Immunochemotherapy Combinations Research Articles

Efficacy and Safety of a Therapy Combining Sintilimab and Chemotherapy With Cryoablation in the First-Line Treatment of Advanced Nonsquamous Non-Small Cell Lung Cancer: Protocol for a Phase II, Pilot, Single-Arm, Single-Center Study.

Immunotherapy has significantly advanced lung cancer treatment, particularly in nonsquamous non-small cell lung cancer (NSCLC), with overall response rates between 50% and 60%. However, about 30% of patients only achieve a stable disease state. Cryoablation has shown potential to enhance immunotherapy by modifying the tumor's immune microenvironment through the release of antigens and immune factors. Addressing how to boost the immune response in these patients is critical. This study aims to investigate the efficacy and safety of immunochemotherapy in combination with cryoablation as a first-line treatment for advanced NSCLC. This is a phase II, pilot, open-label, single arm, single center, interventional study. Patients with stage IIIB to IIIC or IV NSCLC with T staging ranging from T1 to T2b will receive sintilimab (200 mg/m2 every 3 weeks) and chemotherapy. After 2 cycles, the feasibility of cryoablation will be considered for those with stable disease by a multidisciplinary team. Cryoablation with 3 freeze-thaw cycles will be performed for the main lesion. The third cycle of systemic therapy will begin 7 (SD 3) days after cryoablation. A total of 20 patients will be enrolled. Treatment will continue until the disease progresses, there is unacceptable toxicity, a participant withdraws consent, other discontinuation criteria are met, or the study reaches completion. The primary objective is to assess progression-free survival (PFS). The secondary objective is to assess efficacy through duration of response, disease control rate, overall survival (OS), and the safety profile. The exploratory objective is to investigate and compare immune factor changes after 2 cycles of immunochemotherapy and at 1, 3, and 7 days after cryoablation. Survival time will be estimated using the Kaplan-Meier method to calculate median PFS and OS. Any adverse events that occur during the trial will be promptly recorded. The project was funded in 2024, and enrollment will be completed in 2025. The first results are expected to be submitted for publication in 2027. This study will provide evidence for the efficacy and safety of the combination of immunochemotherapy and cryoablation as a first-line treatment for advanced NSCLC. Although it has a limited sample size, the findings of this study will be used in the future to inform the design of a fully powered, 2-arm, larger-scale study. ClinicalTrials.gov NCT06483009; https://clinicaltrials.gov/study/NCT06483009. PRR1-10.2196/64950.

B-227 Customized molecular tests for minimal residual disease: a tool for therapeutic decisions in follicular lymphoma patients

Abstract Background Monitoring of minimal residual disease (MRD) is based on accurate laboratory tests which can recognize a small fraction of malignant cells that survived the course of treatment. Several studies of the B-non-Hodgkin lymphoma group have been presented that MRD positivity at the end of treatment is a negative prognostic index. Follicular lymphoma (FL) is a chronic indolent malignancy, which response highly to immuno-chemotherapy followed by prolonged remissions but with inevitable relapse in most patients. The GALLIUM study showed that immuno-chemotherapy combinations, 6 cycles of bendamustine-obinutuzumab (BO), is the most efficacious treatment, but with severe side effects .In addition, 90% of patients achieved negative MRD from peripheral blood (PB) or bone marrow (BM) after only 3 BO cycles. These findings raise the possibility for MRD based treatment approach, where the duration of chemotherapy could be decided according to MRD status at mid-induction (MI). Identification of a marker in the PB and/or BM of each FL patient which will be use to the design of a sensitive RQ-PCR test for MRD detection for follow-up. Methods Qualitative PCR for translocation 14:18 and for the VDJ rearrangement sequence of the immunoglobulin heavy chain was used for marker identification. MRD monitoring was done by RQ-PCR. MRD monitoring for VDJ was designed specifically to each patients based on his VDJ sequence. MRD was assessed on PB and BM at MI. Results Marker for monitoring was identified at 11/21 patients in this study. After 3 combined therapy cycles, 7 patients were found to have MRD negativity by RQ-PCR therefore continue with immuno-therapy only. MRD positivity was assessed in BM of 3 patients (0.11%, 0.022%, and 0.133%). These 3 patients continued with the combined therapy. RQ-PCR sensitivity was 10-4-10-5. Conclusions This study will reveal the ability to use sensitive and specific MRD that has to be designed for each patient according to his marker and enable the establishment of a treatment with a high safety profile for FL patients. Correlation between MRD status and clinical and safety parameters will be assessed at the end of the study, 30 months after the first treatment, taking into account MRD status from different time point of the follow-up period.

Impact of timing of immunotherapy in survival among patients with advanced lung adenocarcinoma treated with first-line immunochemotherapy: A propensity score matching.

e20560 Background: Immunochemotherapy combinations have been the mainstream first-line standard treatment of advanced non-small cell lung cancer (NSCLC), wherein concurrent chemotherapy and immunotherapy are conventionally fixed to an established dosing regimen. Few studies had suggested the remarkable impact of the timing of immunotherapy on immunochemotherapy combined therapy. However, this issue has not been addressed in advanced NSCLC cohort. Methods: This study was a retrospective analysis of 532 patients with advanced lung adenocarcinoma (LUAD) without EGFR/ALK mutations who underwent immunochemotherapy as first-line systemic treatment between June 2018 to June 2022 at 3 facilities. Patients were divided into two groups (induced and non-induced) according to the different timing of immunotherapy in combined therapy, which defined induced as receiving 1 or more cycles of full-dose chemotherapy alone before concurrent immunochemotherapy. The bias between induced and non-induced groups was minimized with Propensity Score Matching (PSM). Patients outcomes, including progression-free survival (PFS) and overall survival (OS), were compared between the two groups by Kaplan-Meier survival curves and Cox regression analyses. Results: Survival analysis showed that both PFS and OS of the induced chemotherapy group patients were significantly longer than that of non-induced group (PFS: 14.63 months vs. 10.13 months, p = 0.004; OS: Not reached vs. 20.27 months, p = 0.0013). In the COX regression, after adjusting for confounders, induction chemotherapy was found to be a remarkable favorable factor for both PFS and OS (PFS: HR = 0.73, p= 0.018; OS: HR = 0.69, p= 0.034). After pretreatment features and treatment parameters were included in PSM, 104 patients were identified in each groups with matched characteristics, and moreover, the results of survival analysis remained consistent and showed significant difference between induced and non-induced group (PFS: 14.63 months vs. 10.23 months, p = 0.029; HR = 0.71, p= 0.030. OS: Not reached vs 18.27 months, p = 0.0013; HR = 0.52, p= 0.002). Conclusions: For advanced LUAD patients treated with first-line immunochemotherapy combinations, the timing of immunotherapy had significant impact on prognosis, which suggested notable benefit of induction chemotherapy before concurrent immunochemotherapy.

Efficacy and Safety of Ino Combined with Reduce Dose R-GDP Regimen in Patients with Relapsed/Refractory B-Cell NHL in China

Background: The combination of immunochemotherapy resulted in satisfactory efficacy and survival for B-cell Non-Hodgkin Lymphoma (NHL). But many patients face no response to combination therapy or the disease progression again. This study aimed to investigate the efficacy and safety of Inotuzumab Ozogamicin (InO) combined with reduce dose R-GDP as a salvage therapy in patients with relapsed/refractory (R/R) B-NLH. Patients and methods: Seven patients with R/R B-NLH or even failure of anti-CD19 and CD22 chimeric antigen receptor (CAR) T cell therapy received InO combined with reduce dose R-GDP combination therapy. All patients received Rituximab (R) 375mg/m 2 intravenously (IV) on day -1, and InO 0.8 mg/m 2 (IV) on day 0. Then Gemcitabine (G) 500-1000mg/m 2(IV), Dexamethasone (D) 40 mg/day (IV) on day 1-4 and Cisplatin (P) 40-75mg/m 2 (IV) on day 1 of each 21-day cycle (±2 days). Treatment was continued for up to two cycles unless progressive disease (PD) or intolerable toxicity occurred. The primary endpoint of this study was the Complete remission (CR) and Overall response rate (ORR). The secondary endpoint of this study was Progression-free survival (PFS), Overall survival (OS) and Adverse events (AE), particularly hematological toxicity. In our study, the response evaluation was detected using computed tomography (CT) or PET-CT. Results: Seven patients with R/R B-NLH received 1-2 cycles of InO combined with reduce dose R-GDP therapy. Three patients did not respond to anti-CD19 and CD22 CAR-T cell therapy or their disease progressed again. The other four patients did not respond to more than 3 lines of combined immunochemotherapy and never achieved Partial response (PR) or CR. Four patients with R/R B-NLH who received 1-2cycles of InO combined with reduce dose R-GDP therapy achieved CR and survived to this day. Three of the four patients had previously received anti-CD19 and CD22 CAR-T cell therapy. Two patients with R/R B-NLH achieved PR after one cycle of InO combined with reduce dose R-GDP therapy, the other one patient achieved Stable disease (SD) only. One R/R B-NLH patient who achieved CR after one cycle of this salvage therapy had a PFS of one year to date without any other treatments. The other three R/R B-NLH patients who achieved CR after 1-2 cycles of this salvage therapy had a PFS of 3-6 months without any other treatments. The other two patients who achieved PR after 1 cycle of this salvage therapy survived 7 months and 2 months, while the only one patient who achieved SD survived one month without any other treatment. The main AE of this study was hematological toxicity. Three patients were defined as 3-4 grade of neutropenia, four patients were defined as 3-4 grade of anemia and three patients were defined as 3-4 grade of thrombocytopenia in this study. Except for one patient who was defined as grade 3 of thrombocytopenia recovered nine months after this salvage therapy, all other patients recovered two to three months after this study. There have been no deaths from severe infections due to hematological toxicity. Conclusions Ino combined with reduce dose R-GDP therapy in patients with R/R B-NLH could be an effective and safety therapy. However, the GDP regimen needs to be reduced appropriately to avoid severe hematological toxicity.

PD-1 Inhibitors and Chemotherapy Combined with or without Radiotherapy for Patients with Oligometastatic Esophageal Cancer

Oligometastatic esophageal cancer (OMEC) is an intermediate state between local advanced and widespread metastatic disease, which is associated with better prognosis compared to poly-metastatic esophageal cancer (EC). The previous studies demonstrated the survival benefit from local radiotherapy for OMEC patients. But the data of PD-1 inhibitors combined with radiotherapy for OMEC is still scarce. The purpose of the present study was to determine the efficacy and safety of PD-1 inhibitors plus radiotherapy in OMEC. OMEC was defined as "up to five measurable metastatic lesions and up to three organs involved". Patients with OMEC receiving PD-1 inhibitors plus chemotherapy in a single center were retrospectively analyzed in this study. They were dichotomized according to whether or not they had received radiotherapy. The efficacy and safety of immunochemotherapy combined with radiotherapy (RT group) and immunochemotherapy alone (NRT group) were investigated. A total of 226 patients were included; 108 patients received PD-1 inhibitors plus chemotherapy and radiotherapy, while other 118 patients were treated with immunochemotherapy alone. Baseline characteristics were well balanced between the groups. The overall response rate (ORR) was 58.3% in the RT group and 41.5% in the NRT group (P = 0.012), respectively. The median PFS was 13.5 months (95% CI, 10.0-17.1) for the RT group and 8.8 months (95% CI, 9.2-12.0) for the NRT group (P = 0.000). The addition of radiotherapy was the major prognostic factor for PFS (hazard ratio, 0.56; 95% CI, 0.406-0.761; P = 0.000) by univariate Cox regression analysis. Patients were well-tolerated, and the overall incidence of adverse events was similar between the RT group and NRT group. In addition, the incidence of treatment-related pneumonitis did not differ between the two groups. Grade 3-5 pneumonitis was observed in 3.7% and 5.1% of patients in the RT and NRT groups, respectively. The additional of radiotherapy to PD-1 inhibitors and chemotherapy improved PFS of patients with OMEC and showed acceptable toxicity. Further prospective studies investigating the combination of immunochemotherapy and radiotherapy are warranted.

Monoclonal antibodies binding to different epitopes of CD20 differentially sensitize DLBCL to different classes of chemotherapy.

Rituximab (R), an anti-CD20 monoclonal antibody (mAb) and the world's first approved antibody for oncology patients, was combined with the CHOP chemotherapy regimen and markedly improved the prognosis of all B- cell-derived lymphomas, the most common hematological malignancy worldwide. However, there is a 35% disease recurrence with no advancement in the first-line treatment since R was combined with the archetypal CHOP chemotherapy regimen nearly 30 years ago. There is evidence that R synergizes with chemotherapy, but the pharmacological interactions between R and CHOP or between newer anti-CD20 mAbs and CHOP remain largely unexplored. We used in vitro models to score pharmacological interactions between R and CHOP across various lymphoma cell lines. We compared these pharmacological interactions to ofatumumab, a second-generation anti-CD20 mAb, and CHOP. Lastly, we used RNA-sequencing to characterize the transcriptional profiles induced by these two antibodies and potential molecular pathways that mediate their different effects. We discovered vast heterogeneity in the pharmacological interactions between R and CHOP in a way not predicted by the current clinical classification. We then discovered that R and ofatumumab differentially synergize with the cytotoxic and cytostatic capabilities of CHOP in separate distinct subsets of B-cell lymphoma cell lines, thereby expanding favorable immunochemotherapy interactions across a greater range of cell lines beyond those induced by R-CHOP. Lastly, we discovered these two mAbs differentially modulate genes enriched in the JNK and p38 MAPK family, which regulates apoptosis and proliferation. Our findings were completely unexpected because these mAbs were long considered to be biological and clinical equivalents but, in practice, may perform better than the other in a patient-specific manner. This finding may have immediate clinical significance because both immunochemotherapy combinations are already FDA-approved with no difference in toxicity across phase I, II, and III clinical trials. Therefore, this finding could inform a new precision medicine strategy to provide additional therapeutic benefit to patients with B-cell lymphoma using immunochemotherapy combinations that already meet the clinical standard of care.

A phase 2 study of HLX07 as monotherapy or combination therapy in patients with locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma.

4029 Background: Esophageal cancer is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. Most patients are diagnosed at the advanced stage, and the prognosis remains poor. About 40–84% of ESCC cases showed overexpression of EGFR which was related to shorter overall survival and disease-free survival, indicating that treatment targeting EGFR could be a new strategy. This study aimed to evaluate the efficacy and safety of HLX07, a novel recombinant humanized anti-EGFR monoclonal antibody (mAb), as monotherapy or combination therapy in patients with locally advanced, unresectable/metastatic ESCC. Methods: In this open-label, multicenter phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed locally advanced, unresectable/metastatic ESCC or esophageal adenosquamous carcinoma were enrolled. Patients with no prior systemic antitumor therapy were assigned to group A and given HLX07 1000 mg plus serplulimab 200 mg (anti-PD-1 mAb) and chemotherapy (5-FU 2400 mg/m2 + cisplatin 50 mg/m2), Q2W IV. Patients who had failed first-line immuno-chemotherapy combination or at least two lines of other systemic antitumor therapy were assigned to group B and given HLX07 monotherapy (1000 mg Q2W IV). The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) assessed by an independent radiological review committee and investigators per RECIST v1.1. Secondary endpoints included other efficacy measures, safety, pharmacokinetics, immunogenicity, and biomarker explorations. Results: As of February 4, 2023, 49 patients were enrolled in group A (n=30) and group B (n=19), with a median age of 64.5 and 59.0 years, respectively. 26 (86.7%) patients in group A and all patients in group B were male. The median follow-up duration was 2.9 months, and the preliminary efficacy was presented. Among the 42 efficacy evaluable patients (29 in group A and 13 in group B), investigator-assessed ORRs were 55.2% (95% CI 35.7–73.6%) and 23.1% (95% CI 5.0–53.8%) in the respective groups. Investigator-assessed median PFSs were not reached in group A and 1.5 months (95% CI 1.2–not evaluable) in group B. 15 (50.0%) patients in group A and 5 (26.3%) in group B had grade ≥3 treatment-emergent adverse events (AEs). AEs of special interest were observed in 16 (53.3%) and 11 (57.9%) patients, respectively, most commonly rash (43.3% vs 47.4%) and hypomagnesemia (33.3% vs 36.8%). No drug-related death was reported. Conclusions: The encouraging antitumor activity and manageable safety profile support further development of HLX07 as a new treatment option for patients with advanced ESCC, both in first-line and late-line settings. Clinical trial information: NCT05221658 .

SO-33 Neoadjuvant immunotherapy in gastrointestinal tumors with mismatch repair deficiency: An institutional analysis

Clinical trials have reported robust anti-tumor activity of immunotherapy (IO) in metastatic deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) solid tumors. However, data documenting the efficacy of IO as neoadjuvant therapy in localized, locally advanced, and oligometastatic dMMR/MSI-H gastrointestinal (GI) cancers are sparse. We performed a single-institution retrospective analysis to evaluate the efficacy of neoadjuvant IO in dMMR/MSI-H GI cancer patients. The current study included histologically documented dMMR/MSI-H GI cancer patients aged >18 years who had localized, locally advanced, or oligometastatic disease and received neoadjuvant IO in a tertiary care cancer center between January 1, 2015 and December 31, 2021. Electronic medical records of the patients were reviewed to gather de-identified data on patient characteristics, tumor characteristics, treatment details, duration of IO, response to IO, and survival. The data cutoff date was March 15, 2022. The analysis included 28 patients with the following patient characteristics: median age- 62 years (range, 32-90); gender- male 15 (53 %) and female 13 (47%), race- Caucasian 21(75%), African American 7 (25%). The tumor types included adenocarcinomas of colon 18/28 (64%), pancreas 4/28 (14%), stomach 2/28 (7%), biliary tract 2/28 (7%), duodenum 1/28 (4%), and rectum 1/28 (4%). The stage distribution was as follows: stage II-1 patient (3%), stage III-17 (61%), and stage IV (oligometastatic disease)- 10 (36%). The surgery was not pursued upfront either because of the extent of the tumors or comorbid conditions precluding surgery. The IO consisted of pembrolizumab in 22 (79%) patients, ipilimumab and nivolumab combination in 4 (14%), and immunochemotherapy combination in 2 (7%). Of the 28 patients, 15 (54%) received IO in the first-line and the rest in the second-line setting. The overall response rate was 75% (21/28): 6 (21 %) radiologic complete responses (CR), 3 (11 %) pathologic CR (pCR), 11 (39%) partial responses, 1(4%) clinical CR (cCR), 5 (18%) stable disease, and 2 (6%) progressive disease. The median duration of IO was 6.5 months (range, 2 to 52), and the median time to best response was 4 months (range, 2 to 10). After a median follow-up of 11.5 months (range, 3-78) from the beginning of IO, the median progression-free survival and overall survival were not reached, and only 4 (14%) patients died. After neoadjuvant IO, 4 (14%) patients underwent surgery, and 3 out of 4 patients did not have a viable tumor in the surgical specimen. All 14 patients who had at least 12 months of follow-up from the beginning of IO remained progression-free. Adverse events (AEs) of any grade were seen in 10 (36 %) patients and 6 (21%) patients had grade > 3 AEs. In this small cohort of patients with dMMR/MSI-H GI tumors, neoadjuvant IO was associated with a high response rate, including complete responses in a significant proportion of patients. Further studies are needed to examine neoadjuvant IO as a standard strategy for patients with locally advanced and oligometastatic dMMR/MSI-H GI cancers. Furthermore, neoadjuvant IO may potentially offer non-operative management in patients with localized and locally advanced dMMR/MSI-H GI cancers.

First-line PD-1 inhibitors immunotherapy and chemotherapy combined with or without radiotherapy for patients with advanced non-small cell lung cancer.

2606 Background: Immunochemotherapy has become a standard first-line regimen for advanced non-small-cell lung cancer (NSCLC). Several studies showed the synergistic effects of immunotherapy and radiotherapy on local and abscopal tumour control. But the data of first-line immunochemotherapy combined with radiotherapy for the advanced NSCLC is still scarce. Methods: Patients with advanced NSCLC receiving first-line PD-1 inhibitors immunotherapy plus chemotherapy in a single center were retrospectively analyzed in this study. They were divided into two groups according to whether they had received radiotherapy. The efficacy and safety of first-line immunochemotherapy combined with radiotherapy (ICRT group) and immunochemotherapy alone (ICT group) were investigated. Results: A total of 135 patients were included; 65 patients received PD-1 inhibitors plus chemotherapy and radiotherapy, while other 70 patients were treated with immunochemotherapy alone. The median interval time between radiotherapy and PD-1 inhibitors immunotherapy was 5 days (range, 0-96 days). The overall response rate (ORR) was 50.8% in the ICRT group and 40.0% in the ICT group, respectively. Patients in the ICRT group achieved significant longer progression-free survival (PFS, median 16.5 vs 10.4 months, P= 0.043) and overall survival (OS, median not reached vs 21.0 months, P= 0.030) compared with those in the ICT group. The addition of radiotherapy was the only prognostic factor for PFS (HR = 0.617, 95%CI: 0.385-0.989, P= 0.045) and OS (HR = 0.512, 95%CI: 0.277-0.947, P= 0.033) by univariate Cox regression analysis. Patients were well tolerated and the overall incidence of adverse events was similar between the ICRT group and ICT group. One patient in ICRT group stopped immunotherapy because of severe immune-associated pneumonia. 3.1% of grade 3-4 radiation-related adverse events were observed. Conclusions: Adding radiotherapy to first-line PD-1 inhibitors immunotherapy and chemotherapy improved outcomes of patients with advanced NSCLC and showed acceptable toxicity. Additional prospective studies exploring the first-line combination of immunochemotherapy and radiotherapy are warranted.

Treatment efficacy of HER2-mutant lung adenocarcinoma by immune checkpoint inhibitors: a multicenter retrospective study.

Despite the remarkable clinical advance of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, there are limited studies focused on evaluating efficacy of ICIs for patients with human epidermal growth factor receptor 2 (HER2)-mutant lung adenocarcinoma. We conducted a multicenter retrospective study of patients with HER2-mutant lung adenocarcinoma who received ICIs therapy at Shanghai Pulmonary Hospital, Shanghai Chest Hospital and the First Affiliated Hospital of Wenzhou Medical University between 2016 and 2021. Response was defined with reference to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Among the 26 patients enrolled in our study, the overall objective response rate (ORR) was 38.5%, disease control rate (DCR) was 84.6% and median progression-free survival (PFS) was 7.4months. Majority of patients were treated with immunochemotherapy combination regimens (16/26, 61.5%), with a median PFS of 8.4months. Among the 9 patients receiving ICIs-based therapy as first-line treatment, 5 patients had partial response (PR) and 4 patients had stable disease (SD), with a median PFS of 9.1months. Of the entire cohort, 5 patients who received ICIs before epidermal growth factor receptor (EGFR)/HER2-targeting drugs achieved a median PFS of 8.4months. Our retrospective study provides clinical evidence that front line of ICIs-based therapy is also worth considering for the treatment to improve survival outcomes of patients with HER2-mutant lung adenocarcinoma.

Application and Outcomes of Bendamustine- or Bortezomib-Based Therapy for Waldenstrom's Macroglobulinemia

Background: Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a rare lymphoproliferative disorder typically affecting older patients and characterized by unique complications of IgM paraproteinemia. Treatment of this disease largely relies on phase 2 clinical trials or extrapolation of data from pooled studies in indolent B-cell lymphomas. We have previously shown a rapid uptake of novel, expensive therapies (bendamustine and bortezomib) for WM/LPL in the US, despite uncertain advantage over classical cyclophosphamide-based chemoimmunotherapy (Olszewski et al., Oncologist, 2016). We now examined patterns of use of these novel agents, associated survival, and cost outcomes, in population-based data. Methods: Using Medicare claims linked to the Surveillance, Epidemiology, and End Results registry, we identified WM/LPL patients aged ≥65 years who initiated first-line rituximab-based therapy in 2008-2014, and had complete Medicare claims available. We classified regimens into: rituximab alone, rituximab in combination with classical cytotoxic agents (cyclophosphamide, fludarabine, etc.) or with novel agents: bendamustine or bortezomib. We evaluated patient characteristics associated with the use of classical immunochemotherapy, bendamustine, or bortezomib, in a multinomial logistic model, reporting relative risk ratio (RRR) with 95% confidence intervals (CI). We then compared overall survival (OS) after therapy in a proportional hazard model adjusting for age, sex, race, comorbidity index, presence of kidney disease, poor performance status, and indicators of WM severity: anemia, neuropathy, need for plasmapheresis, transfusions, or hospitalization prior to therapy. Mean total Medicare spending within 1 year from starting therapy was compared in a log-gamma model, inflation-adjusted to 2013 dollar value. Results: Among 681 patients, 58% received upfront rituximab alone (N=392), 22% rituximab in combination with classical chemotherapy (N=151), 11% with bortezomib (N=76), and 9% with bendamustine (N=62). The proportion receiving bendamustine or bortezomib significantly increased between 2008 and 2014, displacing classical immunochemotherapy, but not rituximab monotherapy (Fig. A). In the multivariable model, patients treated with bortezomib were significantly more likely to be black than white (RRR, 7.49; 95%CI, 1.62-34.7; P=.010), more likely to be diagnosed as WM rather than LPL (RRR 2.38; 95%CI, 1.25-4.53; P=.008), and more likely to have chronic kidney disease (RRR, 3.18; 95%CI, 1.12-9.02; P=.029) or plasmapheresis before treatment (RRR, 2.99; 95%CI, 1.01-8.85; P=.048). Conversely, no black patients received bendamustine, which was also significantly less often administered to women (RRR, 0.46; 95%CI, 0.23-0.92; P=.027), patients with a prior hospitalization (RRR, 0.37; 95%CI, 0.17-0.78; P=.009), or with WM diagnosis code (RRR, 0.55; 95%CI, 0.29-1.04; P=.07). After adjustment for baseline patients characteristics we observed no significant difference in OS between immunochemotherapy combinations with classical agents and with bendamustine (hazard ratio, HR, 0.84; 95%CI, 0.46-1.53; P=.57) or bortezomib (HR, 1.07; 95CI, 0.68-1.69; P=.77; Fig. B). Mean total Medicare spending during the first year of therapy was over $20,000 higher for patients treated with bortezomib (P=.015) or bendamustine (P=.011) compared with the classical immunochemotherapy (Fig. C). Conclusions: Although about half of older patients with WM/LPL in the US continue to be treated with rituximab alone, bendamustine and bortezomib have largely replaced classical cytotoxic agents for those who receive combination immunochemotherapy. Clinicians favor bortezomib for patients with paraprotein-associated complications, and bendamustine for LPL-like presentations, even though differential benefits of these drugs are not supported by prospective evidence. Treatment decisions may thus result from extrapolation of data on myeloma or other lymphomas. Considering no apparent survival difference and higher costs of treatment with the novel agents, their value compared with classical regimens (like dexamethasone-cyclophosphamide-rituximab [Kastritis et al., Blood, 2015]) should be reconsidered in the US practice, and more precisely defined with further clinical research. Download : Download high-res image (145KB) Download : Download full-size image Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding.

Myocardial infarction in diffuse large B-cell lymphoma patients - a population-based matched cohort study.

The outcome for diffuse large B-cell lymphoma (DLBCL) patients has improved with the immunochemotherapy combination R-CHOP. An increased rate of heart failure is well documented following this treatment, whereas incidence and outcome of other cardiac complications, for example myocardial infarction, are less well known. We identified 3548 curatively treated DLBCL patients in Sweden diagnosed between 2007 and 2014, and 35474 matched lymphoma-free general population comparators. The incidence, characteristics and outcome of acute myocardial infarctions (AMIs) were assessed using population-based registers up to 11years after diagnosis. The rate of AMI was estimated using flexible parametric models. Overall, a 33% excess rate of AMI was observed among DLBCL patients compared with the general population (HR: 1.33, 95% CI: 1.14-1.55). The excess rate was highest during the first year after diagnosis and diminished after 2years. High age, male sex and comorbidity were the strongest risk factors for AMI. Older patients (>70years) with mild comorbidities (i.e. hypertension or diabetes) had a 61% higher AMI rate than comparators (HR: 1.61, 95% CI: 1.10-2.35), whereas the corresponding excess rate was 28% for patients with severe comorbidities (HR: 1.28, 95% CI: 1.01-1.64). Among younger patients (≤70), a short-term excess rate of AMI was limited to those with severe comorbidities. There was no difference in AMI characteristics, pharmacological treatment or 30-day survival among patients and comparators. DLBCL patients have an increased risk of AMI, especially during the first 2years, which calls for improved cardiac monitoring guided by age and comorbidities. Importantly, DLBCL was not associated with differential AMI management or survival.

Síndromes linfoproliferativos

Lymphoproliferative syndromes are hematologic neoplasms that have the common trait of clonal proliferation of lymphoid cells. They can be of B-cell or T-cell origin. All have proto-oncogenic and/or suppressor gene abnormalities that give tumor clone cells an advantage in terms of proliferation. Each lymphoproliferative syndrome has specific immunophenotypic and morphological characteristics. Therefore, to establish a certain diagnosis, it is necessary to perform a morphological, immunological, and molecular study in peripheral blood and/or the affected tissue. There are various therapeutic options that depend on the patient's comorbidity, the stage of the disease, and molecular alterations. Options include immunotherapy, a combination of immunochemotherapy, or even an allogeneic hematopoietic progenitor cell transplantation.

Four lines of immunochemotherapy combinations in a young patient with an aggressive metastatic colorectal cancer

We report on a 42-year-old woman with colorectal cancer of the sigmoid colon with synchronous pulmonary metastases being treated since June of 2016. With a poorly differentiated, KRAS, NRAS and BRAF wildtype cancer and an advanced stage of the disease we look back to almost four years of treatment and a sequence consisting of four lines of polychemotherapy. Dynamic treatment without achieving relevant treatment-free periods resulted in a satisfying quality of life and prolonged overall survival. Exceptional cases in young and very fit patients support the benefit of a more aggressive treatment strategy.

Vinorelbine in Non-Small Cell Lung Cancer: Real-World Data From a Single-Institution Experience.

The use of vinorelbine as a single agent or in combination regimens in non-small cell lung cancer (NSCLC) is associated with satisfactory clinical activity. However, the role of vinorelbine-based chemotherapy in chemonaive locally advanced unresectable or metastatic NSCLC patients, according to real-world treatment patterns, has still not been widely explored. Eighty-one patients treated at a single institution were retrospectively analyzed. Thirty-seven received standard first-line single-agent vinorelbine, and 44 received vinorelbine plus platinum drugs, based on physician’s choice; 61.7% were older than 70 years, and 60.5% were affected by ≥2 comorbidities. Sixty-three patients were evaluable for objective response: 22% achieved partial response and 41% stable disease. Median progression-free survival (PFS) was 5.4 months. A benefit in PFS was observed in patients treated with combinations vs. single-agent vinorelbine (6.7 vs. 3.5 months, p = 0.043). Median overall survival (OS) was 10.4 months without a statistically significant difference between treatments (12.4 vs. 7.5 months). In 55 stage IV patients, OS was positively correlated with combination regimens, M1a stage, or ≤2 metastatic lesions. Grade 3–4 toxicity occurred in 33% of patients, and dose reduction in 11%. A statistically significant higher incidence of toxicity was observed in patients receiving combinations, in women, in patients younger than 75 years, or patients with metastases. In this real-word analysis, we confirmed the efficacy and tolerability of vinorelbine as a single agent or combined with platinums in patients usually underrepresented in controlled clinical trials. Single-agent vinorelbine may represent a suitable option in elderly or unfit NSCLC patients and warrants investigation as a potential drug candidate for immunochemotherapy combination regimens.

Pemetrexed Enhances Membrane PD-L1 Expression and Potentiates T Cell-Mediated Cytotoxicity by Anti-PD-L1 Antibody Therapy in Non-Small-Cell Lung Cancer.

Immunotherapy has significantly changed the treatment landscape for advanced non-small-cell lung cancer (NSCLC) with the introduction of drugs targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1). In particular, the addition of the anti-PD-1 antibody pembrolizumab to platinum-pemetrexed chemotherapy resulted in a significantly improved overall survival in patients with non-squamous NSCLC, regardless of PD-L1 expression. In this preclinical study, we investigated whether chemotherapy can modulate PD-L1 expression in non-squamous NSCLC cell lines, thus potentially affecting immunotherapy efficacy. Among different chemotherapeutic agents tested, only pemetrexed increased PD-L1 levels by activating both mTOR/P70S6K and STAT3 pathways. Moreover, it also induced the secretion of cytokines, such as IFN-γ and IL-2, by activated peripheral blood mononuclear cells PBMCs that further stimulated the expression of PD-L1 on tumor cells, as demonstrated in a co-culture system. The anti-PD-1/PD-L1 therapy enhanced T cell-mediated cytotoxicity of NSCLC cells treated with pemetrexed and expressing high levels of PD-L1 in comparison with untreated cells. These data may explain the positive results obtained with pemetrexed-based chemotherapy combined with pembrolizumab in PD-L1-negative NSCLC and can support pemetrexed as one of the preferable chemotherapy partners for immunochemotherapy combination regimens.

Radiotherapy after immunochemotherapy improves outcomes in patients with primary mediastinal large B‐cell lymphoma

AbstractObjectivePrimary mediastinal B‐cell lymphoma is a rare and unique type of non‐Hodgkin's lymphoma that develops more frequently in younger patients and women. The combination of immunochemotherapy and radiotherapy (RT) has been suggested as the primary treatment choice. However, no consensus has been reached. Thus, we carried out an open‐label clinical trial. Patients with complete response after six cycles of immunochemotherapy were randomized to receive or not receive RT (control group).MethodsFrom July 2004 to December 2012, 324 patients with primary mediastinal B‐cell lymphoma were enrolled and randomized at 1:1, with 164 and 160 patients in the RT and control groups, respectively.ResultsThe 5‐year progression‐free survival was 84% (95% confidence interval [CI] 77–89%) in the RT group and 67% (95% CI 60–76%) in the control group (P < 0.01). The 5‐year overall survival was 86% (95% CI 79–96%) in the RT group and 68% (95% CI 60%–74%) in the control group (P < 0.01). Toxicity was minimal and well controlled. No late toxicities were observed.ConclusionRT as adjuvant treatment in patients with complete response after six cycles of immunochemotherapy improved the progression‐free survival and overall survival with minimal toxicities.

Identification of Patients with Follicular Lymphoma Patients at Risk of Failing Frontline Immunochemotherapy and Rituximab Maintenance

Introduction:Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that represents 15-30% of all newly diagnosed lymphomas. It is characterized by a high rate of response followed by continuous relapses being considered incurable with standard immunochemotherapy regimens (Ardeshna et al. Lancet. 2003). The combination of immunochemotherapy and rituximab maintenance (Rm) improves progression free survival (PFS) when compared with a cohort without Rm (51% vs 35%) (Salles G. et al. ASH, 2017), being the standard for many centers. This improvement may have changed the risk assessment in FL. However, there is a need for identifying those patients with a poor prognosis with standard Rm-based therapy and candidates to receive alternative approaches using new drugs such as obinutuzumab with better reported results in this frontline setting (Gallium trial) (Marcus et al., 2017).Methods:From February-2002 to October-2016, all newly diagnosed FL patients with the intention to treat with immunochemotherapy and Rm where included. The participant centers were Son Espases University Hospital and Hospital del Mar of Barcelona. Clinical data were retrospectively collected from clinical histories and standard prognostic variables were evaluated at diagnosis including FLIPI and FLIPI-2. Another prognostic markers were defined: POD12 (progression of disease at 12 months), POD24 (progression of disease at 24 months) and POD30 (progression of disease at 30 months). The regimen effectiveness was evaluated based on the CT or PET/CT findings. Overall survival (OS) and PFS were determined from the date of the first cycle and they were estimated through Kaplan-Meier.Results:A total of 96 patients were included in the study with a median follow-up of 68 months. Main characteristics of the sample are shown in Tables 1. Briefly, median age was 61 years old, 88% where diagnosed in an advanced stage (III-IV), 36% and 38% presented with high risk (3-5) FLIPI and FLIPI2. Five-year OS and PFS was of 94% and 78% respectively. Univariate survival analysis proved that ECOG and response rate affected PFS and that stage and response influenced OS. In this analysis, no significant relation was found between the studied variables and POD12, POD24 or POD30 except beta2-microglobuline in POD30.Conclusions:•Frontline Rm significantly improves outcomes of FL patients.•It seems that it is not possible to predict only with clinical variables which patients are in high risk of failure to a standard approach with immunochemotherapy followed by Rm.•Additional prognostic factors such as molecular markers may help to identify these patients at risk of failure at the beginning of a first line of immunochemotherapy followed by Rm, and candidates for alternative approaches. DisclosuresNo relevant conflicts of interest to declare.

First-Line Therapies for Metastatic Lung Adenocarcinoma Without a Driver Mutation.

Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non-small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.

Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry

IntroductionPrognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. Patients and MethodsIn the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown. ResultsCytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment. ConclusionThe present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment.