.91 years and for EGFR negative patients was 60.11 years. In group I, there was no complete response while 28.5% had partial response, 45.5% had stable disease and 25.7% had progressive disease. In group II, 15.5% patients had complete response, 33.3% had partial response,17.7% had stable disease and 33.3% had progressive disease. Mean progression-free survival in group I (5.65 months) was significantly higher than group II (4.26 months). The mean OS in group I (7.85 months) was slightly higher than group II (6.72 months). Both haematological and non haemaotlogical toxicities were significantly higher in group II. Conclusion: Patients with EGFR positive expression subjected to Gefitinib had significant mean progression-free survival with an acceptable range of non haematological toxicities and no haematological toxicities, as compared to the EGFR negative patients on conventional chemotherapy.

Systemic treatment with or without ablative therapies in oligometastatic breast cancer: A single institution analysis of patient outcomes

PurposeLocal ablative treatment (LAT) is increasingly combined with systemic therapy in oligometastatic breast cancer (OMBC), without a high-level evidence to support this strategy. We evaluated the addition of LAT to systemic treatment in terms of progression-free survival (PFS) and overall survival (OS). Secondary endpoints were local control (LC) and toxicity. We sought to identify prognostic factors associated with longer OS and PFS. Methods and materialsWe identified consecutive patients treated between 2014 and 2018 for synchronous or metachronous OMBC (defined as ≤ 5 metastases). LAT included stereotactic body radiation therapy (SBRT) and volumetric modulated arc therapy (VMAT), surgery, cryotherapy and percutaneous radiofrequency ablation (PRA). PFS and OS were calculated, and Cox regression models analyzed for potential predictors of survival. ResultsOne hundred two patients were included (no-LAT, n = 62; LAT, n = 40). Sixty-four metastases received LAT. Median follow-up was 50.4 months (95% CI [44.4; 53.4]). One patient experienced grade 3 toxicity in the LAT group. Five-year PFS and OS were 34.75% (95% CI [24.42–45.26]) and 63.21% (95% CI [50.69–73.37]) respectively. Patients receiving both LAT and systemic therapy had longer PFS and OS than those with no-LAT ([HR 0.39, p = 0.002]) and ([HR 0.31, p = 0.01]). The use of LAT, HER2-positive status and hormone-receptor positivity were associated with longer PFS and OS whereas liver metastases led to worse PFS. ConclusionsLAT was associated with improved outcomes in OMBC when added to systemic treatment, without significantly increasing toxicity. The prognostic factors identified to extend PFS and OS may help guide clinicians in selecting patients for LAT.

Loco-Regional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancer Patients Undergoing Front-Line Chemotherapy.

Loco-regional therapy (LRT) in de novo metastatic breast cancer (MBC) has been investigated in several clinical trials, with heterogeneous and conflicting results. We conducted a retrospective study of de novo MBC patients treated with front-line chemotherapy (FLC) followed by LRT of the primary tumor. Our aims were to evaluate the characteristics, treatment, and oncological outcomes in terms of progression-free survival (PFS), distant progression-free survival (DPFS), and overall survival (OS) of de novo MBC. We also investigated possible subgroups of patients with better outcomes according to menopausal status, biological sub-type, location, number of metastases, and radiologic complete response after FLC. We included 61 patients in the study. After a median follow-up of 55 months, disease progression occurred in 60.7% of patients and 49.2% died. There were no significant differences in PFS, DPFS, and OS between different subgroups of de novo MBC patients. A trend toward better PFS and DPFS was observed in triple-positive tumors, without a statistically significant difference in OS. No specific subgroup of de novo MBC patients showed a statistically significant survival advantage after FLC followed by LRT of the primary tumor.

Efficacy and Safety of First-line Carboplatin-paclitaxel and Carboplatin-gemcitabine in Patients With Advanced Triple-negative Breast Cancer: A Monocentric, Retrospective Comparison

BackgroundPlatinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear. Materials and MethodsWe evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates. ResultsOf 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009). ConclusionCG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.

The effect of concomitant use of proton pump inhibitors with CDK 4/6 inhibitors on survival in metastatic breast cancer

To evaluate the difference of progression free survival between the patients using concomitant proton pump inhibitors and non-users in the patients using CDK 4/6 inhibitors with HR + and HER2 negative mBC. We included 86 patients with HR + and HER 2 negative mBC treated with CDK 4/6 inhibitors in this study. Patients were divided into two categories according to their status of PPI use. The primary end points was progression free survival (PFS). We compared PPI users and non-users. Forty-five (52.3%) patients used a PPI concomitantly with a CDK 4/6 inhibitor, and 41 (47.7%) did not. The median duration of follow-up was 10.68 (1.94-27.56) months. Of the patients, 50 (58.1%) palbociclib and 36 (41.9%) received ribociclib. The median progression free survival (mPFS) was 10.9months (95% CI: 7.5-14.27) in the group with concomitant PPI use with a CDK 4/6 inhibitor, whereas the median progression free survival could not be reached in the group without concomitant PPI use (p = 0.04). In addition, concomitant PPI use with palbociclib was associated with a shorter PFS; there was no significant difference between the concomitant PPI users and non-users in terms of PFS in the patients using ribociclib. Palbociclib and ribociclib are weak base drugs so their bioavailability is pH-dependent. PPIs can affect their solubility and their concentration in the plasma. Therefore, we must avoid concomitant use of PPIs and CDK 4/6 inhibitors. If we need to use concomitant PPI and CDK 4/6 inhibitors, we should prefer ribociclib than palbociclib.

A Comparison of Alternative Network Meta-Analysis Methods in the Presence of Nonproportional Hazards: A Case Study in First-Line Advanced or Metastatic Renal Cell Carcinoma

ObjectivesNetwork meta-analysis (NMA) of time-to-event outcomes based on constant hazard ratios can result in biased findings when the proportional hazards (PHs) assumption does not hold in a subset of trials. We aimed to summarize the published non-PH NMA methods for time-to-event outcomes, demonstrate their application, and compare their results. MethodsThe following non-PH NMA methods were compared through an illustrative case study in oncology of 4 randomized controlled trials in terms of progression-free survival and overall survival: (1) 1-step or (2) 2-step multivariate NMAs based on traditional survival distributions or fractional polynomials, (3) NMAs with restricted cubic splines for baseline hazard, and (4) restricted mean survival NMA. ResultsFor progression-free survival, the PH assumption did not hold across trials and non-PH NMA methods better reflected the relative treatment effects over time. The most flexible models (fractional polynomials and restricted cubic splines) fit better to the data than the other approaches. Estimated hazard ratios obtained with different non-PH NMA methods were similar at 5 years of follow-up but differed thereafter in the extrapolations. Although there was no strong evidence of PH violation for overall survival, non-PH NMA methods captured this uncertainty in the relative treatment effects over time. ConclusionsWhen the PH assumption is questionable in a subset of the randomized controlled trials, we recommend assessing alternative non-PH NMA methods to estimate relative treatment effects for time-to-event outcomes. We propose a transparent and explicit stepwise model selection process considering model fit, external constraints, and clinical validity. Given inherent uncertainty, sensitivity analyses are suggested.

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker. The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy. We retrospectively identified 119 patients, most of whom (58%) were KRAS wild type. For each patient we evaluated overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). An exploratory analysis was performed among KRAS mutated patients to investigate the impact of specific KRAS mutations on response and survival outcomes. After a median follow-up of 10.3months, the median OS was 14.9months (95% confidence interval [CI] 7.6-22.7) in wild-type KRAS patients versus 14.7months (95% CI 8.0-19.5) in mutated KRAS patients (p = 0.529). No differences were detected between the two groups in terms of PFS and DCR. Patients with a KRAS G12C mutation reported survival and response outcomes that were not statistically different from those of patients with other KRAS mutations. Our data confirmed that KRAS mutational status is not associated with survival and response outcomes in advanced non-squamous NSCLC patients treated with immunotherapy alone or combined with chemotherapy.

Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun.

KRASp.G12C mutation occurs in 12% of newly diagnosed advanced NSCLC and has recently emerged as a positive predictive biomarker for the selection of advanced NSCLC patients who may respond to novel KRASp.G12C inhibitors. The recent discovery of a new binding pocket under the effector region of KRAS G12C oncoprotein has made direct pharmacological inhibition of the KRASp.G12 mutation possible, leading to the clinical development of a new series of direct selective inhibitors, with a potential major impact on patients' survival and quality of life. Promising efficacy and tolerability data emerging from the early phase CodeBreak trial have already supported the regulatory approval of sotorasib as first in class targeted treatment for the second-line treatment of KRASp.G12C-positive NSCLC population, following immunotherapy-based first-line therapies, while the randomized phase III CodeBreak 200 clinical study has recently confirmed a significant superiority of sotorasib over docetaxel in terms of progression-free survival and quality of life. However, KRAS mutant NSCLC is a high heterogeneous disease characterized by a high rate of co-mutations, most frequently involving P53, STK11, and KEAP1 genes, which significantly modulate the composition of the tumor microenvironment and consequently affect clinical responses to both immunotherapy and targeted inhibitors now available in clinical practice. Both pre-clinical and clinical translational series have recently revealed a wide spectrum of resistance mechanisms occurring under selective KRASG12C inhibitors, including both on-target and off-target molecular alterations as well as morphological switching, negatively affecting the antitumor activity of these drugs when used as single agent therapies. The understanding of such biological background along with the emergence of pre-clinical data provided a strong rational to investigate different combination strategies, including the inhibition of SHP2, SOS1, and KRAS G12C downstream effectors, as well as the addition of immunotherapy and/or chemotherapy to targeted therapy. The preliminary results of these trials have recently suggested a promising activity of SHP2 inhibitors in the front-line setting, while toxicity issues limited the concurrent administration of immune-checkpoint inhibitors and sotorasib. The identification of predictive genomic/immunological biomarkers will be crucial to understand how to optimally sequencing/combining different drugs and ultimately personalize treatment strategies under clinical investigation, to definitively increase the survival outcomes of KRASp.G12C mutant advanced NSCLC patients.

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

Outcomes of Hispanic Vs Non-Hispanic Philadelphia-like B Cell ALL Treated in the Central Valley of California

Background: Philadelphia-like B cell ALL (Ph-like ALL) accounts for a majority of poor outcomes in patients with Ph-negative B cell ALL (Ph- ALL). Ph-like ALL is a heterogeneous subgroup characterized by mutations that involve the tyrosine kinase and cytokine receptor signaling pathways. Prior studies have suggested an increased incidence of B-ALL in the Hispanic community may be attributable to a higher incidence of Ph-like ALL. This is clinically relevant as Ph-like ALL is associated with worse outcomes. Advances in molecular testing have identified Ph-like sub-classifications of at least 4 unique groups. Ph-like ALL outcomes have not been well reported following the approval of novel treatment options such as bispecific antibodies and CAR-T cell therapy. Our prior study in 2020 reported mutational distributions of 8 Ph-like ALL patients out of 16 Ph- ALL cases sequenced. This is a follow up analysis of Ph- ALL patients treated in Fresno, CA (49.6% Hispanic population) both before and after the adoption of novel therapies. Methods: Patients diagnosed with Ph negative B-ALL from 01-01-2008 to 12-31-2021 at Community Medical Centers were included. Patients with available tissue and without molecular sequencing at diagnosis were sequenced by Neo-Genomics (14 patients), Foundation Medicine Hematology (23), other NGS (3), and no sequencing available (14). Demographic and disease relevant information was collected. Data was collected on incidence of cytogenetic and molecular abnormalities, disease spread (CNS involvement, organ involvement), CD20% expression, number of mutations (n<3 vs. n≥3), and number of treatment lines. Chi-square or Fisher's exact test and contingency table were used to compare characteristics of patients with Ph-like mutations vs those without. Kaplan-Meier curves were utilized to compare median progression free survival (PFS) after 1st line therapy and median overall survival (OS). Results: A total of 48 patients were included. 23 patients had Ph-like mutation present vs 25 without. 18 Hispanic patients had Ph-like mutation vs 15 without (p=0.183). The Ph-like group had higher BMI (36.4 vs 30.7, p=0.033) and more patients with ≥3 mutations compared to the non-Ph-like group (p=0.018). The distribution of mutations within the Ph like group were: CRLF (44%), JAK-STAT (39%), ABL (13%), and EPOR/JAK-2 (4%). There were no significant differences between the Ph-like and non-Ph-like groups in mean age at diagnosis (40.1 vs 35 years, p=0.27), CNS disease at diagnosis (17.4% vs 11.5%, p=0.350), CD20+ disease (17.4% vs 30.8%, p=0.098), complete response rates (60.9% vs 70.3%, p=0.223), or median PFS after 1st line therapy (284 vs 467 days, p=0.164). The non-Ph-like group had significantly higher median OS vs the Ph-like group (680.5 vs 377 days, p=0.018). Within the Ph-like group, Hispanic vs non-Hispanic patients did not differ significantly in terms of PFS after 1st line therapy (p=0.426) or OS (p=0.287). Survival analysis of patients before vs during/after the year 2017 showed significantly higher median PFS after 1st line therapy in patients treated during/after 2017 than before (1721 vs 631 days, p=0.037), however without significant median OS difference (1097 vs 819 days, p=0.712). There was no significant median PFS (p=0.166) or OS (p=0.731) difference among Ph-like patients treated before vs during/after 2017. Novel agent use in our study: 8/12 patients (Blinatumomab 7, Inotuzumab 1), 6/9 patients (Blinatumomab 2, Inotuzumab 2 CAR- T 1), 2/3 patients (Inotuzumab 2) in second, third and fourth line respectively. Conclusions: Ph-like ALL patients had worse OS outcomes compared to non-Ph-like patients. A significant proportion of both Ph-like and non-Ph-like patients consisted of Hispanics, confirming the high incidence of B-ALL in this ethnic subgroup reported in prior studies. Our Ph-like patients had significantly higher BMI and number of mutations which could be contributing factors to their worse outcomes compared to non-Ph-like patients. Those treated during/after 2017 had significantly improved PFS after induction; this could be due to the FDA approval of novel agents beginning that year. This however did not translate to a significant OS benefit regardless of Ph-like status. Overall, these results re-emphasize the need for further research involving ethnic subgroups and novel therapies for this high-risk and heterogeneous disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Addition of Romidepsin to CHOEP and High-Dose Chemotherapy Plus Stem Cell Transplantation Did Not Ameliorate the Outcome of Untreated Angioimmunoblastic T-Cell or Follicular T-Helper Lymphoma: Subgroup Analysis of Phase II FIL-PTCL13 Study

Introduction: In the phase Ib/II study PTCL13 study (NCT02223208) we demonstrated feasibility of Romidepsin 14 mg/mq in addition to CHOEP followed by high-dose chemotherapy and stem cell transplantation (SCT), but no benefit was observed in term of progression free survival (PFS), and the enrollment of the trial was stopped due to inefficacy of the experimental combination. Other studies showed Romidepsin activity in relapsed or refractory PTCLs, especially in angioimmunoblastic (AITL) subtype, expecially when combined with azacytidine. On this basis, we conducted a sub-analysis of the PTCL13 trial, with the aim to evaluate the role of adding Romidepsin to CHOEP followed by high dose chemotherapy and SCT in newly diagnosis AITL and T-helper follicular lymphoma patients. Methods: Patients aged 18-65 eligible to SCT, with advanced PTCL-NOS, AITL/T-helper follicular and ALK negative anaplastic large cell lymphoma, were eligible to PTCL13 study. Treatment plan consisted of 6 courses of Ro-CHOEP every 21 days (14 mg/ms Ro day 1 and 8), followed by cisplatin-cytarabine-dexamethasone (DHAP) with stem cell harvest and SCT. Patients in complete response (CR) after induction proceeded to autoSCT, while those in partial response (PR), with an available HLA-matched donor, proceeded to alloSCT upfront. Results: 89 patients were enrolled into the phase Ib and II part of the study; median age was 55 years (IQR 49;60); 78 (91%) had stage III-IV and 31 (36%) IPI risk >2. Pathological materials were collected at the time of diagnosis, and centrally reviewed by expert hemo-pathologist; subgroups were: 34 PTCL-NOS, 21 ALK negative and 31 AITL/THF. The clinical characteristics of the 31 AITL/THF patients were: median age 56 years (IQR 52.5-59.5), 63% male, 31% had an intermediate-high IPI score risk and 50% had a bone marrow involvement at diagnosis. The overall response (ORR) at the end of induction with 6 Romidepsin-CHOEP was achieved in 7 AITL/THF patients (22%), with 6 (19%) patients in complete remission (CR); at the end of treatment, the ORR was observed in 15 (47%) AITL/THF patients. ORR and CR results are superimposable to those of the whole population. At a median follow-up of 28 months, the 24-months PFS for AITL/THF was 43% (95% CI: 0.22-0.61) compared to 24-months PFS for ALK-negative 37% (95% CI: 0.16-0.59) and for PTCL-nos 33% (95% CI: 0.18-0.48), p 0.136; the 24-months OS for AITL/THF was 78% (95% CI: 0.57-0.89) compared to 24-months OS for ALK-negative 63% (95% CI: 0.37-0.81) and for PTCL-nos 61% (95% CI: 0.40-0.76), p 0.556. Conclusions: In the FIL-PTCL13 the primary endpoint was not met and the enrollment of the trial was stopped due to inefficacy of the experimental combination. With the limits of the small number and the unpowered analysis, the benefit of adding romidepsin to chemotherapy was not observed in the subgroup AITL/THF patients, even if the PFS and the OS of this subgroup seem better than the others.

Clinical Impact of Next Generation Flow in Bone Marrow Vs Qip-Mass Spectrometry in Peripheral Blood to Assess Minimal Residual Disease in Newly Diagnosed Multiple Myeloma Patients Receiving Maintenance As Part of the GEM2014MAIN Trial

Introduction: GEM2014MAIN is a phase 3, multicenter, open-label, randomized trial exploring maintenance treatment with lenalidomide and dexamethasone (Rd) vs lenalidomide, dexamethasone and ixazomib (IRd) after autologous stem cell transplantation in newly diagnosed patients with multiple myeloma (MM). The study includes yearly analysis of minimal residual disease (MRD) in bone marrow (BM) by Next Generation Flow (NGF) and the results at year 2 guide further management. Mass spectrometry methods measuring low-level immunoglobulins have shown potential for peripheral-blood (PB) based MRD assessment in MM. Aim: In this study, we analyzed and compared the results and clinical impact of MRD evaluation in BM by NGF and in PB by quantitative immunoprecipitation mass-spectrometry (QIP-MS) during maintenance in patients enrolled in the GEM2014MAIN trial. Patients and Methods: Patients achieving at least stable disease at the end of the GEM2012MENOS65 trial were included in the GEM14MAIN, and randomized to receive Rd (lenalidomide 15mg po od days 1-21 and dexamethasone 20mg po od days 1-4 and 9-12) or IRd (Rd plus ixazomib 4mg po od days 1, 8 and 15) in cycles of 28 days. After two years of treatment, BM samples were analyzed by NGF (sensitivity of 3x10-6) as per protocol: if MRD was undetectable, maintenance was discontinued; if detectable, Rd with reduced dexamethasone at 20mg po od only days 1-4 was continued for 3 additional years. At the same time point, MRD was assessed in PB by QIP-MS with anti IgG/A/M, total k and total l beads using the EXENT system (The Binding Site, in development). The association of MRD detection by either method with progression-free survival (PFS) was assessed by the Kaplan-Meier method. Landmark analyses of PFS at 2 years post-maintenance were performed to minimize lead-time bias. Additional survival analyses were carried out to evaluate the clinical impact of MRD evolution during the study period. Results: 156 patients with paired BM/PB samples available after 2 years of maintenance were included in the analysis. NGF detected residual disease in 29% (45/156) of cases and EXENT in 24% (37/156). The results of both techniques were concordant in 85% of cases and discordances were due to 16 patients (10%) NGF+/EXENT- and 8 (5%) NGF-/EXENT+. Of note, 8/16 cases NGF+/EXENT- corresponded to light-chain MM (anti-free light chain beads were not used in this study). Therefore, overall, and considering NGF as a reference, the negative predictive value (NPV) of EXENT was 87% and the positive predictive value (PPV) of 78% (p<0.0001). With a median follow-up of 66 months from the start of the GEM14MAIN, MRD detection by either method associated with a shorter PFS at 5 years as compared to patients with undetectable MRD: NGF: 57% vs 89%, respectively; HR= 6.54 (2.92-14.67); p<0.0001; EXENT: 62%% vs 86%, respectively; HR= 4.79 (1.99-11.53); p=0.0005. We also analyzed the evolution of MRD between enrollment and after 2 years of maintenance, since we already had MRD results by both methods at the end of the GEM2012. Patients were grouped into 1) those with persistent MRD positivity at the two time points or converting from MRD- to + by either method and 2) those with sustained MRD negativity at the two time points or converting from MRD+ to - by either method. Both NGF and EXENT showed that persistent MRD+ or conversion from MRD- to MRD+ were associated with a shorter PFS at 66 months, compared to patients who remained MRD- or converted from MRD+ to MRD-: NGF: 54% vs 89%, respectively; HR = 8.9 (3.55-22.08); p <0.0001; EXENT: 61% vs 86%, respectively; HR: 4.95 (1.91-12.9); p=0.0010. Conclusions: Our study shows that, during maintenance, the identification of MRD by NGF and EXENT and its evolutionary pattern are both associated with a comparable clinical value in terms of PFS. Supported by a NPV of 87% as compared to NGF, mass spectrometry could be used to define the optimal time-point for BM-based MRD assessments as well as, alongside with standard methods, to introduce MRD adapted treatment approaches.

Predictive Value of Minimal Residual Disease on Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results from the European MCL Elderly Trial

On behalf of the European MCL Network Introduction: Rituximab (R) maintenance after immunochemotherapy represents standard of care in older mantle cell lymphoma (MCL) patients. The European MCL Elderly trial has shown the efficacy of R maintenance after R-CHOP in terms of PFS and OS (Kluin-Nelemans et al., JCO 2020). Induction with R-FC showed similar response rates and failure-free survival but inferior OS as compared to R-CHOP. The assessment of minimal residual disease (MRD) represents a promising tool for individualized treatment decisions. Within the European MCL Elderly trial, we investigated whether MRD status predicts the efficacy of maintenance and aimed to identify MRD-based trigger time points for targeted intervention. Patients and methods: The MCL Elderly trial included patients with previously untreated, advanced stage MCL aged 60 years or older and not suitable for autologous stem cell transplantation. MRD assessment was done at predefined time points during and after treatment until clinical progression for patients recruited in France or Germany with baseline samples and at least one follow-up sample. Three central MRD labs performed marker screening (BCL1-JH t(11;14) translocation or IGH rearrangement) and real-time quantitative PCR (qPCR) following standardized ESG guidelines, as previously reported (Pott et al., Blood 2010). MRD status was pooled from bone marrow and peripheral blood results by classifying a patient as MRD negative if all available samples at the respective time point were negative. Predictive value of MRD status at end of induction for efficacy of maintenance was analysed with Cox regression for PFS including the interaction term of MRD status and treatment group. To assess the prognostic value of MRD status for clinical progression, landmarks were defined at midterm induction (MI), end of induction (EOI), and during four 6-months periods following EOI. Results: A molecular marker for MRD assessment was generated in 85% of 288 screened patients and in 80% a qPCR assay fulfilling standardized criteria could be established. Patients in whom a molecular marker could be identified had more frequently generalized disease compared with those without molecular marker (85% vs. 51% stage IV, 78% vs. 37% with bone marrow involvement, median LDH/ULN quotient: 0.93 vs. 0.81). Among patients without clinical progression during induction, MRD-negativity was achieved more frequently and earlier with R-FC (MI: 63% of 82 patients; EOI: 80% of 82) than with R-CHOP (MI: 26% of 84, p<0.0001; EOI: 53% of 89, p=0.0002). The efficacy of maintenance was clearly seen in patients MRD negative at EOI (PFS-HR 0.38, 95% CI 0.21-0.63, Figure 1A) and was slightly less pronounced in MRD positive patients (HR 0.51, 95% CI 0.26-1.02; interaction p=0.48, Figure 1B). Especially after R-CHOP, the efficacy of R-maintenance was higher among MRD-negative patients (HR 0.23, 95% CI 0.10-0.52) than among MRD-positive patients (HR 0.59, 95% 0.28-1.26, interaction p=0.097). Landmark analyses confirmed the prognostic value of MRD status during and after R-FC and during maintenance/follow-up after R-CHOP. Median time from MRD-positivity 6/12/18/24 months from EOI to clinical progression was consistently short with 2.2/1.2/1.6/1.4 years after R-CHOP and 1.0/1.0/0.7/0.7 years after R-FC. Conclusions: The results confirm the strong efficacy of R-maintenance in MRD-negative patients after induction. Omitting or stopping maintenance based on MRD-negativity is thus discouraged. Considering the short time to progression, more effective treatment strategies should be explored in MRD-positive patients to improve the long-term prognosis of patients with MCL. Figure 1: Progression-free survival (PFS) from end of induction (EOI) by maintenance randomization (R vs. no R) in patients MRD-negative (A) or MRD-positive (B) at EOIFigure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Value of PET/CT Combined with Next-Generation Flowcytometry in Minimal Residual Disease Detection and Prognostic Evaluation of Multiple Myeloma

Background: Minimal residual disease (MRD) plays an increasingly vital role in efficacy evaluation of multiple myeloma (MM), especially in the era of novel drugs. Currently, the mainstream MRD evaluation methods include next-generation sequencing (NGS), next-generation flowcytometry (NGF) and positron emission tomography/computed tomography (PET/CT). However, it remains to be solved which method holds the best sensitivity and specificity. Our research intends to compare the sensitivity between 11C-acatate, a novel PET tracer with the traditional one 18F-FDG, and meanwhile, explore the prognostic value of PET/CT and NGF. Methods: Our research included MM patients treated in our center between 2015.11 to 2021.11, who received standard medication and reached at least partial response. The patients were examined by 11C-acatate PET/CT (AC-PET), 18F-FDG PET/CT (FDG-PET) as well as Euroflow MRD assessment. Baseline characteristics including ISS stage, cytogenetic abnormalities, treatment and response were collected. Statistical analysis was conducted using SPSS 24.0, with Χ2 test or McNemar test for Categorical variables, and Kaplan-Meier analysis or COX regression model for survival analysis. Results: A total of 54 patients were included, with 42 patients received dual-tracer PET/CT, 10 patients received FDG-PET only and 2 patients received AC-PET only. 37 patients also underwent NGF MRD evaluation. The average age of all patients were 58.5 years, with ISS III patients accounting for 53.7% and cytogenetically high-risk patients accounting for 60.4%. 46.3% of patients completed autologous stem cell transplantation, and 90.7% of patients reached at least very good partial response. A total of 11 patients found minimal residual disease by PET/CT, with a sensitivity of 18.2% by AC-PET and 7.7% by FDG-PET. Although it appeared that AC-PET had superior sensitivity compared with FDG-PET, the difference was statistically insignificant (p=0.14). The paired test of dual-tracer PET/CT scan revealed a same result (p=0.13). In patients conducted NGF, the MRD positive rate was 40.5%. Paired test between NGF and PET/CT in these patients demonstrated that sensitivity of NGF was significantly higher than PET/CT (p=0.01). In terms of progression-free survival (PFS), single-factor analysis showed that ISS stage II or III, response not reaching stringent complete response and positive MRD by NGF were all adverse prognostic factor, with p value of 0.019, ＜0.001 and 0.008, respectively. Cox regression analysis further determined that positive MRD by PET/CT was also an independent prognostic factor. Conclusion: The novel tracer AC-PET is advantageous over traditional FDG-PET in sensitivity for MRD detection, although not statistically significant. However, the sensitivity NGF is still superior than either method of PET/CT. In terms of PFS, NGF and PET/CT are both independent prognostic factor.

What Is the Benefit of Autologous Stem Cell Transplantation in Multiple Myeloma Beyond the Age of 65? Inputs from Real-World Data in the Emmy Cohort

Background The management of newly diagnosed multiple myeloma (NDMM) patients under 70 years of age, in good health condition and without comorbidities, is based on an induction therapy followed by high-dose therapy with autologous stem cell transplantation (ASCT) and maintenance (1). Several studies have demonstrated this regimen to be effective up to 65 years of age (2). Beyond this age, patients are often excluded from clinical trials and few real-world evidence studies are available. The EMMY study, a large-scale real-world study designed to assess the epidemiology and real-life management of MM, describes the use of ASCT in patients aged of 65 and over and its efficacy compared to other treatments. Methods EMMY is a non-interventional, prospective study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 800 to 1000 additional patients each year (3616 patients included at the end of 2020). Data are updated annually from hospital records up to 2021. NDMM patients aged 65 years and over, who received a front-line therapy with ASCT (ASCT+), were identified and described. Progression-free survival (PFS) (median and rates at 36 and 48 months (m)), time to next treatment (TTNT) (median and rates at 36m and 48m) and overall survival (OS) rates at 36m and 48m were described for ASCT+ patients ≥65 years and compared to ASCT+ patients <65 years identified in EMMY (Wilcoxon test). ASCT+ patients ≥65 years were also compared with non-autologous transplant patients (ASCT-) of the same age ([65-75[ years). Same analyses were conducted for the subgroup of ASCT+ / ASCT- patients aged of 66-70 years. Results Among the 1597 NDMM patients enrolled in EMMY, 156 NDMM patients ≥65 years of age received a first-line therapy with ASCT; 129 (82.7%) had less than 70 years and 27 beyond (17.3%). Patients were male (55.1%), without comorbidities (72.4%) with an ECOG of 0 or 1 (89.4%) and an ISS score of 1, 2, 3 for 30.3%, 39.4% and 30.3% of them. For those patients, mPFS was estimated at 47.7m (95 CI% [34.4 to not reached]) with 36m and 48m PFS rates estimated at 56.1% (95 CI% [46.2; 66.0]) and 48.6% (95 CI% [37.0; 60.3]). mTTNT was not reached while 36m and 48m TTNT rates were 67.6% (95 CI% [57.7; 77.4]) and 57.4% (95 CI% [45.3; 69.4]). Regarding OS, 36m and 48m rates were 96.2% (95 CI% [92.8; 99.5]) and 89.3% (95 CI% [81.0; 97.6]). Survival outcomes for ASCT+ patients aged ≥65 years did not differ from those for ASCT+ patients aged <65 years (n=397 in EMMY) for PFS (p=0.32), TTNT (p=0.54), and OS (p=0.54). ASCT+ patients aged ≥ 65 years had similar characteristics (M/F ratio, ECOG, ISS, comorbidities) than ASCT+ patients aged <65 years. Compared with ASCT- patients of same age (n=397), ASCT+ patients aged ≥65 years had higher survival outcomes with a significant improvement in PFS (mPFS of 47.7m vs. 19.4m and 36m rates of 56.1% vs. 32.8%, p<0.0001, Figure 1), in TTNT (mTTNT not achieved vs 23.4m in ASCT- patients and 36m rates of 67.6% vs. 34.7%, p<0.0001); and in OS (36m rates of 96.5% vs. 74.0%, p=0.0013). ASCT+ patients aged ≥ 65 years had a median age of 67.5 years (vs. 70.8 years), ECOG 0-1 for 89.4% (vs. 69.0%), comorbidities for 27.6% (vs. 44.3%) and ISS II or III for 69.7% (vs. 76.4%) compared to ACST- patients aged ≥65 years. Same comparisons performed with the 66-70 years subgroup of ASCT+ (n=105) and ASCT- (n=192) patients confirmed previous survival outcomes results in terms of PFS (mPFS of 47.5m vs 20.6m, p=0.0004), TTNT (p<0.0001) and OS (p=0.0002). Conclusion These results are among the first estimates of the higher efficacy of ASCT in selected patients aged 65 years and over. Almost half patients (46.2%) up to 70 years of age received ASCT as first-line therapy, less frequently (about 10%) beyond. Although the use of ASCT is usually reserved to healthy patients, its clinical benefit over 65 years is significant in terms of survival and equivalent to that observed in younger patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Integration of Efficacy and Safety Outcomes Identifies the Net Clinical Benefit of Targeted Agents in Upfront Therapy of Chronic Lymphocytic Leukemia: Results of Network Meta-Analysis

In the absence of head-to-head randomized trials, indirect comparisons of therapy with targeted agents (TAs) across trials may well be informative in the management of chronic lymphocytic leukemia (CLL). However, such published analyses have mostly described progression-free survival (PFS) and provided sparse data on overall survival (OS) or toxicity. We, therefore, conducted a network meta-analysis (NMA) of published upfront CLL TA studies which incorporated a variety of efficacy and safety outcomes, in an attempt to predict the net benefit of TAs. We searched MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) assessing the efficacy and safety of Bruton kinase inhibitors (BTKis) and venetoclax-based regimens in treatment-naïve CLL. Efficacy outcomes (PFS, OS, time to next treatment [TTNT], overall response rate [ORR], complete remission [CR], minimal residual disease [MRD]), safety, and toxicity were evaluated. The surface under the cumulative ranking curve (SUCRA) was obtained for each treatment. The SUCRA provides a numeric representation (range from 0 to 100%), allowing for an overall ranking. The closer the SUCRA value to 100%, the higher the likelihood that therapy is in the top rank, whereas the closer to 0 the SUCRA value, the more likely treatment is in the bottom rank. Nine RCTs met the criteria of low risk for bias according to the Cochrane Handbook for Systematic Reviews of Interventions. Five were excluded because they lacked a common comparator arm (RESONATE2, ALLIANCE, ECOG-ACRIN, FLAIR, SEQUOIA). Four trials were suitable for network analysis (ILLUMINATE, ELEVATE-TN, CLL14, GLOW). Chlorambucil-obinutuzumab (CO) was the control arm across these studies (n=610). In all, these included 1547 patients and evaluated ibrutinib-obinutuzumab (IO) (ILLUMINATE; n=113), venetoclax-obinutuzumab (VO) (CLL14; n=216), acalabrutinib (A) monotherapy (ELEVATE-TN; n=179), A plus obinutuzumab (AO)(ELEVATE-TN; n=179) ibrutinib-venetoclax (IV)(GLOW; n=195). In this NMA, we used the longest published follow-up for each trial (GLOW 27.7 months, CLL14 52,4 months, ILLUMINATE 45 months, ELEVATE-TN 46.9 months). Patients with disrupted TP53 were excluded from the GLOW study and hence from our analysis. AO had the highest probability of efficacy in terms of PFS (SUCRA,0.9923), OS (SUCRA, 0.9010), and ORR (SUCRA,0.8670). In contrast, venetoclax-based regimens had the highest likelihood of achieving a better quality clinical and MRD responses. IV ranked first in terms of CR (SUCRA 0.9208) and VO in terms of undetectable MRD (SUCRA,0.9020). In the analysis of TTNT, IO was preferable (SUCRA,0.9810)(Tab 1). We developed a ranking chart for efficacy outcomes. The average (Av) SUCRA for PFS, OS, ORR, and CR was used to create an efficacy rankogram (k ranks ranged from 1 to 6). In the aggregate efficacy analysis, AO ranked first (Av SUCRA,0.8544) and CO last (Av SUCRA, 0.0575). The full Av SUCRA ranking order was AO, IV, VO, IO, A, CO (Av SUCRA, 0.8544, 0.5793,0.5747,0.4456,0.3864, 0.0575) (Fig 1). When outcomes of toxicity were included, the ranking order changed. The average SUCRA values for toxicities (assessed by the common terminology criteria adverse events (CTCAE) as grade 3 and above, which included neutropenia, infections, diarrhoea, and atrial fibrillation facilitated the development of a safety rankogram in which reduced toxicity is associated with an increased SUCRA value. The toxicity SUCRA ranking selected A first. The full toxicity SUCRA ranking is as follows : A, CO, AO, IV VO and IO (Av SUCRA; 0.70160.6650,0.4390,0.4377, 0.4325 and 0.3242)(Fig 2). A mixed efficacy-toxicity (E-T) rankogram was generated from the efficacy and toxicity Av SUCRA scores; this showed that AO ranked first followed by A, CO, IV, VO, and IO (ET-Av SUCRA: 0.6467, 0.5440,0.5247,0.5085,0.5035, 0.3850)(Fig 3). This is the first NMA that can aid the selection of upfront therapy in CLL patients with intact TP53. In patients who are physically fit a model based solely upon efficacy may be able to inform treatment decisions.On the other hand , a model based exclusively on toxicity outcomes may guide therapy selection in unfit patients. If a combined efficacy/toxicity model is utilized , it identifies a preference for acalabrutinib-based regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combining Plasma Cell Leukemia-like Status with the Second Revision of the International Staging System Improves Risk Classification

Introduction Newly diagnosed multiple myeloma (NDMM) is characterized by a highly variable clinical course, with an overall survival (OS) ranging from less than 3 years to over 10 years. While patients with standard risk disease have benefited significantly from the introduction of novel agents, it remains unclear what the best upfront treatment strategy is for those with high-risk disease. As a result, risk-adapted trial designs (e.g., the MUKnine b OPTIMUM study, NCT03188172) are becoming more common in NDMM and are driving research efforts to improve the identification of high-risk disease. High-risk NDMM can be identified with the recently published Second Revision of the International Staging System (R2-ISS), which combines several conventional risk markers including tumor burden and cytogenetic aberrations that generally reflect increased proliferation and resistance to apoptosis (D'Agostino et al. - J Clin Oncol 2022). We have recently shown that NDMM with high levels of circulating tumor cells can be identified based on a plasma cell leukemia-like (PCL-like) transcriptome that reflects aggressive disease, which is different from the high-risk biology that is recognized by conventional risk models (Hofste op Bruinink et al. - J Clin Oncol 2022). Hence, we hypothesized that combining PCL-like status with the R2-ISS classification would improve prognostic accuracy. Methods Baseline characteristics including serum β2 microglobulin, albumin, lactate dehydrogenase and high-risk cytogenetic markers including deletion of chromosome 17p, t(4;14) and gain/amplification of chromosome 1q were collected from NDMM patients enrolled in the HOVON-65/GMMG-HD4 (EudraCT 2004-000944-26), HOVON-87/NMSG-18 (EudraCT 2007-004007-34), MRC-IX (ISRCTN68454111), Total Therapy 2 (NCT00083551), Total Therapy 3 (A: NCT00081939 and B: NCT00572169) and MMRF CoMMpass studies (NCT01454297) and used to determine the R2-ISS classification. Transcriptomic profiles were generated from CD138-enriched bone marrow tumor cells and used to calculate PCL-like status. For progression-free survival (PFS), an event was defined as either progressive disease or death from any cause. For OS, an event was defined as death from any cause. Hazard ratios (HRs) for PCL-like status, the R2-ISS classification or a combination thereof were estimated using a Cox proportional hazards model stratified by study cohort and corrected for age ≤ 65 years. Two-sided P values < 0.05 were considered statistically significant. Results For a total of 976 NDMM patients of known age, both the R2-ISS classification and PCL-like status could be determined, with a median follow-up time of 53 months. 31% of patients were classified as R2-ISS low (R2-ISS I), 31% as R2-ISS low-intermediate (R2-ISS II), 33% as R2-ISS intermediate-high (R2-ISS III) and 5% as R2-ISS high (R2-ISS IV), whereas 9% were classified as PCL-like MM and 91% as not PCL-like MM (i.e., intramedullary MM, i-MM). PCL-like status was associated with both an inferior PFS (HR, 1.8; 95% confidence interval (CI), 1.4 to 2.3; P = 0.001) and OS (HR, 2.2; 95% CI, 1.7 to 2.9; P < 0.001). This also applied to the R2-ISS classification when comparing R2-ISS IV to R2-ISS I, II and III (HR for PFS, 2.5; 95% CI, 1.9 to 3.4; P < 0.001 and HR for OS, 3.0; 95% CI, 2.2 to 4.2; P < 0.001). PCL-like status retained its prognostic significance in a multivariate model when combined with the R2-ISS classification, both in terms of PFS (HR, 1.8; 95% CI, 1.4 to 2.4; P = 0.001) and OS (HR, 2.2; 95% CI, 1.6 to 2.9; P < 0.001). Of note, 1% of NDMM patients were both classified as PCL-like MM and R2-ISS IV, which translated into a median PFS of 4 months (95% CI, 3 months to not reached) and a median OS of 7 months (95% CI, 4 months to not reached). Patients with PCL-like MM and R2-ISS III (3%) had a comparable median OS to those with i-MM and R2-ISS IV (4%) (35 and 30 months, respectively). Conclusions 1. PCL-like status has independent prognostic value in the context of the R2-ISS classification in NDMM. 2. The presence of both PCL-like MM and R2-ISS IV may confer exceptionally high risk in NDMM, with a median OS of only 7 months. 3. NDMM patients with PCL-like MM and R2-ISS III have a comparable OS to those with i-MM and R2-ISS IV, comprising a median OS of 35 and 30 months, respectively.

Rituximab Maintenance (RM) after First-Line (1L) Treatment Is Associated with a Lower Risk of Early-POD in Patients with Mantle Cell Lymphoma (MCL)

Background RM after 1L immunochemotherapy has improved the Progression-Free Survival (PFS) and Overall Survival (OS) in MCL in phase III clinical trials and in real-life patients. Early progression/relapse (E-POD) after 1L has been significantly associated with a shorter OS in younger patients with MCL after intensive 1L and autologous stem-cell transplantation (ASCT), although these patients did not receive RM (Visco et al, BJH 2019). The aim of our study was to analyze the impact of the use of RM on the risk of early-POD in a real-life cohort of patients with MCL. Methods We retrospectively reviewed all patients diagnosed with MCL between January 2000 and December 2021 at 6 tertiary centers. Only patients receiving 1L at diagnosis and achieving complete (CR) or partial response (PR) were eligible for maintenance and therefore included in this analysis. Patients were categorized as "RM” if they had received RM after 1L or as "non-RM” if they had not. Relapse/progression after 1L occurring before or after the first 24 months (m) from diagnosis was considered early or E-POD and late or L-POD, respectively (Visco et al, BJH 2019). Patients not relapsing after 1L were considered L-POD only if their follow-up time (FU) from diagnosis was 24 months or longer. Patient's characteristics, biological risk factors at diagnosis, as well as the type of 1L were recorded (intensive immunochemotherapy with high-dose cytarabine -HiDAC- or standard immunochemotherapy without HiDAC -non-HiDAC-), with or without ASCT consolidation. The duration of response (DOR) after 1L, PFS and OS were also analyzed for all patients. Statistical analyses were performed with the R-4.1.0 software. Univariate logistic regression was carried out to study the association between E-POD and maintenance. Survival analysis (DOR, PFS and OS) were calculated using the Kaplan-Meier method and the univariate Cox was used for statistical comparison. Results Out of 212 patients attaining CR or PR after 1L, 87 (41%) received maintenance therapy (RM group) whereas 125 patients (59%) did not (non-RM group). The RM regimens administered were: rituximab monotherapy (R)/8 weeks (wk) x 2 years (N=41), R/8 wk x 3 years (N=27) and other R-based regimens (with BTK inhibitors, N=7; other R schedules, N=12). Except for a higher percentage of patients older >65 years at diagnosis in the RM group (51.7% RM vs. 37.6% non-RM, p=0.042), the rest of baseline characteristics were well balanced between the two groups (Table 1). Regarding 1L, more patients in the full cohort had received a non-HiDAC regimen [120 pts (56.6%) non-HiDAC vs. 92 pts (43.4%) HiDAC], but the proportion of patients receiving RM was similar after both types of 1L. Only 22 out of the 87 patients in the RM group (25.3%) had undergone previous ASCT consolidation (Table 1). With a median follow-up of 72.8 months (51.52 m and 92.65 m in the RM and non-RM groups, respectively), median PFS was 44.39 m (36.11-55.46), with a significant advantage for the RM group (61.04 m vs. 32.82 m, HR=1.7 [1.15-2.51], p=0.01) (Figure 1). Moreover, median DOR was 30.03 m (26.02-42.94), also significantly longer in the RM group (53.88 m vs. 24.21 m, HR=1.61 [1.12-2.3], p=0.01). Median OS was 12.18 yrs (8.66-NR) in the full cohort, with no significant differences between the two groups (14.03 yrs vs. 11.48 yrs, HR=1.34 [0.74-2.45], p=0.34). Regarding POD24, a statistically significant association was observed between not receiving RM and early-POD: 49 patients (40.5%) were E-POD in the non-RM group compared with only 19 (24.4%) in the RM group (OR=2.11 [1.14-4.04], p=0.020) (Table 1). Conclusions Only 41% of our real-life cohort received RM despite it being considered a safe and effective strategy for MCL patients. In line with previous studies, in our series RM after 1L is associated with a significant advantage in terms of PFS and DOR, although it did not have impact on OS. In our cohort, RM is significantly associated with a lower risk of early-POD, in all age groups and regardless of the 1L induction strategy, therefore confirming the benefit of this strategy in the management and outcomes of MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

NIMG-62. RADIOMIC-BASED PROGRESSION-FREE SURVIVAL STRATIFICATION OF PEDIATRIC LOW-GRADE GLIOMA IS ASSOCIATED WITH MOLECULAR ALTERATIONS

Abstract Pediatric low-grade glioma (pLGG) encompasses a variety of tumor subtypes with heterogeneous treatment response and relatively long progression-free survival (PFS). Radiomics may serve as a non-invasive and in-vivo tool for early prediction of PFS as a surrogate marker for treatment response and to objectively gauge the efficacy of novel treatment strategies. Here, we present a multivariate model based on radiomic features and clinical variables for risk stratification of pLGGs in terms of PFS and seek associations of the predicted risk groups and mutations in key molecular markers using data from PedCBioportal. Pre-operative multi-parametric MRI scans (T1-pre, T1-post, T2, T2-FLAIR) of 129 patients with newly diagnosed pLGG (median age, 7.76, range, 0.35-19.58 years; median PFS, 28.5, range, 1.1-124.8 months) were collected and quantitative radiomic features (n = 881) were extracted. A multivariate Cox proportional hazard’s (Cox-PH) regression model was fitted based on clinical (age, sex, and extent of tumor resection) and radiomic variables using 4-fold cross-validation. A subset of radiomic features (n = 27) that were most predictive of PFS was selected by applying Elastic Net regularization penalty during Cox-PH model fitting. High-, medium- and low-risk groups were determined based on model predictions. Cox-PH modeling showed excellent performance for prediction of PFS as suggested by the concordance index of 0.78. Radiogenomic assessment (data available in 94/129 patients) showed more enrichment of mutations in NF1 and RB1 genes in the high-risk group, as compared to the low- and medium-risk groups. We showed the potential value of radiomics in providing upfront prediction of PFS, which may further be used as an added treatment arm for early assessment of treatment response of the pLGG patients enrolled in the clinical trials. In the next step of this work, we will expand the cohort and cross-validate these results in an external cohort.