Favorable Progression-free Survival Research Articles

Extended ICI treatment after first-line chemoimmunotherapy could predict the clinical benefit of ramucirumab plus docetaxel in advanced non-small lung cancer: Post hoc analysis from NEJ051 (REACTIVE study).

The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first-line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non-small cell lung cancer (NSCLC). Our study comprised 288 patients with advanced NSCLC who received RD as the second-line treatment after first-line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum-based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression-free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD-L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second-line RD treatment in patients with advanced NSCLC.

CTNI-81. REAL-WORLD TREATMENT RESULTS OF RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA TREATED BY MEDICAL THERAPIES

Abstract Recurrence of primary central nervous system lymphoma (PCNSL) is a condition which often leads to morbidity and mortality. Consensus regarding the optimal treatment regimen for relapsed PCNSL has not been achieved due to the rarity of the disease. In this study, we conducted a retrospective, single-institution study to investigate real world treatment results of relapsed PCNSL treated by several medical therapeutic regimens. Relapsed PCNSL patients treated at the authors’ institution were identified, and progression-free survival (PFS), overall survival (OS) were analyzed among patients treated by medical therapies. Patients treated by radiotherapy, treated for intraocular or systemic relapses, or best supportive care, were excluded from the survival analysis. 83 patients with first, 44 with second, 25 with third relapse were identified. Upon each relapse, number of patients who received medical therapies for CNS lesions, radiotherapy, treatment for intraocular or systemic relapse, and best supportive care were 48 (57.8%), 5(6%), 4(4.8%), 26(31.3%) (first relapse), 31(70.5%), 3(6.8%), 1(2.3%), 9(20.5%) (second relapse), 13(52.0%), 0, 1(4%), 11(44.0%) (third relapse), respectively. A total of 101 CNS relapses were treated by medical therapies, and PFS (months), OS (months) of the four groups of treatments (rituximab, methotrexate, procarbazine and vincristine [R-MPV], methotrexate [MTX], tirabrutinib, and others) were as follows. PFS: 13.0, 4.5, 2.7, 3.0, and OS: 70.0, 26.4, 51.2, 9.7 (all relapse). PFS: 12.7, 7.0, 3.0, 3.2, and OS: 58.9, 33.1, not reached(n/r), 16.1 (first relapse). PFS: 34.3, 3.9, 25.3, 1.5, and OS: n/r, 28.1, 25.5, 7.5 (second relapse). PFS: 10.1, 3.9, 2.4, 2.9, and OS: 14.9, 22.3, n/r, 8.1 (third relapse). In relapsed PCNSL, favorable PFS was observed in patients treated by R-MPV. Favorable OS was also observed in tirabrutinib, which might suggest that tirabrutinib failure were effectively salvaged by R-MPV. R-MPV might confer better prognosis in relapsed PCNSL.

NCOG-13. OUTCOMES OF CNS WHO GRADE 2 OLIGODENDROGLIOMA IN ADULT PATIENTS ; IMPACT OF ADJUVANT TREATMENT ON OVERALL RESULTS

Abstract OBJECTIVE Patients with oligodendroglioma (ODG), isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted, CNS WHO grade 2 have a median overall survival of longer than 10 years. Patients with ODG who are high-risk by RTOG criteria are offered radiation in combination with procarbazine, lomustine, and vincristine (PCV). The study aims to analyze the patient’s outcomes and assess the efficacy of postoperative treatment. METHODS A total of 138 adult patients who underwent resection for newly diagnosed grade 2 ODG between 1994 and 2021 were enrolled. Sixty-three (45.7%) were observed after gross total resection (GTR) or near total resection (NTR), 5 (0.4%) received adjuvant treatment after GTR or NTR, 37 (26.8%) were observed after subtotal resection (STR) or biopsy, and 33 (24.0%) received adjuvant treatment after STR or biopsy. The study analyzed progression-free survival (PFS), overall survival (OS), and risk variables. RESULTS Out of the 138 patients, 38 (27%) patients received adjuvant treatment, with 30 of them (78.9%) underwent radiotherapy only, 6 (15.8%) underwent radiochemotherapy, and 2 (5.3%) received chemotherapy alone. The median PFS was 6.8 years. Multivariate analysis revealed STR or biopsy (p=0.04), initial MR imaging enhancement (p=0.002), and postoperative observation(p=0.006) were associated with poorer PFS outcomes. The 5-year overall survival rate was 95.5% and the 10-year overall survival was 76.1%. Poor OS prognosis was associated with STR or biopsy (p=0.03), preoperative seizure (p=0.002), and initial MR imaging enhancement (p< 0.001). CONCLUSIONS : GTR and NTR is essential for achieving prolonged PFS and OS in ODG patients. Postoperative treatment is associated with favorable PFS outcomes but does not significantly affect OS. For an accurate diagnosis and appropriate treatment, the utmost care should be taken to avoid underestimating the results of the biopsy.

Second Vs Third Line Treatment with Axicabtagene Ciloleucel for Large B Cell Lymphoma - a Real-Life National Multicenter Retrospective Cohort Study with Propensity Score Matching

Background: Superiority of Axicabtagene Ciloleucel (Axi-Cel) in relapsed/refractory (R/R) large B cell lymphomas (LBCL) compared with standard of care was shown in both the 3 rd and 2 nd line setting. However, optimal timing for incorporation of CAR-T is not well established. We aimed to compare efficacy, toxicity profile, and product kinetics of Axi-Cel as 2 nd vs 3 rd line of treatment. Methods: we performed a national real world retrospective study of consecutive patients treated with Axi-Cel as 2 nd line with propensity score-matched patients treated with 3 rd line treatment. Patients were matched for age (±2 years), Eastern Cooperative Oncology Group (ECOG) performance status, and disease status at lymphodepletion. Disease status and response were defined by the Lugano criteria, cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) were defined by ASTCT Consensus (2019) and progression-free survival (PFS) was calculated from infusion to index event. Immunophenotyping from peripheral blood at day 7+ was used to analyze expansion of CAR-T cells. Results: Between 01/2019and 06/2023, 44 patients treated with Axi-Cel fulfilled the inclusion criteria, 22 in each cohort. Groups were well matched in the propensity score domains (mean difference 2, p=.65 for age, mean square .32, p=.57 for ECOG, and mean square .26, p=.61 for disease status at lymphodepletion). Median follow up was 2.2 (range, 1-28.8) months in 2 nd line group and 10.8 (range, 1-39) months in the 3 rd group. Median age was 68 (range, 39 - 84) and 66 (range, 32 - 80) years in the 2 nd and 3 rd line groups, respectively. There were no differences between gender (p=.76), LBCL subtypes (p=.16), % of patients receiving bridging therapy (p=.55), % of patients with elevated LDH levels prior to lymphodepletion (p=.98), and n days from collection to treatment (p=.29) between the 2 groups. There was a lower % of patients with primary refractory disease in the 2 nd, compared to 3 rd line therapy group (63% vs. 36%, respectively, p=.09) and a higher % of patients with transformed disease (42% vs. 14%, respectively, p=.04). Both overall and grade 3-4 incidences of CRS were similar between the 2 nd line and the 3 rd line groups (86% vs. 95%, p=.16 and 18% in both groups, p=1, respectively). Median days to CRS onset was also similar (1, range 0 - 5 and 2, range 0 - 7, p=.1, respectively). Both overall and grade 3-4 incidences of ICANS) were similar between the 2 nd line and the 3 rd line groups (41% vs. 64%, p=.48 and 14% vs. 18%, p=.73, respectively. Median days to ICANS onset was lower in the 2 nd line compared to the 3 rd line group (4, range 0 - 8 and 6, range 0 - 7, p=.06, respectively). There were no differences between the groups in the median tocilizumab doses (p=.21), % of patients receiving steroids (p=.12), cumulative steroids dose (p=.17), % of patients receiving growth factors (p=1), and duration of admission (p=.51). Median day +7 CAR-T blood levels were higher in the 2 nd line compared to the 3 rd line group (126 (range,1-791) vs. 18.1 (range, 0-988) cells/microL, p=.05, respectively). 1-month overall response rate (ORR) was 86% (CR=77%) in the 2nd line group vs 64% (CR=45%), in the 3rd line group, p=.081 Figure 1a. Three-months progression-free survival was 88% (95%, CI 64%-100%) vs. 59% (45%-73%), respectively, Figure 1b. Cox regression identified 2 nd line treatment associated with better progression-free survival (HR=.15, p=.007) and progressive disease at lymphodepletion associated with worse progression-free (HR=8.5, p=.007), while age, gender, and ECOG performance status did not impact progression. Conclusions: This matched comparison showed favorable ORR and PFS rates when Axi-Cel is utilized as a 2nd line treatment vs 3rd line. Toxicity profile is similar. Higher CAR-T expansion in the 2nd line might provide insight regarding product quality and exhaustion phenotype when manufactured earlier in the LBCL treatment course. A longer follow-up is needed to test whether these findings translate to durable remission and cure.

Haploidentical Hematopoietic Cell Transplantation Combined with an Unrelated Cord Blood Unit for Adult Acute Myeloid Leukemia Results in Improved Survival Compared to Haploidentical Hematopoietic Cell Transplantation: Results of a Multicenter, Randomized, Phase III Trial

Introduction Haploidentical hematopoietic cell transplantation (haplo-HCT) is a potent treatment to improve the prognosis of acute myeloid leukemia (AML), but relapse and graft-versus-host disease (GVHD) related to dysregulation of alloreactivity are still the main causes of death posttransplantation. Cord blood graft usually has a promising graft-versus-leukemia effect with a lower cumulative incidence of GVHD. To improve the transplantation strategy, haplo-cord HCT combining haploidentical and unrelated cord blood (UCB) grafts (haplo-cord HCT) has been attempted. Previous studies showed significant improvement in prognosis in B-cell acute lymphoblastic leukemia or refractory acute leukemia patients with haplo-cord HCT compared to haplo-HCT. However, outcomes of haplo-cord HCT for AML patients are not yet clear. This is the first multicentric randomized trial designed specifically for the efficacy and safety of haplo-cord HCT for AML. Methods This is a multicenter, randomized, open-label, phase III study conducted in 5 centers in China (NCT03719534). Patients aged 18-60 years, diagnosed with AML (except for acute promyelocytic leukemia) with measurable residual disease, had an available haploidentical donor and were suitable for allotransplantation were enrolled. Patients were randomized 1:1 to receive UCB and haploidentical grafts infusion after Bu/Cy-based regimen or haploidentical graft infusion only after Bu/Cy-based regimen. The UCB unit, which had at least 3/6 matched HLA loci to the recipient and more than 1×10 4 CD34 + cells/kg of recipient weight, was infused immediately after resuscitation and eight hours before the haploidentical graft infusion. The primary endpoint was 3-year overall survival (OS) and secondary endpoints included progression-free survival (PFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). Results From June 1, 2017, to June 30, 2021, 268 patients were enrolled (Table 1). With a median follow-up of 36.00 months, the 3-year OS was 80.5% (95% CI 73.7-87.9) in the haplo-cord HCT group and 67.8% (95% CI 60.0-76.5) in the haplo-HCT group, respectively (p=0.013, figure 1A). Haplo-cord HCT group showed favorable 3-year PFS and CIR than haplo-HCT group (PFS: 70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p=0.012; CIR: 12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p=0.024, figure 1B,C). The 3-year NRM was similar in the two groups (figure 1D). Within two years posttransplantation, the most common grade 3-4 adverse events (AEs) in the haplo-cord HCT and haplo-HCT groups were infections (33.8% and 29.1%), acute GVHD (20.3% and 12.7%) and chronic GVHD (12.0% and 16.4%). AEs leading to death occurred in 8.3% of haplo-cord HCT and 14.9% haplo HCT patients. Post- hoc analysis showed similar median levels of haploidentical chimerism in bone marrow (BM) between the two groups. However, UCB microchimerism was detected in the haplo-cord HCT patients by SNP-NGS in +1m posttransplantation (BM: 0.3%, IQR 0.04-1.6; peripheral blood: 0.06%, IQR 0.03-0.4) and its chimerism percentage decreased with time (figure 1E). Compared to haplo-HCT group, haplo-cord HCT group showed a faster cumulative incidence of neutrophil recovery (p=0.026, figure 1F) and a similar cumulative incidence of platelet recovery. Monitor of immune reconstitution showed a more rapidly increasing rate of T cells in the early period after transplantation in the haplo-cord HCT group (figure 1G). Improved recovery of Th2 (p=0.042), Th17 (p=0.047), Treg (p=0.045), and Tc2 (p=0.045) cells was observed in haplo-HCT group. Conclusions Coinfusion of a UCB unit in haplo-HCT can improve OS in AML patients without excessive AEs, and affect T-cell reconstitution pattern posttransplantation. Haplo-cord HCT could serve as a suitable therapeutic option for this patient population.

Efficacy and safety of utidelone plus capecitabine in advanced first-line therapy for metastatic breast cancer: A multicenter real-world study

BackgroundThe purpose of this study was to compare the efficacy and safety of utidelone plus capecitabine for advanced first-line versus second-line or above therapy in metastatic breast cancer patients who had previously received anthracycline and taxane. At the same time, we compared the efficacy of utidelone plus capecitabine and vinorelbine plus cisplatin in advanced first-line treatment of metastatic breast cancer. Patients and methodsA retrospective cohort of 11 patients with metastatic breast cancer previously treated with anthracycline and taxane (including neoadjuvant and adjuvant therapies) for advanced first-line with utidelone plus capecitabine, 32 patients treated with second-line or above, and 60 patients with vinorelbine plus cisplatin between October 2011 and August 2022 was collected. The first and second groups were treated with utidelone plus capecitabine, and the third group was treated with vinorelbine plus cisplatin. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), objective response rate (ORR), and treatment safety. ResultsBy 03/31/2023, median PFS reached 11.70 months (95 % CI 0.093–0.141) in utidelone plus capecitabine group in the advanced first-line therapy, compared to 5.60 months (95 % CI 0.025–0.079) in the second-line or above therapy [HR 0.42, (95 % CI 0.226–0.787), P = 0.0077]. In utidelone plus capecitabine, the median OS was not reached in the advanced first-line therapy, with a mean overall survival of 23.16 months (95 % CI 0.198–0.265); whereas the median OS in the second-line or above therapy was 19.50 months (95 % CI 0.083–0.307), with a mean overall survival of 16.89 months (95 % CI 0.136–0.202) [HR 0.26, (95 % CI 0.098–0.678), P = 0.0495]. The ORR for advanced first-line therapy was 27.27 % (95%CI 0.060, 0.610) compared with 15.63 % (95%CI 0.053, 0.328) for second-line or above. In advanced first-line therapy, utidelone plus capecitabine was superior to vinorelbine plus cisplatin with a median PFS of 6.12 months (95 % CI 0.051–0.072) [HR 0.49, (95 % CI 0.286–0.839), P = 0.0291]. Compared with utidelone plus capecitabine, the median OS in vinorelbine plus cisplatin advanced first-line therapy group was 35.37 months (95 % CI 0.258–0.449), and the mean overall survival was 40.79 months (95 % CI 0.315–0.501) [HR 0.54, (95 % CI 0.188–1.568), P = 0.2587]. The ORR for vinorelbine plus cisplatin was 18.33 % (95 % CI 0.095, 0.304). The most common adverse events in our study were neurological toxicity, hand-foot syndrome, hematological toxicity, gastrointestinal toxicity, and hepatic and renal function abnormalities. There were no deaths due to adverse effects during the utidelone plus capecitabine treatment period. ConclusionsIn MBC, advanced first-line therapy with utidelone plus capecitabine resulted in more favorable PFS, OS, and ORR than second-line or above therapy. In advanced first-line therapy, utidelone plus capecitabine had superior PFS, and ORR compared with vinorelbine plus cisplatin. This study concludes that utidelone plus capecitabine is a more valuable chemotherapy option in advanced first-line MBC.

Complete blood and urine paraprotein tests as response assessments in multiple myeloma patients treated with bortezomib, cyclophosphamide, and dexamethasone.

This study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma (MM) during the induction phase of treatment with bortezomib, cyclophosphamide, and dexamethasone (BCD). We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with BCD as front-line regimen at Peking Union Medical College Hospital from January 1, 2013 to December 31, 2018. There were 107 patients with International Staging System (ISS) III and 51 with paraprotein of light chain. Of these, 77 completed nine cycles of the BCD regimen. As the number of treatment cycles increased, the proportions of serum and urine immunofixation electrophoresis (IFE) tests elevated from 40.39% to 62.22% and 16.75% to 37.78%, respectively. More than 90% of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle, but that of urinary M protein was less than 60%. The detection rate of urinary M protein in light chain MM was more than 70% per cycle. Patients with a very good partial response (VGPR) had longer progression-free survival (PFS) than those with uncertain VGPR (32 vs. 26 months, p = 0.0336). Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation, those who were regularly assessed at every other cycle showed more favorable PFS than those who visited irregularly (27 vs. 22 months, p = 0.059). Urinary M protein detection rate is significantly lower than that in serum, leading to an overestimation of efficacy, premature reduction of treatment intensity, and shortened PFS. Precise response assessments are critical to treatment decisions and clinical diagnoses.

Prostate-specific antigen doubling time predicts the efficacy of site-directed therapy for oligoprogressive castration-resistant prostate cancer

BackgroundIn recent years, site-directed therapies (SDTs) targeting progressive lesions in patients with oligometastatic prostate cancer have attracted attention. However, whether they effectively treat oligoprogressive castration-resistant prostate cancer (CRPC) remains unclear. Here, we investigated the efficacy of SDT in patients with oligoprogressive CRPC and identified prognostic factors. MethodsWe reviewed 59 patients with oligoprogressive CRPC who underwent SDT targeting prostate or metastatic lesions between April 2014 and March 2022. We evaluated the associations between several pretreatment clinical variables and treatment procedures and a >50% prostate-specific antigen (PSA) response, progression-free survival (PFS), and time to next treatment (TTNT). ResultsA PSA response of >50% was observed in 66% of patients. The median PFS and TTNT were 8.3 months and 9.9 months, respectively. Patients with PSA doubling time ≥6 months showed a higher >50% PSA response rate (87% vs. 45%; P < 0.001), longer PFS (median, 15.0 vs. 5.0 months; P < 0.001), and longer TTNT (median, 16.3 vs. 5.9 months; P < 0.001) than patients with PSA doubling time <6 months. In multivariate analyses, a PSA doubling time of ≥6 months independently predicted a >50% PSA response, favorable PFS, and TTNT (P = 0.037, 0.025, and 0.017, respectively). ConclusionPSA doubling time of ≥6 months may be a key indicator of the favorable efficacy of SDT for oligoprogressive CRPC.

Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: immune monitoring from the E1912 trial

AbstractBruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.

Transarterial Chemoembolization Plus Lenvatinib and PD-1 Inhibitors for Hepatocellular Carcinoma with Main Trunk Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

In recent years, immune checkpoint inhibitors have been used in combination with tyrosine kinase inhibitors and local therapies, creating a new era in treating hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). However, the benefits of this triple therapy remain unclear. Thus, this study evaluated whether the combination of transarterial chemoembolization (TACE), lenvatinib, and programmed death-1 (PD-1) inhibitors (triple therapy) was effective and safe for unresectable HCC with main trunk portal vein tumor thrombus (Vp4). This study enrolled patients receiving triple therapy at four institutions between August 2018 and April 2022. Patient characteristics and course of treatment were extracted from patient records. Tumors and tumor thrombus response were evaluated using an HCC-specific modified RECIST. Kaplan-Meier curve analysis demonstrated overall survival (OS) and progression-free survival (PFS). Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Median follow-up duration was 18 (4.0-26.3) months. Overall, 41 patients with HCC and Vp4 receiving first-line triple therapy were enrolled. The intrahepatic tumor objective response rate was 68.3%. The median OS was 21.7 (range, 2.8-30.5) months, whereas the median PFS was 14.5 (range, 1.3-27.6) months. Twelve patients received sequential resections. Resection was independently associated with favorable OS and PFS. Fever (31.7%), hypertension (26.8%), fatigue (24.4%), abnormal liver function (63.4%) and decreased appetite (21.9%) were the AEs frequently associated with treatment. No treatment-related mortality occurred. TACE plus lenvatinib and PD-1 inhibition was effective and tolerable for treating unresectable HCC with Vp4, with a high tumor response rate and favorable prognosis.

Treatment Efficacy Outcomes Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Survival Analysis of a Phase IB trial

Aggressivelocal treatment to a limited number of metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies have shown the safety of combining high dose stereotactic body radiation therapy (SBRT) with single agent anti-PD1/PD-L1 therapy. Here, we report secondary survival endpoint outcomes from a phase Ib clinical trial investigating the safety of combining ablative, high dose radiation with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. Patients with up to 6 sites of extracranial metastatic disease were eligible for trial enrollment. All sites of disease were treated with stereotactic body radiation therapy to a dose of 30 - 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (Tremelimumab) and anti-PD-L1 (Durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until dose limiting toxicity or progression was observed. Primary toxicity outcomes were previously reported. Progression free and overall survival was analyzed using Kaplan Meier statistical methods. Fifteen patients were treated with SBRT and received at least one dose of dual agent immunotherapy per protocol. The median follow up was 43 months. The median number of extracranial metastatic sites was 2. Seven patients had 3 or more sites of extracranial disease. The most commonly treated sites were separate metastatic pulmonary lesions or osseous metastatic lesions. Median progression free survival (PFS) was 42 months and median overall survival (OS) was 48 months. Seven patients remain alive without evidence of progressive disease. Prior history of brain metastases was associated with significantly worse PFS (Median PFS 4 months vs 42 months, HR 6.1 (95% CI 1.6 - 37.0) p = 0.0248), but no difference in OS (Median OS 24 vs 42 months, HR 1.9 (95% CI 0.3 - 10.4). Ablative SBRT radiation to up to 6 sites of disease followed by dual checkpoint immunotherapy in oligometastatic NSCLC resulted in a favorable progression free survival (42 months) and overall survival (48 months) compared to historical controls. These findings suggest potential benefit to patient outcomes compared to immunotherapy or radiation alone in this patient population and warrant further investigation.

The Role of Radiation Therapy for Metastatic Cervical Cancer

Survival rates for women with metastatic cervical cancer (CC) are low, with limited management options. Radiation therapy (RT) for metastatic disease has led to prolonged survival in other malignancies, however, the data are scarce in CC. Herein, we evaluated the effect of RT for metastatic CC. A total of 58 patients with metastatic CC between September 2019 and January 2023 were retrospectively analyzed. All the patients were treated with platinum-based chemotherapy combined with targeted therapy or immunotherapy followed with or without RT (NRT). The recent efficacy, survival status and prognostic factors were analyzed statistically. Objective response rate (ORR) was 63.6% with one complete and twenty partial responses in RT group (n = 33) and 40.0% with two complete and eight partial responses in NRT group (n = 25), respectively (p = 0.074). Disease control rate (DCR) of the RT and NRT groups were 79.4% vs 80.0%, respectively (p = 0.861). Median follow-up time was 17 months (3-39months). In RT group, 11(33.3%) patients experienced local regional or distant failure and 9 (27.3%) patients were dead. In NRT group, 15(60%) patients had progression and 8 (32%) patients dead. There was no significant difference between the two groups in overall survival (OS); however, RT group displayed superior progression-free survival (PFS) (1-year OS: 72.7% vs. 68.0%, p = 0.460; 1-year PFS: 66.7% vs. 40.0%, p = 0.039). The multivariate analysis showed that RT, immunotherapy, lymph node metastasis only relevant predictor of superior PFS but not OS. In subgroup analysis, patients treated with RT appeared to have a better PFS in some specific cohorts, such as age>45 years (72.0% vs 36.4% P = 0.015), squamous carcinoma histology (71.0% vs 40.9% P = 0.017), metastatic at diagnosis (75.0% vs 47.6% P = 0.012), non-targeted therapy (72.4% vs 43.8% P = 0.040). No significant increase in treatment-related toxicity was observed in the RT group compared with the NRT group. RT provided superior PFS in metastatic CC patients compared to NRT, and well tolerated. Moreover, RT, immunotherapy, lymph node metastasis only were independent significant prognostic factors for PFS. Subgroup analysis showed that combination of RT and chemotherapy obtained favorable PFS in metastatic CC patients with age>45 years, squamous carcinoma histology, metastatic at diagnosis, non-targeted therapy. Studies with a larger sample size and longer follow-up are warranted.

Bridging Radiotherapy Prior to Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphomas: An ILROG Multi-Institutional Study

To report an ILROG multi-institutional analysis of bridging radiotherapy (BRT) prior to CD19-targeting chimeric antigen receptor T-cell (CAR T) therapy for relapsed/refractory aggressive B-cell lymphomas (BCL). Weretrospectively reviewed 115 patients (pts) with diffuse large BCL (n = 101, 88%), primary mediastinal BCL (n = 11, 10%), mantle cell lymphoma (n = 2, 2%), and T-cell/histiocyte rich large BCL (n = 1, 1%) who received BRT prior to commercial CAR T from 2018-2020 across 6 institutions. BRT toxicities were graded per CTCAE v5.0, cytokine release syndrome (CRS) per ASTCT, and immune effector cell-associated neurotoxicity syndrome (ICANS) per either ASTCT or CTCAE v5.0. Progression-free survival (PFS) and overall survival (OS), measured from CAR T infusion, were estimated using the Kaplan-Meier method. PFS was modeled using Cox regression with stepwise variable selection. BRTwas given prior to axicabtagene ciloleucel (axi-cel; n = 82, 71%), tisagenlecleucel (tisa-cel; n = 31, 27%), or brexucabtagene autoleucel (n = 2, 2%). Median age was 62 years with median of two prior lines of therapy. Most pts had advanced stage III/IV disease at leukapheresis (n = 87, 76%), elevated pre-leukapheresis LDH (n = 73, 63%), and bulky disease (n = 55, 50%) (1 lesion ≥7.5 cm). 78 pts (68%) had extranodal disease, 12 (10%) had central nervous system (CNS) involvement, and 36 (31%) had bone involvement. Systemic bridging therapy was given to 42 pts (37%). Median intervals from leukapheresis to BRT start and from BRT completion to CAR T infusion were 5 days (IQR -6, 11) and 12 days (IQR 9, 23), respectively. BRT was delivered to 163 total sites; most commonly the abdomen/pelvis (n = 58, 50%), head/neck (n = 34, 30%), thorax (n = 20, 17%), extremity/soft tissue (n = 20, 17%), and CNS (n = 13, 11%). Median biologically effective dose was 31.3 Gy (IQR 24, 39). Most common regimen was 30 Gy in 10 fractions (n = 27, 17%). 40 pts (35%) received comprehensive BRT (to all active lesions). There were no grade ≥3 BRT toxicities. Grade ≥3 CRS occurred in 9 pts (8%), including 8/82 (10%) after axi-cel and 1/31 (3%) after tisa-cel. Grade ≥3 ICANS occurred in 23 pts (20%), including 22/82 (27%) after axi-cel and 1/31 (3%) after tisa-cel. Median follow up was 26.9 months. 1- and 2-year OS rates were 60% and 49%. 1- and 2-year PFS rates were 41% and 35%. Comprehensive BRT associated with superior PFS (HR 0.34, 95% CI 0.19-0.62, p<0.001) in a multivariable model with age ≥60, ECOG ≥2, advanced stage, CNS disease, pre-leukapheresis LDH, and axi-cel. In this multi-institutional study, pts receiving BRT prior to CAR T therapy for BCL frequently had bulky disease yet experienced favorable PFS and OS. There were no serious toxicities attributable to BRT, and the rates of CRS and ICANS are comparable to those after CAR T alone. Comprehensive BRT associated with superior PFS.

Increased expression of leucine-rich α-2 glycoprotein 1 as a predictive biomarker of favorable progression-free survival in meningioma.

Most meningiomas, which are frequent central nervous system tumors, are classified as World Health Organization (WHO) grade 1 because of their slow-growing nature. However, the recurrence rate varies and is difficult to predict using conventional histopathological diagnoses. Leucine-rich α-2 glycoprotein 1 (LRG1) is involved in cell signal transduction, cell adhesion, and DNA repair and is a predictive biomarker in different malignant tumors; however, such a relationship has not been reported in meningiomas. We examined tissue microarrays of histological samples from 117 patients with grade 1 and 2 meningiomas and assessed their clinical and pathological features, including expression of LRG1 protein. LRG1-high meningiomas showed an increased number of vessels with CD3-positive cell infiltration (P = 0.0328) as well as higher CD105-positive vessels (P = 0.0084), as compared to LRG1-low cases. They also demonstrated better progression-free survival (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.016-0.841) compared to LRG1-low patients (P = 0.033). Moreover, multivariate analysis indicated that high LRG1 expression was an independent prognostic factor (HR, 0.13; 95% CI, 0.018-0.991; P = 0.049). LRG1 immunohistochemistry may be a convenient tool for estimating the prognosis of meningiomas in routine practice. Further studies are required to elucidate the key role of LRG1 in meningioma progression.

High-dose (60 Gy) intensity-modulated radiotherapy with concurrent weekly cisplatin followed by intracavitary radiation in locally advanced cervical cancer: A phase II prospective clinical trial

ObjectiveRadiotherapy dose-escalation using intensity-modulated radiotherapy (IMRT) has been necessary to improve treatment results in cervical cancer. MethodsThis was a phase II prospective clinical trial. 88 patients with FIGO II-IVa cervical cancer were enrolled in a single center. They received high-dose (60 Gy) IMRT with weekly cisplatin to the primary tumor and clinically positive nodes followed by intracavitary radiation. The primary endpoint was 30-month PFS rate (Target; 82%, an increase of 20% compared to GOG 120 trial using standard-dose radiotherapy). Secondary endpoints were tumor response, toxicity, recurrence, distant metastasis, and overall survival. ResultsProgression-free survival rate at 30 months was 82.8%. Overall survival, locoregional recurrence, distant metastasis, and para-aortic recurrence rates at 30 months were 93.6%, 8.2%, 9.2%, and 2.4%, respectively. Forty-five (51.1%) of 88 patients achieved downstaging on MRI during radiotherapy and 80 (90.9%) patients had clinically complete response at three months after high-dose IMRT and intracavitary radiotherapy. The 30-month recurrence-free survival (92.9% vs. 73.1%, P = 0.009) and overall survival (100% vs. 87.0%, P = 0.006) were significantly higher in the downstaged group than in the non-downstaged group during radiotherapy. Grade 3 or higher hematologic toxicity was found in 11 (12.5%) patients and grade 3 or higher non-hematologic toxicity was found in 3 (3.4%) patients. Fourteen had chronic urinary (8.0%), intestinal (5.7%) toxicity, pelvic insufficiency fracture (2.3%) or vesicovaginal fistula (2.3%). ConclusionHigh-dose (60 Gy) IMRT with concurrent weekly cisplatin in locally advanced cervical cancer yielded favorable progression-free survival outcome. Tumor response during radiotherapy can be a significant prognostic factor for PFS.Clinical trial information: This prospective trial is registered at ClinicalTrials.gov Identifier: NCT02993653.

Principal component analysis yields results comparable to those of an elaborate Boolean strategy: simplifying the assessment of measurable residual disease in chronic lymphocytic leukemia patients.

Measurable residual disease (MRD) is becoming increasingly important in the chronic lymphocytic leukemia (CLL) context. It is of independent prognostic significance in terms of favorable progression-free and overall survival. The standardized methods used to assess CLL MRD are based on flow cytometry and real-time quantitative PCR. We here present a nine-color assay for CLL MRD with the ROR-1 marker antigen as recommended by the European Research Initiative (ERIC) on CLL; the sensitivity is at least 10-5. We used 54 samples to develop a new principal component analysis (PCA) method based on the Kaluza© "radar" presentation mode. We used a Navios flow cytometer (Beckman Coulter©). We confirmed the linearity of our method over more than five dilutions. The specificity limit was 1.3×10-6 and the lower limit of detection was 3.6×10-6. Compared to the Boolean method, the sensitivity, specificity, and positive and negative predictive values of our PCA method were 100%. When MRD was detectable, PCA and Boolean assays were in agreement (linear regression, R2=0.99). We developed a new PCA-based method for detection of CLL MRD. Our method is comparable to that of the consensus method in terms of sensitivity, and it is also much easier and faster.

The Glasgow Prognostic Score Predicts Survival Outcomes in Patients with Extensive-Stage Small Cell Lung Cancer

Introduction: The Glasgow prognostic score (GPS) is an inflammation-related score based on C-reactive protein and albumin concentrations. Few studies have assessed the correlation between the GPS and the efficacy of chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). Therefore, this study aimed to evaluate the utility of the GPS in predicting the survival outcomes of patients with ES-SCLC. Methods: This retrospective study evaluated patients with ES-SCLC who had undergone chemotherapy between February 2008 and November 2021. GPS values were evaluated before the initiation of first-line chemotherapy. The Kaplan-Meier method and Cox proportional hazards models were used to assess progression-free survival (PFS) and overall survival (OS). Results: The GPS values of the 113 patients were zero (54 patients, 48%), 1 (37 patients, 33%), and 2 (22 patients, 19%). The median follow-up duration was 10.7 months. Median PFS was 6.2, 5.6, and 3.8 months in the GPS 0, 1, and 2 groups, respectively, suggesting that the GPS zero group had a significantly more favorable PFS than the GPS 2 group (p < 0.001). Median OS was 17.1, 9.4, and 5.6 months in the GPS 0, 1, and 2 groups, respectively, suggesting that the GPS zero group had a significantly more favorable OS than the GPS 2 group (p = 0.001). Multivariate analysis confirmed that a GPS of 2 independently predicted unfavorable PFS (hazard ratio [HR], 2.89; 95% confidence interval [CI]: 1.68–4.88; p < 0.001) and OS (HR, 3.49 [95% CI: 1.83–6.63], p < 0.001). Conclusion: The study’s findings suggest that the GPS can predict the survival outcomes of patients with ES-SCLC who have undergone chemotherapy. The GPS is an easy-to-calculate biomarker and would be ideal for routine use in clinical settings.

The role of comorbidity indices and histochemical markers in surgically resected and non-resected primary central nervous system lymphoma.

The role of surgical resection in primary central nervous system lymphoma (PCNSL) was not recognized until recently. However, prognostic factors for surgically treated PCNSL remain unclear. In the present study, we aimed to identify and compare the prognostic value of comorbidity indices and immunohistochemical markers in patients with surgically and non-surgically treated PCNSL. This retrospective single-center study analyzed patients who underwent either surgical resection or stereotactic biopsy for newly diagnosed PCNSL between January 2012 and December 2021. Clinical demographics, comorbidity indices, and immunohistochemical markers were analyzed. We included 23 and 18 patients who underwent stereotactic biopsy and surgical resection, respectively. The median overall survival (OS) was 11.05months. Using multivariate Cox regression, we identified pretreatment prognostic nutritional index (PNI) (p = 0.009), positive BCL2 staining (p = 0.026), and infratentorial involvement (p = 0.004) as independent prognostic factors of OS. Predictors of progression-free survival (PFS) included PNI (p = 0.040), infratentorial involvement (p = 0.021), and surgical resection for PCNSL (p = 0.048). Subgroup analyses revealed that positive BCL2 (p = 0.048) and PD-L1 (p = 0.037) staining were associated with worse OS in the biopsy group. PNI and infratentorial involvement could significantly impact both OS and PFS in patients with PCNSL. Surgical resection could predict favorable PFS but not OS. Moreover, BCL2 and PD-L1 expression can be employed as prognostic markers in these patients.

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the Fondazione Italiana Linfomi MCL0208 trial.

In the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P< .05) and 85% vs 60% (P< .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P= .62). Moreover, the CRBN polymorphism (n= 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL.

Efficacy and Safety Profile of PD-1 Inhibitors Versus Chemotherapy in the Second-Line Treatment of Advanced Esophageal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Programmed death 1 (PD-1) inhibitors have emerged as the new standard of care for the second-line treatment of advanced esophageal squamous cell carcinoma. There have been lots of research lately concerning the topic. A comprehensive assessment of the efficacy and safety profile between PD-1 inhibitors and chemotherapy is warranted. Hence, we carried out a systematic review and meta-analysis to illustrate this issue. Pubmed, Embase, Cochrane Library, and Embase were searched systematically until May 1, 2022. We extracted data on efficacy and safety and calculated the pooled hazard ratios (HRs) and relative ratios (RRs) with 95% CI using randomized-effect or fixed-effect models. A subgroup analysis was applied to explore the factors modifying the response to PD-1 inhibitors. Ultimately, a total of 5 studies involving 1970 patients were included in our meta-analysis. PD-1 inhibitors group could attain greater overall survival (OS) benefit (HR = 0.73, 95% CI: 0.66-0.81, P < 0.001) and nearly favorable progression-free survival (HR = 0.89, 0.76-1.04, P = 0.13). Treatment-related adverse events (RR = 0.76, 95% CI: 0.64-0.91, P = 0.004) and level 3-5 treatment-related adverse events (RR = 0.40, 95% CI: 0.32-0.49, P < 0.001) were significantly diminished in PD-1 inhibitors groups. Among all modifying factors, programmed death ligand 1 combined positive score was positively associated with the patient's OS. The analysis suggests that PD-1 inhibitors exhibited better survival outcomes and safety profiles than standard-of-care chemotherapy. High levels of programmed death ligand 1 combined positive scores were associated with an enhanced response to PD-1 immunotherapies concerning OS.