Part Of First-line Therapy Research Articles

Oligometastatic non-small cell lung cancer: Impact of local and contemporary systemic treatment approaches on clinical outcome.

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy.

Radiotherapy in younger patients with advanced aggressive B-cell lymphoma—long-term results from the phase 3 R-MegaCHOEP trial

The role of consolidative radiotherapy (RT) for patients with aggressive B-cell lymphoma has not been fully elucidated. The R-MegaCHOEP trial investigated the use of high-dose chemotherapy and rituximab with subsequent autologous stem cell transplantations compared to conventional immunochemotherapy (R-CHOEP) for high-risk patients up to 60 years. The study protocol included RT for patients with bulky (maximum diameter ≥7.5 cm) or extranodal disease. Two-hundred sixty-one patients were analyzed, 120 of whom underwent RT. The most frequently irradiated regions were mediastinum (n = 50) and paraaortic (n = 27). Median RT dose was 36 Gray in median fractions of 1.8 Gray. Acute toxicities were mostly mild to moderate, with only 24 and 8 grade 3 and 4 toxicities reported during RT. Patients with bulky disease who received RT showed significantly better 10-year EFS, PFS and OS (EFS: 64% vs. 35%; p < 0.001; PFS 68% vs. 47%; p = 0.003; OS: 72% vs. 59%; p = 0.011). There was no significant increase in secondary malignancies with the use of RT. RT administered for consolidation of bulky disease after immunochemotherapy improved the prognosis of young high-risk patients with aggressive B-cell lymphoma and should be considered part of first-line therapy. The trial was registered with ClinicalTrials.gov, number NCT00129090.

Consolidative Autotransplantation Achieves High Cure Rates in Adverse-Risk Large B Cell Lymphoma

There remains an unmet need to optimize the first-line treatment of patients with high-risk large B cell lymphoma (LBCL), particularly those with a high International Prognostic Index (IPI) score or a positive interim positron emission tomography (PET) scan who experience poor outcomes with R-CHOP. This study was conducted to evaluate the real-world effectiveness of consolidative autologous stem cell transplantation (ASCT) among patients with high-risk LBCL. This retrospective study included consecutive patients with LBCL and IPI score 4 or 5 who underwent consolidative ASCT as part of first-line therapy in Alberta, Canada. Progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS) were determined using the Kaplan-Meier method. The study cohort comprised 114 patients with median age of 60 years (range, 18 to 73 years), of whom 81 (71%) had an IPI score of 4 and 33 (29%) had an IPI score of 5. With a median follow-up of 5.6 years, the 5-year PFS was 72% (95% confidence interval [CI], 62% to 79%), 5-year OS was 74% (95% CI, 64% to 81%), and 5-year DSS was 80% (95% CI, 71% to 87%). There was no significant difference in PFS among patients with and patients without positive interim PET scans (n = 24), MYC and BCL2 and/or BCL6 rearrangements (n = 26), or central nervous system involvement (n = 15). Consolidative ASCT is associated with high cure rates and favorable survival outcomes in patients with high-risk LBCL and may overcome the adverse prognostic impact of a positive interim PET scan.

СПИРОНОЛАКТОН В СОСТАВЕ АНТИГИПЕРТЕНЗИВНОЙ ТЕРАПИИ ПЕРВОЙ ЛИНИИ: ВЛИЯНИЕ НА СОСУДИСТОЕ РЕМОДЕЛИРОВАНИЕ

Introduction. Previously, clinical studies have proven a pronounced antihypertensive effect of spironolactone in patients with true resistant hypertension. The effectiveness of spironolactone as part of first-line therapy, as well as the effect on vascular wall remodeling, has not been studied. Target. To study the effect of spiroconolactone as part of the first line of therapy when added to telmisartan on indicators of vascular wall stiffness in patients with hypertension at high/very high cardiovascular risk. Materials and methods 32 patients (54 (45; 59) years old) were randomly divided into two groups: in the main group receiving spironolactone at a dose of 25 mg in addition to telmisartan (ARB/spironolactone) and in the group receiving hydrochlorothiazide/ARB combination (control). group). Inclusion criteria: age of patients (30-65 years), hypertension at high/very high cardiovascular risk without antihypertensive therapy, no contraindications to prescribed drugs. At baseline and 6 months later, all patients underwent clinical (office) blood pressure (BP) measurements, ABPM, endothelium-dependent vasodilation (EDVD), vascular remodeling indicators: central blood pressure (CAP), augmentation index, pulse wave velocity (PWV). In patients in the ARB/spironolactone group, serum potassium levels were assessed at baseline and after 4 weeks of treatment. Results. In both groups, a significant decrease in clinical and average daily blood pressure was revealed, as well as a decrease in the augmentation index and CAP. PWV in the carotid-radial segment (CWCR) did not significantly decrease in both groups, while PWV in the carotid-femoral area (CWCF) decreased in the ARB/spironolactone group from 9.8 (9.0; 10.6) m/s to 8.6 (8.0; 10.2) m/s (p = 0.0007). The dynamics of SPWcr was 0.9 (1.3;-0.5) m/s in the ARB/HCT group. In all patients, blood potassium was within reference values. Conclusions. Spironolactone as part of first-line therapy, when added to ARBs in patients with hypertension at high/very high cardiovascular risk, led to a significant decrease in clinical and mean daily blood pressure, as well as a decrease in PWCF.

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism.

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.

Long-Term Survival of Patients with Mantle Cell Lymphoma after Total Body Irradiation, High-Dose Chemotherapy and Stem Cell Transplantation: A Monocenter Study.

In patients with mantle cell lymphoma (MCL), long-term remissions can be achieved by stem cell transplantation (SCT). Different conditioning treatment protocols exist with or without total body irradiation (TBI). There are few data published on the role of TBI before autologous stem cell transplantation (autoSCT) or allogenic stem cell transplantation (alloSCT). We report on the long-term survival data of patients treated by TBI prior to autologous or allogenic SCT at our center. In a retrospective analysis, the data of patients treated at the University Hospital of Muenster from May 2004 to February 2015 were collected and evaluated. For the analysis, all data of patients who were histopathologically diagnosed with MCL and underwent TBI prior to stem cell transplantation (SCT) were evaluated. A total of 22 patients (19 men and 3 women) were treated with a TBI-based conditioning prior to SCT. The median age at initial diagnosis was 57.5 years (38-65 years). Seventeen patients had Ann Arbor stage IV, two patients had Ann Arbor stage III, and three patients Ann Arbor stage II disease. AutoSCT was performed in 19 patients and alloSCT was performed in 3 patients. In 18 patients, autoSCT was applied as part of first-line therapy, and in one patient after relapse. Two patients received alloSCT after relapse of MCL, and one patient received alloSCT during first-line therapy after an inadequate treatment response. TBI was performed in 12 patients with 10 Gy and in 6 patients with 12 Gy, these patients subsequently received autoSCT. In the group of four patients who received TBI with four Gy, four patients subsequently received alloSCT and one patient received autoSCT. Median overall survival after autoSCT and previous TBI was 11.4 years (142 months). In total, 11 out of 19 patients treated with autoSCT lived longer than 6.8 years (82-202 months). After alloSCT and previous TBI, the median overall survival was 3.25 years (14-59 months). A large proportion of patients with advanced MCL survived remarkably longer than 11.4 years after high-dose chemotherapy, TBI, and SCT. The present results of multimodal treatment support the published reports that TBI-based high-dose therapy followed by autoSCT is highly effective in this prognostically unfavorable disease situation.

Outcomes of Multiple Myeloma Patients Refractory to Standard Dose Vs Low Dose Lenalidomide

Background: Lenalidomide (Len) containing regimens are extensively used as first line therapy in multiple myeloma (MM). Since most patients (pts) eventually relapse while on these regimens or on Len maintenance, refractoriness to Len is an important factor in determining the choice of therapy at first relapse. It remains debatable if resistance to Len varies between pts who progress on a standard dose of Len (e.g., 25 mg daily, in combination with other agents or otherwise), and those who progress on single agent low dose Len (e.g., 10 mg daily). To this extent, often pts progressing on standard doses are considered refractory to Len, while pts progressing on maintenance doses are considered Len sensitive. In this study, we sought to assess the impact of refractoriness to standard dose vs low dose Len on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts diagnosed from January 2004 to December 2018, who progressed on/ after receiving first line therapy with Len containing regimens. We divided pts into 3 groups based on refractoriness to Len at first relapse- 1. Pts progressing on or within 60 days of receiving 25 mg Len (Standard Dose Refractory), 2. Pts progressing on or within 60 days of receiving 5-15 mg Len (Low Dose Refractory), and 3. Pts who received Len as a part of first line therapy but progressed after 60 days of stopping Len (Not Refractory). In addition to Len, we classified pts as refractory to proteasome inhibitors (PI) or daratumumab (Dara) at first relapse. We classified salvage regimens into Dara, PI, immunomodulatory drug (IMiD), PI+IMiD, elotuzumab, and VDT PACE like regimens. We used the International Staging System (ISS) and mSMART criteria for risk stratification. We assessed progression free survival (PFS) and overall survival (OS) on next line therapy, as well as for next Len containing line of therapy using Kaplan Meier and Cox models. Results: A total of 312 pts were included. Median age at diagnosis was 65 years and 60% pts were male. Overall, 30%, 33%, and 23% pts were ISS stage I, II, and III respectively; 33% pts had a high-risk FISH abnormality. At first relapse, 54 (17 %) pts were Standard Dose Refractory, 124 (40 %) were Low Dose Refractory, and 134 (43 %) were Not Refractory. For next line of therapy, no PFS difference was found between Standard Dose Refractory and Low Dose Refractory pts (14.5 months vs 12.6 months, p=0.76, Figure 1). As compared to Not Refractory pts (median PFS 29 months), the median PFS was inferior for both Standard Dose Refractory (PFS 14.5 months, p=0.002) and Low Dose Refractory pts (PFS 12.6 months, p<0.001). Using the Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, type of salvage regimen, and receipt of ASCT at relapse; the Not Refractory group had a better PFS (Hazard Ratio (HR)= 0.37, 95% CI: 0.24-0.57), while no difference was seen in the Standard Dose Refractory group (HR= 0.95, 95% CI: 0.59-1.51) as compared to the Low Dose Refractory group. Among the 312 pts, 124 (39.7 %) pts had received another Len containing regimen after the first line regimen at any time during the disease course. For this line of therapy, when compared to Not Refractory pts (median PFS 37 months), the median PFS for the Standard Dose Refractory group was 6 months (p<0.001) and for the Low Dose Refractory group was 10 months (p<0.001). Again, no PFS difference was found between Standard Dose vs Low Dose Refractory groups (p=0.79, Figure 1). On adjusting for parameters as above, the Not Refractory group had a better PFS (HR= 0.24, 95% CI: 0.13-0.44), while no difference was seen in the Standard Dose Refractory group (HR= 1.26, 95% CI: 0.6-2.63) when compared to the Low Dose Refractory group. In terms of OS, no differences were seen among Low Dose Refractory, Standard Dose Refractory, and Not Refractory groups, both from the time of first relapse (HR= 1 vs 1.03 (0.57-1.85) vs 0.62 (0.36-1.07) respectively), and from start of next Len containing regimen (HR= 1 vs 2.3 (0.78-6.74) vs 1.2 (0.45-3.18) respectively); after adjusting for above listed characteristics. Conclusions: The PFS for next line therapy and next Len containing line of therapy did not differ between pts refractory to standard dose vs low dose Len, and both were significantly inferior to pts who were not refractory to Len. These data suggest that resistance to Len is not dose dependent, and definition of Len refractoriness should not depend on the dose of Len to which the pts were considered refractory. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53-wild Type Mantle Cell Lymphoma

Background: Despite improved approaches to prognostication in mantle cell lymphoma (MCL), the impact of specific genomic aberrations is not well-described beyond TP53, which is well recognized as a high-risk marker across malignancies and widely assessed at time of diagnosis. However, since outcomes in patients without TP53 aberrations can be highly variable and difficult to predict, additional molecular markers are needed to identify patients who are at high risk for early relapse and inferior OS (Bond et al, Blood Adv 2021). In this study, we used comprehensive whole exome and transcriptome sequencing to genomically assess the prognostic impact of recurrent abnormalities in patients with MCL with and without TP53 aberrations. Methods: The Atlas of Blood Cancer Genomes (ABCG) project is a worldwide effort to systematically profile the genetic alterations and expression changes in all blood cancers. We recruited MCL patients with detailed clinical data available and subjected their tumors to whole exome and transcriptome sequencing. TP53-aberrant cases were identified from the genomic and diagnostic data. Progression-free survival (PFS) and overall survival (OS) were measured from the date of diagnosis until date of progression/relapse or death (PFS) or death (OS) using the Kaplan-Meier method and statistical comparisons by the logrank test. Results: Whole exome and whole transcriptome sequencing was performed successfully for 252 patients with MCL. Consistent with previous descriptions of the disease, median age at diagnosis was 65 years (range: 32-96), and 73% of patients were male. Seventy-five percent of patients had stage IV disease, and MIPI score was high, intermediate, or low in 34%, 34%, and 32% of patients, respectively. Ki67 proliferative index was ≥30% in 48% of patients with available data (n=115). Most patients received commonly used MCL therapies. Of the 185 patients for whom first-line treatment was known, 28% received bendamustine-containing regimens, 42% received cytarabine-containing regimens, and the remaining 30% received other regimens. Twenty-one percent of patients underwent autologous stem cell transplant consolidation as part of first-line therapy. Seventeen percent of patients had blastoid or pleomorphic histology, and 3% had leukemic non-nodal type MCL. Median PFS for the entire cohort was 41 months, and median OS was 138 months. As expected, patients with a confirmed TP53 abnormality (n=39) had inferior median OS compared to TP53-WT patients (n=84; 39 months vs 138 months, p<0.001). Recurrent mutations identified in TP53-aberrant and TP53-WT patients are presented in Figure 1. Among TP53-WT patients, the following genes were mutated in ≥10% of cases: ATM (45%), KMT2D (23%), PTPN13 (13%), NOTCH1 (13%), NSD2 (11%), and SPEN (10%). Incidence of ATM mutations in TP53-aberrant patients was 21% and was less common in patients with TP53 mutations (14%) rather than deletions (30%). Presence of an ATM mutation (median variant allele frequency 43%; range 15-96%) in TP53-WT patients was associated with inferior median PFS (38 months vs 138 months for ATM WT, p=0.023) (Figure 2); median OS was also shorter in patients with ATM mutations (104 vs 138 months, p=0.035). Although the incidence of ATM mutations was lower in TP53-aberrant patients, there was no significant association between ATM mutation and PFS or OS in that subgroup. Conclusions: To our knowledge, this study represents the largest genomic characterization of clinical outcomes in MCL patients. These findings suggest a pathogenic role for ATM mutations in patients with TP53-WT MCL and provide molecular insights into their heterogeneous outcomes. Although ATM mutations have been previously shown to be mutually exclusive with TP53 mutations (Mareckova et al, Leukemia & Lymphoma 2019), to our knowledge this is the first study that shows prognostic differences by ATM mutation status among TP53-WT patients. Our data indicate that ATM mutations are a significant prognostic factor and should be assessed at diagnosis along with TP53. Further clinical investigation of ATM mutations in TP53-WT MCL patients will be important to determine how this molecular marker may inform risk stratification and treatment approaches. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Carfilzomib and Lenalidomide for the Treatment of Primary Plasma Cell Leukemia: Final Results of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged ≥66 Years

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis, requiring urgent action to prevent early mortality and to control the disease and complications. The EMN12/HOVON-129 study assessed the efficacy of carfilzomib and lenalidomide as part of first-line therapy in pPCL. The trial enrolled patients (pts) aged 18 years and older, with different treatment for those 18-65 and ≥66 years. Here we report the results for pts in the age-group ≥66 years. Methods. The EMN12/HOVON-129 study is a prospective, non-randomized, phase 2, multicenter study for previously untreated pPCL pts. Inclusion criteria were newly diagnosed pPCL (in this study defined as >2x109/L circulating monoclonal plasma cells and/or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction and creatinine clearance <15 ml/min. There were no restrictions based on blood counts. Pts ≥66 years received induction therapy with eight 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg on days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23), followed by maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16 for the first twelve cycles; then 56 mg/m2 on days 1,15) and lenalidomide (10 mg on days 1-21/28 days) until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate, overall survival (OS), and toxicity. Results. From October 2015 to August 2021, we enrolled 61 pts with pPCL: 36 aged ≤65 years and 25 aged ≥66 years. Among the 25 pts aged ≥66 years, median age was 71 years (range 66-84); 68% had bone disease; and WHO performance status was 2 in 24% and 3 in 16% of pts. Median plasma cell percentage in bone marrow biopsy was 80% (10-100). Median peripheral blood plasma cell count was 3.8x109/L (range 2.0-52); median platelet count was 142x109/L (range 13-384); and median GFR was 56 ml/min (range 24-95). Most of pts had high-risk disease features, as proved by elevated LDH in 52% and high frequency of poor-risk genetic lesions (del(17p) in 20%, t(4;14) in 4%, t(14;16) in 4%, and gain/amp(1q) in 48%). In addition, 12% of pts had extramedullary plasmacytomas. ISS stage III was present in 68% and Revised ISS stage III in 40%. At the data cut-off (July 1, 2022), among the 25 pts, 17 (68%) received the planned 8 cycles of induction treatment, achieving ≥partial response (PR) in 80%, ≥very good (VG)PR in 68%, and ≥complete response (CR) in 32% of pts. Sixteen pts (64%) received maintenance treatment. Best response on protocol was ≥PR in 80%, ≥VGPR in 68% and ≥CR in 36%; 3 out of 4 pts in CR who could be evaluated for minimal residual disease (MRD) achieved MRD negativity (10-5) by flow cytometry. With a median follow-up of 24.6 months (range 7.9-59.6), the median PFS was 13.8 months (95% CI 9.2-35.5), which was sufficient to reject our null hypothesis (median PFS=6.5 months). With 16 pts having died (8 due to disease progression, 2 unknown, 1 pneumonia, 1 sepsis, 1 systemic aspergillus infection, 1 small intestinal SPM, 1 disseminated intravascular coagulation, 1 respiratory failure due to COPD exacerbation), median OS was 24.8 months (95% CI 14-not reached [NR]; Figure). Adverse events mainly occurred during the first two cycles of KRd and decreased thereafter. Overall, 36% of pts had grade (G)3 and another 36% G4 adverse events. G3 and G4 hematologic toxicity rates were 8% and 12%, respectively. Infections (20% and 16%) and respiratory events (16% and 4%) were the most common G3 and G4 non-hematologic toxicities. Twenty-two pts (88%) discontinued protocol treatment, mainly because of progression (13 pts, 59%). Conclusions. KRd is a potent treatment strategy to control disease in pPCL pts over 65 years of age, with not negligible, but generally manageable, treatment-related toxicities. Of note, along with a significant improvement of PFS, median OS substantially doubled compared to what has been reported in recent retrospective studies and, particularly, in the only other prospective trial (with the doublet lenalidomide-dexamethasone) so far conducted in transplant ineligible, elderly pts with pPCL (Musto P et al. Leukemia. 2014;28:222-5). This trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CTNI-07. LOMUSTINE/TEMOZOLOMIDE CHEMOTHERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED IDHWT GLIOBLASTOMA ACCORDING TO CETEG/NOA-09: REAL-WORLD EXPERIENCE IN A MULTICENTER COHORT

Abstract INTRODUCTION The CeTeG/NOA-09 trial demonstrated superior median overall survival (mOS, 48.1 months) in MGMT-methylated glioblastoma treated with lomustine/temozolomide compared to temozolomide. We retrospectively analyzed an off-study cohort of patients treated with lomustine/temozolomide to gather real-world data on this new regimen. METHODS Adult patients from 20 centers in Germany, Austria and Switzerland were included. Inclusion criteria were MGMT-methylated IDHwt glioblastoma newly diagnosed prior to end of 2020, and lomustine/temozolomide treatment as part of first-line therapy. RESULTS 321 patients with a median age of 57 years (range, 21-78) and a median follow-up of 19.9 months were included. In the whole cohort, mOS was 41.0 months (95%CI, 33.0 – not reached). In patients starting lomustine/temozolomide immediately upon initiation of radiotherapy strictly following the CeTeG protocol (88%), mOS was 52.8 months (35.8 – not reached) as compared to 24.6 months (17.6 – not reached) in patients starting lomustine/temozolomide after completion of radiotherapy/concomitant temozolomide (12%, logrank test: p = 0.06). Patients with a KPS &amp;lt; 80 had a shorter mOS of 19.7 months (95%CI, 16.6 – not reached) compared to 41.0 months (33.0 – not reached, p = 0.009) in KPS 80-100. Gross total resection (GTR, 53.9%) was associated with longer mOS (52.8 months, 95%CI 24.1 – not reached) compared to partial resection/biopsy (30.5 months, 95%CI 36.8 – not reached, p=0.004). Multivariable Cox regression analysis confirmed GTR (HR 0.66, p = 0.033) and younger age ( ≤ 50 years: HR 0.42, p = 0.001), but not KPS (80-100 vs. lower: HR 0.66, p = 0.12) as independent prognostic factors. DISCUSSION In this real-world multicenter cohort, survival was similar to the promising results of CeTeG/NOA-09. Further analyses should investigate a potentially reduced benefit from lomustine/temozolomide in patients with low KPS/no GTR and a possible detrimental effect from deferred lomustine/temozolomide initiation. The median follow-up is admittedly short, updated data will be presented.

Cardiotoxicity among socioeconomically marginalized breast cancer patients

PurposeEvidence of cardiotoxicity risk related to anthracycline or trastuzumab exposure is largely derived from breast cancer cohorts that under-represent socioeconomically marginalized women, who may be at increased risk of cardiotoxicity because of high prevalence of cardiovascular disease risk factors. Therefore, we aimed to estimate cardiotoxicity risk among socioeconomically marginalized breast cancer patients treated with anthracyclines or trastuzumab and describe clinical consequences of cardiotoxicity.MethodsWe linked electronic health records with institutional registry data from a Comprehensive Community Cancer Program within a safety-net health system. Eligible patients were adult females, diagnosed with first primary invasive breast cancer between 2013 and 2017, and initiated anthracyclines or trastuzumab as part of first-line therapy. We estimated cumulative incidence (risk) of cardiotoxicity with corresponding 95% confidence limits (CL) using the Aalen-Johansen estimator with death as competing risk.ResultsOur study population comprised 169 women with breast cancer (103 initiated anthracyclines and 66 initiated trastuzumab). Cumulative incidence of cardiotoxicity was 21% (95% CL: 12%, 32%) at one year and 25% (95% CL: 15%, 35%) at three years among women who initiated trastuzumab, whereas cumulative incidence was 3.9% (95% CL: 1.3%, 8.9%) at one year and 5.9% (95% CL: 2.4%, 12%) at three years among women who initiated anthracyclines. More than half of patients with cardiotoxicity experienced interruption of cancer treatment.ConclusionOur findings suggest high risk of cardiotoxicity among socioeconomically marginalized breast cancer patients after initiation of anthracyclines or trastuzumab. Strategies are needed for optimizing cancer treatment effectiveness while minimizing cardiotoxicity in this population.

Иммунотерапия в комбинации с лучевой терапией при лечении пациентов с плоскоклеточным раком кожи

Squamous cell skin cancer (SCC) is the second most common malignant neoplasm. The incidence of SCC continues to grow. As a rule, the tumor is characterized by a benign clinical course and is cured surgically, but in some cases, the development of locally common (and/or metastatic) forms is observed. For a long period of time, there were no methods of drug therapy of patients with such forms of SCC that would lead not only to a local effect, but also to an increase in life expectancy. In most cases, SCC is characterized by a high mutational load, the presence of PD-L1 expression, which potentially suggests a possible sensitivity of the tumor to immunotherapy. This knowledge contributed to the conduct of clinical studies of anti-PD-1 immunotherapy in locally common inoperable and/or metastatic forms of SCC. In the USA, in 2018, the first drug for the treatment of patients with locally advanced inoperable and/or metastatic form of SCC, cemiplimab, was approved for the first time. In 2020 another anti-PD-1 drug, pembrolizumab, was approved, which allowed expanding the possibilities of drug therapy for this category of patients. Despite the high frequency of objective responses against the background of anti-PD-1 immunotherapy in the first line (about 50%), a number of patients have stabilization of the disease or progression of the process. Stabilization of the disease is not enough for most patients, taking into account the peculiarities of clinical manifestations characteristic of SCC, which requires the search for new approaches and the use of immunotherapy with other treatment options to improve immediate and long-term results. The article presents a clinical case of a patient with locally advanced right shin SCC who received anti-PD-1 immunotherapy (nivolumab) in combination with radiation therapy as part of first-line therapy. On the background of such therapy, it was possible to achieve some success.

Outcomes for transplant-eligible, newly diagnosed Black patients (Pts) with multiple myeloma (MM): The Levine Cancer Institute (LCI) experience.

8053 Background: Studies have revealed disparities for Black (B) pts with MM, including more advanced disease at presentation, delayed therapy with novel agents such as immunomodulatory drugs (IMIDs) and proteasome inhibitors (PIs), reduced access to autologous stem cell transplant (ASCT), and under-representation in clinical trials. However, B pts tend to be younger at diagnosis and less likely to harbor high risk disease biology, suggesting outcomes could be better relative to their White (W) counterparts. To better understand outcomes by race in the setting of more optimal treatment access, we pursued a retrospective analysis of pts treated at LCI undergoing ASCT as part of first line therapy. Methods: 255 pts (181 W pts, 74 B pts) transplanted between 3/2014 – 12/2018 were included. Analysis was restricted to pts with MM who underwent a single ASCT as part of first line therapy. Pts with &lt; 1 year of follow-up and no overall survival (OS) events were excluded. Proportions were compared between groups with Fisher’s exact tests; OS and progression free survival (PFS) were evaluated with Kaplan Meier methods and compared between groups with log-rank tests. Results: Median follow-up for B and W pts was 5.0 yrs (0.9 – 7.8 yrs) and 4.1 yrs (0.5 – 8.0 yrs). At initial presentation, median age was 59 yrs (24 – 76 yrs) and 61 yrs (35 – 78 yrs, P= 0.038), anemia was present in 81.3% and 64.6% ( P= 0.020), renal impairment in 41.3% and 33.1% ( P= 0.335), and high-risk cytogenetics [gain 1q21, t(4;14), t(14;16) or del(17p)] in 25.4% and 35.9% ( P= 0.162) of B and W pts, respectively. Median time from diagnosis to ASCT was 0.6 yrs (0.3 – 2.4 yrs) and 0.5 yrs (0.3 – 2.0 yrs) for B and W pts. 35.2% of all B pts and 43.9% of all W pts treated at LCI during the study period underwent ASCT (48.3% and 64.4% of pts ≤70 yrs of age, P= 0.002), while 63.5% and 80.1% received PI/IMID-based induction therapy ( P= 0.009) and 90.5% and 93.4% received maintenance therapy post-ASCT ( P= 0.438), respectively. Although ≥very good partial responses were achieved in fewer B pts than W pts after induction (65.8% and 80.7%,( P= 0.014), there was no difference after ASCT (95.8% and 93.9%, P= 0.759). Median PFS was 5.9 yrs (95% CI 3.4 – 6.6) and 3.6 yrs (95% CI 3.0 – 4.5) for B and W pts ( P= 0.039). Median OS trended in favor of B pts ( P= 0.163) with 5-year OS of 83.0% (95% CI 71.2% - 90.3%) and 74.2% (95% CI 65.8% - 80.9%), respectively. Conclusions: Despite disparities in optimal induction therapy, Black pts with MM who underwent frontline ASCT enjoyed better PFS relative to W pts. Optimizing access to PI/IMID-based induction therapy and ASCT will be necessary to further improve OS.

Abstract P5-14-21: Cardiotoxicity among socioeconomically disadvantaged breast cancer patients

Abstract Background Current knowledge of cardiotoxicity risk after breast cancer treatment with anthracyclines or trastuzumab is largely derived from cohorts that under-represent socioeconomically disadvantaged patients. Cardiotoxicity risk among socioeconomically disadvantaged breast cancer patients may be exacerbated considering high prevalence of smoking, obesity, and other cardiovascular disease (CVD) risk factors in this population. Estimates of cardiotoxicity risk in this population may be useful for informing surveillance and management needs during active therapy and survivorship. Therefore, we aimed to estimate cumulative incidence of cardiotoxicity after anthracycline or trastuzumab initiation among socioeconomically disadvantaged breast cancer patients. Methods We linked electronic health records (EHR) with institutional registry data from the JPS Oncology and Infusion Center, which is a Comprehensive Community Cancer Program and part of a safety-net health system that provides care for low-income, uninsured, and under-insured individuals. Eligible patients were women aged ≥18 years, diagnosed with first primary invasive breast cancer between 2013 and 2017 with follow-up through 2020, and initiated anthracyclines or trastuzumab as part of first-line therapy. Cardiotoxicity was defined as heart failure or cardiomyopathy using diagnosis codes that were confirmed by supporting documentation in EHR, or cardiac dysfunction indicated by drop of left ventricular ejection fraction (LVEF) ≥10% from baseline to &amp;lt;55% after treatment. We used the mid-point value if LVEF was reported as a range. We used a competing-risk framework with death as the competing event to estimate overall and age-group specific cumulative incidence of cardiotoxicity with corresponding 95% confidence limits (CL). Results Our study population comprised 169 women with breast cancer (103 initiated anthracyclines and 66 initiated trastuzumab), for whom the median age was 51 years (interquartile range [IQR]: 44 - 58). The majority of women were racial/ethnic minorities (75%), uninsured or provided care through a hospital-based managed care plan for low-income qualifiers (57%), and stage I or II at diagnosis (56%). Cumulative incidence of cardiotoxicity was 22% (95% CL: 13%, 32%) at one year and 25% (95% CL: 15%, 36%) at three years among women who initiated trastuzumab, whereas cumulative incidence was 3.9% (95% CL: 1.3%, 8.9%) at one year and 5.9% (95% CL: 2.4%, 12%) at three years for women who initiated anthracyclines. For trastuzumab initiation, cumulative incidence of cardiotoxicity at three years was 32% (95% CL: 17%, 49%) for women aged &amp;gt;50 years and 19% (95% CL: 7.6%, 34%) for women aged ≤50 years. For anthracycline initiation, cumulative incidence of cardiotoxicity at three years was 5.5% (95% CL: 1.4%, 14%) for women aged &amp;gt;50 years and 6.5% (95% CL: 1.7%, 16%) for women aged ≤50 years. Conclusion We observed high risk of cardiotoxicity among socioeconomically disadvantaged breast cancer patients, particularly within the first year after initiation for either anthracyclines or trastuzumab. Imprecision precludes definitive understanding whether cardiotoxicity was higher for women aged &amp;gt;50 years but combining estimates from other socioeconomically disadvantaged populations may provide additional insight. Our estimates help extend knowledge about cardiotoxicity to under-represented populations. Citation Format: Yan Lu, Aaron W. Gehr, Ifedioranma Anikpo, Rachel J. Meadows, Kevin J. Craten, Rim Bannout, Kalyani Narra, Anuradha Lingam, Bhavna Tanna, Bassam Ghabach, Rohit P. Ojha. Cardiotoxicity among socioeconomically disadvantaged breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-21.

An up-to-date evaluation of dolutegravir/abacavir/lamivudine for the treatment of HIV

ABSTRACT Introduction There are more than 30 agents available for the treatment of HIV with guidelines shifting toward integrase strand transfer inhibitors (INSTIs) as part of first line therapy. The fixed dose combination of dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) is a convenient, well tolerated, and highly effective option for treating HIV infection and remains a first line therapy across several prominent guidelines. Areas covered In this drug evaluation, the authors provide a comprehensive overview of DTG/ABC/3TC for the treatment of HIV including the pharmacokinetics, pharmacodynamics, efficacy, safety, and tolerability. The authors also provide the reader with their expert perspectives on this particular treatment strategy. Expert opinion While DTG/ABC/3TC remains a valuable HIV treatment option, newer combination regimens have entered the market. Bictegravir with tenofovir alafenamide and emtricitabine offers the benefit of same day initiation and efficacy in hepatitis B co-infection, while new two-drug regimens enhance the simplicity of HIV treatment. Continued study is required into the mechanisms and optimal management strategies for weight gain for many regimens, including DTG/ABC/3TC.

ADAMS-TS13 Inhibitor Level and Risk of Relapse in Acquired Idiopathic Thrombotic Thrombocytopenic Purpura

▪Introduction:Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to reduced activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13). This disorder can be due to a congenital deficiency state or be acquired (immune TTP (iTTP)) due to an antibody which either inhibits or causes clearance of ADAMTS13.The aim of our study was to determine whether ADAMTS13 inhibitor titer at initial presentation could serve as a predictor of refractory disease and relapse in iTTP. We also measured clinical outcomes across different gender and racial subgroups.Methods:The United States Thrombotic Microangiopathy (USTMA) iTTP registry was used to extract patient information for two academic institutions in Eastern North Carolina.Descriptive statistics were used to analyze the data. The first iTTP episode recorded in the data base was used as the index episode. All patients included in the final analysis had an ADAMTS13 activity of <10%. An inhibitor level of 5 Bethesda units was arbitrarily chosen as the cutoff between low (<5) and high (>/5) inhibitor level. Response time was defined as the number of days of plasma exchange (PEX) required to achieve a platelet count of 150,000 for two consecutive days. Relapse was defined as occurrence of a new episode of iTTP 30 days after achievement of response. Refractory disease was defined as persistence of thrombocytopenia or absence of a sustained platelet count increment or platelet counts of < 50,000 despite 4-7 days of plasma exchanges and steroid treatment. Rituximab resistance was defined as lack of platelet recovery to more than 150,000 within 11 to 14 days of administration of the first dose of Rituximab.Results:A total of 161 patients with iTTP were identified. Ten patients had ADAMTS13 activity >10% and 15 patients did not have a reported inhibitor level. These subjects were not included in the final analysis.The cohort had 28% male (n =38/136) and 72% (n=98/136) female patients. There were more African American patients 73% (n=99/136) than Caucasians 24% (n=32/136). There were also 2 Hispanic, 1 Native American and 2 patients with unidentified race.Median ADAMTS3 inhibitor titer was 1.05 (Range 0-87). Forty three patients with ADAMTS13 activity <10 % had an inhibitor level of 0 (i.e undetectable).They were included in the low inhibitor group.Overall, 88% patients (n=120/136) had low inhibitor level and only 12% (n=16/136) had a high inhibitor. Thirteen percent females (n=13/98) and 8% (n=3/38) males had a high inhibitor level (p=0.387). Fourteen percent (n=14/99) African Americans and 6 % (n=2/32) Caucasians had a high inhibitor, p=0.23.In the low inhibitor group 30% (n=36/120) patients suffered at least one episode of relapse whereas 31% (n=5/16) had relapsed in the high inhibitor group.The median time to response was 6 days (range 1-76) in the low inhibitor group and 7 days (range 4-20) in the high inhibitor group (p=0.61). While looking at the various subgroups, median time to response for males was 6 days (range 4-21), females 6 days (range 1-76) , African Americans 6 days (range 3-29) , and Caucasians 6 days (range 1-76).The frequency of refractory disease was 31 % (n=5/16) in the high inhibitor group and 29% (n=34/119) in the low inhibitor group. At the time of enrollment in the registry, Rituximab was not a part of first line therapy. Only 26 out of 136 patients had received Rituximab. In the low inhibitor group 5 patients displayed Rituximab resistance whereas there were no patients in the high inhibitor group with Rituximab resistance.Conclusion:When evaluating patients presenting with iTTP in two centers in North Carolina, no correlation was found between a high inhibitor levels of >/ 5 Bethesda units and risk of relapse or refractory disease. A larger study is needed to evaluate this further. DisclosuresNo relevant conflicts of interest to declare.

Impact of Light Chain Isotype on Clinical Features and Outcomes in Systemic AL Amyloidosis

Purpose: In systemic AL amyloidosis, light chain (LC) isotype has been shown to predict outcome in patients undergoing upfront autologous transplantation. However, less than one-third of newly diagnosed AL patients are transplant-eligible. The objective of our study was to characterize the relationship between LC isotype, organ involvement, response, and survival in patients with newly diagnosed AL amyloidosis irrespective of transplant-eligibility.Methods: We performed a retrospective cohort study on 112 patients with AL amyloidosis who had treatment records at Columbia University Irving Medical Center (CUIMC) between 2015-2019. Two-sided Fisher's exact test was used for categorical variables and two-sided Wilcoxon rank sum test was used for continuous variables. Survival analysis was done using Kaplan Meier method. Overall survival (OS) was the time from randomization to death due to any cause. Event-free survival (EFS) was the time to initiation of a subsequent line of therapy or death due to any cause, whichever was earlier. Two-sided log-rank test was used to test differences between survival curves.Results: Kappa LC isotype was seen in 26% of patients. The proportion of patients with Mayo 2004 stage IIIA or IIIB disease in kappa and lambda isotype was 33% and 35% respectively (p=0.91). Bortezomib-based and daratumumab-based initial therapy was administered in 70% and 8% of patients respectively, with 36% having auto-transplant as part of first-line therapy. Patients with kappa LC isotype had a significantly higher baseline difference in free light chain (dFLC) and involved/uninvolved serum free light chain ratio (sFLCr) compared to lambda (median dFLC, 61.5 vs 21.6 mg/dl respectively, p=0.02; and median sFLCr, 63.5 vs 10.6 respectively; p<0.01). Kappa LC isotype was also associated with a near-significant higher bone marrow plasma cell (BMPC) burden at baseline (median BMPCs, 20% vs 10% respectively; p=0.06). Patients with lambda LC isotype had a significantly higher incidence of kidney involvement compared to kappa (64% vs 38% respectively, p=0.02). There was no significant difference in the incidence of t(11;14) between the two groups. The incidence of hematologic very good partial response or better (≥VGPR), involved free light chain less than 20 mg/dl (iFLC<20), and dFLC less than 10 mg/dl (dFLC<10) at the end of first-line therapy was similar in the two groups (Table in Figure 1). There was no difference in cardiac or renal response rates between the two groups. The proportion of patients requiring a subsequent line of therapy in kappa and lambda isotype was 41.4% and 39.8% respectively (p=0.88). At a median follow-up of 43 months for surviving patients, there was no significant difference in event-free survival (hazard ratio (HR) [kappa/lambda]: 0.76 [0.43-1.38]; p=0.37). However, there was a non-significant trend toward superior OS (HR [kappa/lambda]: 0.47 [0.18-1.23], p=0.12; 4-year OS: 86% vs 67% respectively) in patients with kappa LC isotype. Achievement of hematologic ≥VGPR, iFLC<20 mg/dl, and dFLC<10 mg/dl at end of first-line therapy was associated with a superior OS in our cohort irrespective of light chain isotype.Conclusion: Lambda AL amyloidosis is associated with significantly higher renal involvement compared to kappa. Despite a higher baseline disease burden (dFLC, sFLCr, and percent BMPC) in kappa compared to lambda, there was a trend toward superior OS in the former, which may imply decreased tissue toxicity of kappa FLCs. Further studies should investigate proteomic signatures and immunoglobulin gene usage according to light chain isotype and correlation with clinical phenotype. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL)

Primary Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) As First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma (LBCL)

New-onset versus relapsing giant cell arteritis treated with tocilizumab: 3-year results from a randomized controlled trial and extension.

ObjectiveTocilizumab plus prednisone induces sustained glucocorticoid-free remission in patients with GCA. However, its long-term benefits in new-onset vs relapsing disease are uncertain, and the value of weekly vs every-other-week dosing has not been evaluated.MethodsIn Giant-Cell Arteritis Actemra (GiACTA) part 1, patients with new-onset or relapsing GCA received blinded tocilizumab weekly (TCZ QW), tocilizumab every-other-week (TCZ Q2W) or placebo for 52 weeks, with a prednisone taper. In part 2 (open-label), patients were treated at investigator discretion for 104 weeks. In this analysis, patients were evaluated according to their original treatment assignments, and outcomes beyond 52 weeks were assessed. Outcomes of interest included time to first flare and cumulative glucocorticoid exposure over 3 years according to baseline disease status.ResultsPart 1 enrolled 250 patients; 215 entered part 2. At baseline, 48% had new-onset disease and 52% had relapsing disease. In patients with new-onset and relapsing disease, the median time to first flare in the TCZ QW group was 577 and 575 days, respectively, vs 479 and 428 days with TCZ Q2W and 179 and 224 days with placebo; the median cumulative glucocorticoid dose was 3068 mg and 2191 mg with TCZ QW, 4080 mg and 2353 mg with TCZ Q2W, and 4639 mg and 6178 mg with placebo.ConclusionTCZ QW delayed the time to flare and reduced the cumulative glucocorticoid dose in patients with relapsing GCA and new-onset GCA. These data support initiating TCZ QW as part of first-line therapy in all patients with active GCA.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov, NCT01791153.

Retrospective study of treatment patterns and outcomes post-lenalidomide for multiple myeloma in Canada.

Lenalidomide is an important component of initial therapy in newly diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28.5% received further immunomodulatory derivative-based (IMiD-based) therapy (lenalidomide/pomalidomide) without a proteasome inhibitor (PI) (bortezomib/carfilzomib/ixazomib), 26.2% received PI-based therapy without an IMiD, 19.5% received both an IMiD plus PI, 13.5% received daratumumab-based regimens, and 12.1% underwent salvage ASCT. Median progression-free survival (PFS) was longest for daratumumab-based therapy (22.7months) and salvage ASCT (23.4months) and ranged from 6.6 to 7.3months for the other treatments (P<.0001). Median overall survival (OS) was also longest for daratumumab and salvage ASCT. A total of 87 non-ASCT patients received subsequent therapy, with 66.7% receiving bortezomib-based therapy and 13.8% receiving other PI-based therapy. Median PFS was 15.4 and 24.8months for bortezomib-based and other PI-based therapy, respectively (P=.404). During most of the study period, daratumumab was not funded; in this setting, switching to a different therapeutic class following relapse on lenalidomide produced the longest remissions for non-ASCT patients. Further prospective studies are warranted to determine optimum treatment following relapse on lenalidomide, especially in the light of increased access to daratumumab.