Rest Of Pts Research Articles

Abstract PO1-16-11: Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study

Abstract Background: BC is the most incident cancer worldwide in < 40 years old (y) women. Increasing body mass index and changes in reproductive history contribute to the growing incidence of premenopausal BC. A higher proportion of luminal B-like and estrogen receptor negative (ER─) tumors, an increased risk of early relapse, and more unfavorable longer-term outcomes for young women with ER+ tumors when compared to older women, have been reported. In this analysis, we focus on age-specific BC characterization from a real-world population-based perspective. Methods: Pts were enrolled in the non-interventional and ambispective RegistEM study in ABC diagnosed between 2016 and 2019. We describe the features and outcomes of < 50 y pts at their initial BC diagnosis according to their BC subtype. BC subtypes were based on the most recent tumor tissue sample (distant metastasis, and in its absence, primary BC). Comparisons between < 40 and ≥ 50 y groups were performed. Results: Pts < 50 y represent 39% (n=685) of total pts with available data (n=1739, any age group) in the registry. By age, 12% (n=212) were < 40y, and 27% (n=473) 40-49y. At first BC diagnosis, 75% and 25% pts had early BC (EBC) and de novo metastatic BC (MBC), respectively. In EBC pts, stage II (50%) and III (28%) were the most frequent at diagnosis; invasive non-special type carcinoma was the predominant morphology, and grade 2 was the most common histological grade, but grade 3 was predominant in TN pts and HER2+ < 40y pts. The median time to recurrence was < 2y in TN pts, 3y in HER2+ pts, and 6y in luminal HER2─ pts. At ABC diagnosis, the median age was 47y, all pts were female but one, 98% white, and 60% premenopausal (94% were premenopausal at EBC diagnosis). A family history of BC and/or ovarian cancer was reported in 34% pts, and a hereditary-risk genetic test was performed in 39% (254 of 652) pts; 12% (n=30) had BRCA1/2 mutations, with a proportion higher in TN pts (9 of 33, 27%) vs. luminal HER2─ (21 of 183, 12%) and HER2+ (0 of 38) pts. Visceral disease was the most frequent in all subgroups, highlighting statistical differences (p=0.022) between age groups ( < 40y 55% vs. ≥50y 71%) only in TN pts. 60% had ≤ 2 locations involved, similarly in all subgroups. The presence of >2 metastatic locations was statistically higher in HER2+ pts ≥50y (54%) vs both < 40y (32%) and 40-49y (48%). Brain disease was more present at ABC diagnosis in TN (9%) and HER2+ (7%) than in luminal HER2─ (3%). Median no. of treatment lines (L) was 3 (range 0-11), and median follow-up 44 mo (95% CI: 41-44). 99% pts received 1L, the distribution of treatments by BC subtype within each age subgroup was similar; median duration of 1L was 21 months (mo) in luminal HER2─, 17 mo in HER2+, and 5 mo in TN pts. 68% of pts who received 1L, reached 2L. Duration of 2L dropped dramatically: 8 mo in luminal HER2─, 6 mo in HER2+, and 2 mo in TN pts. No differences between ≥50y and the rest of pts were observed in PFS for any treatment line. 49% pts had died at the database cut-off date (05-April-23), with no differences between age groups, but TN pts had the highest death rate (80%). Additional data according to BC subtypes and age groups are in the table. Conclusions: Luminal HER2─ was the predominant BC subtype in all age subgroups. Visceral disease was more prevalent in young TN pts compared to older pts. TNBC pts experienced a shorter median time to recurrence and the highest mortality rate regardless of age, compared to HER2+ and luminal HER2- pts, indicating the need for targeted interventions in this subgroup. Citation Format: Sara López-Tarruella, Angel Guerrero, Isabel Álvarez, Silvia Antolin Novoa, Ariadna Tibau, Josefina Cruz, César A Rodríguez, Purificación Martínez, J. Ignacio Chacón, María Hernández, Mireia Margelí, Encarna Adrover, Catalina Falo, Iria González, Álvaro Rodríguez-Lescure, María Marín, César Gómez, Juan de la Haba-Rodríguez, J. José Illaramendi, Raquel Andrés, Andrea Blasco, Mª José Escudero, Susana Bezares, Federico Rojo. Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-11.

A study of cadonilimab combined with regorafenib as second-line or later therapy in patients with advanced hepatocellular carcinoma (aHCC).

e16154 Background: Current second-line treatment options for aHCC patients (pts), including single TKI or anti-PD-1+anti-CTLA4, result in limited survival benefits, objective responses or increasing concerns regarding adverse effects. An exploration of safer and more effective second-line or later therapies for aHCC is paramount. Cadonilimab is a first-in-class bispecific, humanized IgG1 antibody targeting PD-1 and CTLA-4, which has the potential to boost immune surveillance in HCC. Previous data indicated that cadonilimab possesses an improved safety profile and an encouraging anti-tumour activity compared to combined administration of anti-PD-1 plus anti-CTLA-4 antibodies. Regorafenib was the first TKI that approved globally as a second-line treatment of aHCC. Here, we evaluated the safety of cadonilimab plus regorafenib as second-line or later therapy in pts with aHCC. Methods: The study population derived from prospectively collected retrospectively analyzed data (10/2022-02/2023) of pts treated with cadonilimab plus regorafenib as second-line or later therapy for aHCC at Tianjin Cancer Hospital Airport Hospital. The primary endpoint was safety. Results: We identified 29 pts with aHCC who received cadonilimab plus regorafenib. The median age was 59 years; 86.2% were male; 72% were ECOG PS 0; 72% had a Child-Pugh score of A at diagnosis. High risk factors for HCC included MVI (3pts), ≥3 tumour lesions (10pts), tumour diameter ≥5cm (5pts), AFP≥400ng/mL (5pts). Six pts (21%) received cadonilimab plus regorafenib in the second-line while the rest of pts (79%) received it as third-line or later. All pts previously received at least one line of immunotherapy combined with anti-angiogenic target agents. Seven pts received triple combination regimens (ICIs+TKIs/Bev+HAIC) before. At time of data extraction, no pts were assessed for efficacy due to the COVID-19 pandemic (especially the outbreak in early December 2022) and short follow-up time, we focused on the safety and tolerability in this report. Any grade treatment related adverse events (TRAEs) occurred in 24pts (83%). The most common TRAEs of any grade were hypoalbuminemia (24%), lymphocyte count decreased (21%), rash (14%), nausea (14%) and infusion reaction (14%). Only four (14%) patients experienced grade 3 TRAEs including infusion reaction (2pts), lymphocyte count decreased (1pt) and gastrointestinal hemorrhage (1pt, regorafenib related). No grade 4-5 TRAEs were observed. Conclusions: The combination of cadonilimab plus regorafenib was generally well tolerated. The prospective trail of cadonilimab combined with regorafenib as second-line or later therapy for aHCC is ongoing (NCT05644379). Although it needs to be reconfirmed, the treatment responses of some patients are encouraging (including sharp decrease in AFP level and/or reduced tumor size). Related data will be reported in the future.

Abstract P4-07-29: Olaparib plus Trastuzumab in HER2[+] BRCA-Mutated Advanced Breast Cancer Patients: The OPHELIA Study

Abstract Background: Olaparib (O) is approved for the treatment of HER2[-] patients (pts) with early or metastatic breast cancer and a germline BRCA mutation. Nevertheless, there is no evidence that HER2[+] tumors are resistant to PARPi. Preclinical data support that HER2[+] cells are sensitive to PARPi and strongly suggest that PARP inhibition augments the efficacy of trastuzumab (T). To test whether PARPi is synergistic with anti-HER2 therapy, the OPHELIA study has assessed the efficacy and safety of O in combination with T in pts with HER2[+] germinal BRCA-mutated advanced breast cancer (ABC). Methods: OPHELIA (NCT03931551) is an open-label, multicenter, single-arm, phase II trial. The study enrolled pts aged ≥18 years diagnosed of HER2[+] ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease (including a pertuzumab- or trastuzumab emtansine based regimen). Pts received O (300 mg oral, twice daily) plus T (either loading dose of 8 mg/kg IV infusion, and subsequent 3-weekly doses of 6 mg/kg IV infusion; or 600 mg SC injection, on day 1 of every 21-day cycle) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was investigator-assessed clinical benefit rate (CBR) for at least 24 weeks as per RECIST v.1.1. Secondary endpoints included overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS); and safety and tolerability as per NCI-CTCAE v.5.0. The primary analysis evaluated CBR (H0: ≤5%; H1: ≥30%) based on exact binomial test. Sample size was designed to attain a 90% power at 10% one-sided alpha level. Results: From Mar 25, 2019, through Mar 2, 2022, 5 pts (from a total of 42 pts evaluated) were enrolled at 17 sites in Spain. Median age was 37.0 (range 32–54) years, 1 (20.0%) patient was male, 4 (80.0%) pts carried germinal BRCA2 mutations, 4 (80.0%) pts had received ≥ 3 advanced disease treatments lines, and 4 (80.0%) pts presented ≥ 2 metastatic sites. At data cutoff (Mar 2, 2022), with a median follow-up of 18.7 months (min: 11.7; max: 22.1), 40.0% of pts remained on therapy. CBR at 24 weeks was 80.0% meeting the primary endpoint (4 of 5 pts; 95% CI, 28.4% to 99.5%, p< 0.001). ORR (1 complete and 2 partial responses) was 60.0% (95% CI, 17.4% to 94.7%), and median DoR was 3.8 months (95% CI, 2.5 to 8.3 months). Two (40.0%) pts had PFS events due to disease progression at 5.2 and 1.2 months, respectively. Rest of pts were treated for 5.5, 11.2, and 19.0 months. There were 2 (40.0%) deaths at 14.0 and 18.5 months. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (60.0%; 0% G≥3), nausea (60.0%; 0% G≥3), vomiting (40.0%; 0% G≥3), and back pain (40.0%; 0% G≥3). Anemia (40.0%; 20.0% G≥3) and lymphopenia (40.0%; 20.0% G≥3) were the most frequent hematological TEAEs. One (20.0%) patient discontinued treatment because of a drug-related TEAE (leukopenia). A dose reduction of O was reported in 1 (20.0%) patient. No treatment-related deaths were reported. Conclusions: HER2 overexpression in germline BRCA-mutated ABC is infrequent. The activity observed in these 5 pts indicates that O+T combination might be of help in this group of pts. We strongly believe that randomized data are not needed, and RWE studies might help us to understand the real activity of this combination. Toxicity was as expected. Citation Format: José E. Alés-Martínez, Judith Balmaña, Pedro Sánchez-Rovira, Francisco Javier Salvador Bofill, José Ángel García-Sáenz, Isabel Pimentel, Serafin Morales Murillo, Adela Fernández, Ainhara Lahuerta Martínez, Neus Ferrer, Pilar Zamora, Begoña Bermejo, Tamara Díaz-Redondo, María Helena Lopez-Ceballos, María Galán, Andrea Malfettone, Laura Calabuig, Miguel Sampayo-Cordero, José Manuel Pérez-García, Javier Cortés, Antonio Llombart-Cussac. Olaparib plus Trastuzumab in HER2[+] BRCA-Mutated Advanced Breast Cancer Patients: The OPHELIA Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-29.

P566: IMPACT OF FRONTLINE INDUCTION APPROACH ON POST-STEM CELL TRANSPLANT (SCT) OUTCOMES IN OLDER ADULTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML)

Background: A hypomethylating agent plus venetoclax (VEN) is standard of care for older, unfit patients (pts) with newly diagnosed AML. However, the optimal induction regimen for older pts with AML who are adequately fit for SCT is not well-established. Aims: We investigated the post-SCT outcomes of older adult pts with newly diagnosed AML based on the intensity of the induction regimen received. Methods: This is a retrospective analysis of pts ≥60 years (yr) of age with newly diagnosed AML who received allogeneic SCT after achieving first remission (CR, CRi or MLFS) between 9/2012 and 7/2021 at our cancer center. Out of 127 pts, 44 pts received intensive chemotherapy (IC) without VEN as induction therapy, 36 pts received low-intensity therapy (LIT) without VEN, and 47 pts received LIT with VEN. Overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) after SCT were compared among the groups. Results: The baseline characteristics of the groups are shown in Table 1. Pts in the IC cohort was significantly younger (median age of 63 yrs) than pts who received LIT with or without VEN (median age of 68 yrs, p<0.01). Pts in the IC group were more likely to have ECOG PS of 0 (34%) as compared to those who received LIT (14%, p=0.07). Most pts had adverse ELN cytomolecular risk on presentation (43% in IC, 50% in LIT without VEN, and 55% in LIT with VEN). The median numbers of cycles prior to SCT were 3 in all groups. Pts in LIT without VEN group were more likely to receive matched unrelated donor (75%) than those in the LIT with VEN (49%) and IC groups (50%) and were less likely to receive a haploidentical SCT (3% vs. 17% and 14%, respectively). Pts in LIT with VEN group were more likely to receive reduced-intensity conditioning (92%) prior to SCT, compared with 53% and 58% in the IC and LIT without VEN groups, respectively (p<0.01). HLA matching was well-balanced in 3 groups. The majority of pts were in CR/CRi prior to SCT (100% in the IC group, 95% in the LIT without VEN group, and 92% in the LIT with VEN group), while the rest of pts achieved MLFS. MRD negativity prior to SCT was achieved in more pts treated with IC (77%) or LIT with VEN (66%), compared with LIT without VEN (49%). For the entire cohort, the median follow-up was 37 months (mos) post-SCT. Post-SCT outcomes are shown in Figure 1. The 2-yr OS was highest in the LIT with VEN group (73%) when compared with the IC or LIT without VEN groups (58% and 44%, respectively); OS was statistically superior with LIT with VEN compared with LIT without Ven (p=0.02) and there was a trend towards superior OS compared with IC (p=0.17). 2-yr RFS was also superior in the LIT with VEN group (62%) as compared with the IC or LIT without VEN groups (54% and 42%, respectively). 2-yr CIR was highest in LIT without VEN group (36%), and was similar in the LIT with VEN (19%) and IC groups (18%). 2-yr NRM was highest in IC group (27%) as compared with the LIT with VEN (11%) and LIT without VEN groups (22%) (p=0.02 for IC vs. LIT with VEN). Image:Summary/Conclusion: LIT with VEN resulted in comparable—and possibly superior—outcomes compared with IC in SCT eligible patients ≥60 yrs with newly diagnosed AML. Despite the older age and worse PS of the LIT with VEN group, their post-SCT NRM was lower than those who received IC, which translated to numerically superior OS. These results support LIT with VEN as an effective and tolerable induction strategy in older SCT-eligible pts with newly diagnosed AML.

Anxiety in MINOCA patients according to latest definitions

Abstract Background Anxiety is a global public health problem affecting the lives of large numbers of patients (pts) and their families. Some studies suggest that pts with MINOCA (myocardial infarction with non-obstructive coronary arteries) have more anxiety levels than the rest of pts with myocardial infarction (MI). The aim of this study is to compare anxiety levels between pts with MINOCA and the rest of MI pts using a validated scale: The State Trait Anxiety Inventory (STAI). Methods An analytical and observational study was developed in a University Hospital. We analysed the clinical data of all consecutive MI pts admitted to our centre from July 2017 to December 2020. Inclusion criteria were determined by the 4th Universal Definition of Myocardial Infarction and the latest definitions of MINOCA according to the 2020 ESC Guidelines. A group of experts reviewed all MINOCA cases in order to exclude those who did not fulfil the selection standards and takotsubo syndrome and myocarditis pts were excluded. STAI questionnaire was completed by each patient during admission. Data collected included “trait anxiety”, that refers to relatively stable individual differences in anxiety-proneness, whereas “state anxiety” is a temporary emotion due to a particular situation (hospitalization in this case). Total score in each subgroup ranges from 0 to 60 points, where a higher score correlates with major anxiety levels. Follow up analysis included major adverse cardiovascular events (MACE: cardiovascular readmission, myocardial reinfarction, stroke and death from any cause). Survival analysis is based on Cox regression. Median follow-up was 25±23 months. Results From a total of 413 consecutive MI pts, 243 (58.8%) completed the questionnaire. Of them, 32 (13%) were MINOCA pts. There were no significant differences in trait anxiety between both groups (MINOCA mean value 21±14 points vs rest of MI 19±10 points, p=0.9), nor in state anxiety (20±14 vs 19±10 points, p=0.8). There were also no significant differences when data were analysed by percentiles: 37.5% of MINOCA pts were below P25 and 28% of the rest of MI were also in this percentile. At the other end of the scale, 31.3% of MINOCA pts were above P75, as well as 22.7% of the rest of MI pts (table 1). During follow up, punctuation in trait anxiety in MINOCA pts showed no differences in MACE (HR 1.01, CI 95% (0.9–1.07)), nor did punctuation in state anxiety (HR 1.01, CI 95% (0.9–1.06)). This was also observed in the rest of MI pts: trait anxiety HR 1.01, CI 95% (0.9–1.04) and state anxiety HR 0.9, CI 95% (0.9–1.01). Conclusion In this study, there were no significant differences in anxiety levels between MINOCA pts and the rest of MI pts. The lack of takotsubo pts in this study reflect real data from MINOCA according to the latest definitions. Subjective emotions could lead to mistaken findings, making it necessary to determine emotional disorders with validated and objective tools. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): European Society of Cardiology Table 1. Percentile values of STAI.

Insomnia incidence in myocardial infarction with and without obstructive coronary arteries

Abstract Background Insomnia can either be a primary problem or it may be associated with other psychological conditions, ranging from anxiety to depression. Some studies have reported that pts with MINOCA (myocardial infarction with non-obstructive coronary arteries) have more emotional disorders than the rest of pts with myocardial infarction (MI). However, a relationship with insomnia has not been yet described. The aim of this study is to compare insomnia levels between patients with MINOCA and the rest of MI patients using a validated scale: Insomnia Severity Index (ISI) (Figure 1). Methods We performed an analytical and observational study in which all consecutive MI pts from July 2017 to December 2020 were recruited. We used the latest definitions of MINOCA according to the 2020 ESC Guidelines. A group of experts reviewed all MINOCA cases in order to exclude those who did not fulfil criteria. Therefore, takotsubo syndrome and pts with myocarditis were excluded. ISI questionnaire was completed by each patient during admission. Total score ranges from 0 to 28 points. Depending on the final score, pts could have no clinically significant insomnia (0–7 points), subthreshold insomnia (8–14 points), clinical insomnia of moderate severity (15–21 points) and severe clinical insomnia (22–28 points). Follow up analysis included major adverse cardiovascular events (MACE: cardiovascular readmission, myocardial reinfarction, stroke and death from any cause). Survival analysis is based on Cox regression. Median follow-up was 25±23 months. Results From a total of 413 consecutive MI pts, 244 (59%) completed the questionnaire. Of them, 32 (13%) were MINOCA pts. There were no statistically significant differences in insomnia levels between both groups (Table 1). Even in absolute terms, both groups presented same mean levels: MINOCA mean value 7.6±6 points vs rest of MI 7.7±6 points, p=0.8. When separated by sex, women in the MI group had higher punctuation levels than men (24% of moderate clinical insomnia in women vs 8.9% of men, p=0.03). Punctuation in ISI questionnaire showed no significant differences in MACE in MINOCA pts (HR 0.9, CI 95% (0.7–1.2)), nor in the rest of MI pts (HR 0.9, CI 95% (0.9–1.03)). Conclusions Levels of insomnia were similar in MINOCA pts than in the rest of MI pts. Follow up showed no differences in MACE between both groups regarding insomnia according to ISI. Women had higher punctuation levels than men, with more clinical insomnia in a moderate grade. Subjective emotions could lead to mistaken findings, making it necessary to use ISI questionnaire or other objective validated scales to correctly study some disorders and their distribution in different populations. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Society of Cardiology Table 1. Insomnia severity indexFigure 1. ISI Questionnaire

OAB-057: Temporal-weight estimation of the copy number alterations of of 1384 Multiple Myeloma patients defines an ancestrality index impacting patients survival

<h3>Background</h3> MM is a hematological malignancy always evolving from pre-malignant stages, with progressive increase of genomic complexity. MM is characterized by a large abundance of copy number alterations (CNA); many of them, regarded as "driver", stack up progressively from early tumor stages, causing biological changes that give rise to tumor hallmarks and malignant phenotypes. The combined application of whole genome analysis and mathematical models allows to deeply describe these alterations and to infer their order of acquisition during oncogenesis from their clonality levels, assuming that clonal ones are more ancestral than subclonal. Aims: (1) To define the temporal order of acquisition of CNA, leading to the onset of symptomatic MM and (2) to define a scoring model able to stratify patients (pts) according to the ancestrality of the alterations observed in their genomic landscape. <h3>Methods</h3> Genomic data collected from a total of 1384 newly diagnosed MM pts were included in the study: SNPs array data were collected from 514 pts of our Institution (BO dataset); in 870 pts, WES data were downloaded from CoMMpass study. CN calls and clonality levels were harmonized by an analysis pipeline including ASCAT, GISTIC v2 and custom R scripts. Timing estimates were obtained with BradleyTerry2 package. Survival analysis were performed on R. <h3>Results</h3> A full call-set of CNAs was obtained by harmonizing BO and CoMMpass datasets. The clonality information was first extrapolated from the whole call-set, to define the temporal order of acquisition of non-primary CNAs. CNAs were then accurately ranked, by using the obtained timing estimates, characterized by a quite narrow confidence interval. Of interest, chr 1q gains and chr 13q losses were frequently clonal and ranked as ancestral events, whereas chr 17p losses were late occurring events. By weighting the CNAs carried by any given pts at diagnosis with their relative timing estimate in a combinatorial process, an Ancestrality Index (AI) was defined for each pts (median AI=3.4, IQR=1.7-6.0). The AI was found to be significantly associated with progression free (PFS) and overall survival (OS) (p3.4 (i.e. with a more "ancestral" profile) had a worse outcome as compared to the rest of pts (OS 40% vs 58%, PFS 42% vs 56%, at a median follow up of 92m and 34m, p<0.001).The risk attributed to this "ancestral" category was independent from other high-risk cytogenetic features (i.e. del17p, t(4;14), t(14;20), t(14;20)). <h3>Conclusions</h3> By means of whole genome analysis and dataset harmonizing, the temporal order of acquisition of MM CNAs has been confidently described. A score reflecting the disease ancestrality of MM pts at diagnosis was generated and associated to survival outcomes. Overall, these findings support the evidence that MM pts at diagnosis carrying an excess of ancestral alterations, expected to likely be drivers, are prone to have a dismal prognosis.

INFLUENCE OF ACTIVE CARDIOMONITORING ON THE OVERALL SURVIVAL OF PATIENTS WITH CHRONIC LYMPHOLEUKEMIA RECEIVING IBRUTINIB

Introduction: overall survival of patients (pts) with chronic lymphocytic leukemia (CLL) depends not only on the severity of the CLL, the anticancer therapy used and the comorbidity of pts. The most important role in the management of these pts is played by the supervision of a cardiologist. Methods: we examined and observed in dynamics for 5 years 217 pts with CLL, constantly receiving ibrutinib, which induces arterial hypertension (AH) and atrial fibrillation (AF) in a part of the pts. All pts underwent echocardiography (ECHO), 24-hour Holter ECG monitoring (HM), assessment of comorbidity using the Charlson index and screening of fragility using the G8 questionnaire. Daily measurement of blood pressure, heart rate in the morning and in the evening with keeping a diary of measurements, was recommended for all pts, but only 81 pts were performed, who constantly contacted us remotely using instant messengers and made up an active cardiac monitoring group. Correction of treatment was carried out in accordance with these data. Results: a study of the overall survival of patients with CLL receiving ibrutinib, depending on cardiac monitoring, was carried out, starting from the first visit. The age of pts in the active cardiac monitoring group (n = 81) and in the rest of pts (n = 136) did not differ and amounted to 66.0 (60.0-70.0) years and 66.0 (59.0-74.0) years respectively. The number of men and women in the groups was comparable. In the active cardiac monitoring group, there were significantly more pts with AH - 86.5% and with AF - 42.7% compared to 50.4% with AH and 15.9% with AF in the remaining pts (p < 0.0001 in both cases) and a comparable number of pts with coronary artery disease. According to screening HM, there were more pts with short episodes of AF in the active cardiac monitoring group - 31.4% versus 8.0% in the rest of the pts (p < 0.0001). Accordingly, the number of pts receiving cardiac treatment in the active cardiac monitoring group was 87.6%, the rest was 53.6% (p <0.0001). ECHO parameters did not differ in the groups. Indicators that significantly affect survival in the general group (Charlson index, scores of the G8 questionnaire) did not have significant differences in the active cardiac monitoring group and in other pts with CLL. The groups also did not differ in hematological status and the number of cases of second tumors. Despite a significantly more pronounced cardiac comorbidity, CLL pts under active cardiac monitoring, including continuous remote monitoring, demonstrated better survival compared to other patients (p <0.0001). Conclusions: carrying out active cardiac monitoring, including constant remote observation, allows achieving higher overall survival rates for CLL pts, despite the more severe cardiac status compared to other patients under the periodic supervision of a cardiologist. Keywords: Cancer Health Disparities No conflicts of interests pertinent to the abstract.

Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients

Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients

Frequent Mutations and Their Influence on Prognosis in Patients with Acute Myeloid Leukemia

Background. Several genetic alterations such as translocations, gene mutations and deletions play an important role in myeloid leukemogenesis. The cytogenetic information is a very significant tool to classify pts at their initial diagnosis into prognostic categories. For pts with cytogenetically normal AML, prognosis can be specified by mutational status of the genes NPM1, FLT3, CKIT, NRAS and DNMT3A.The aim of the research was to investigate the frequency and prognostic impact of FLT3, NPM1, CKIT, NRAS and DNMT3A mutations in AML pts and to analyze their interaction with other prognostic markers.Methods. This study was performed in 200 adult pts (190 pts with de novo and 10 pts with secondary AML), previously untreated, median age 55 years (18-86). According to the results of cytogenetic analyses pts were separated in four groups: with favourable (9,0%), unfavourable (14,0%) prognosis, with normal karyotype (NK) (48,5%) and other aberrations (28,5%). Mutations in FLT3, CKIT and NPM1 were analysed by PCR and in NRAS by sequencing. Mutation analysis of DNMT3A R882 was performed by high-resolution melting curve analysis. Cytogenetic studies were analysed on bone marrow samples using standard GTG-method.Results. Mutations in FLT3, CKIT, NRAS and NPM1 genes were detected in 105/200 (52,5%) pts. A total of 128 mutations were revealed in this group: 24,0% - FLT3-ITD, 6,5% - FLT3-TKD, 20,5% - in NPM1, 10,0% - in NRAS and 3,0% - in CKIT. 82 pts had single mutations and in 23 pts mutations occurred simultaneously: 17 with FLT3-ITD and in NPM1, 2 with FLT3-ITD and FLT3-TKD, 1 with FLT3-TKD and in NPM1, 3 with NPM1 and NRAS mutations. We found that mutations with the significantly higher incidence (p=0,001) were observed in the group of pts with NK (80/97), whereas there were only 8/28 pts with mutations in the group with complex karyotype. When analyzing the age-related features, it was shown that the majority of mutations were detected in the group of pts at the age from 60 to 69 years.Mutations FLT3-ITD and FLT3-TKD were associated with higher WBC count comparing with pts without mutations (p=0,001 and p=0,014, respectively). The median follow-up for overall (OS) and relapse-free (RFS) survival for pts with FLT3-ITD against ptswith FLT3-ITD- was: 5,4 vs 12,8 months and 4,9 vs 10,0 months (p=0,001 and p=0,001), respectively. Mutation FLT3-TKD was also found to be prognostically unfavorable, but only comparing with pts with FLT3-ITD- genotype.As the result of OS and RFS analyses in pts with and without NPM1 mutations we revealed the significant favorable influence of NPM1 mut on the prognosis (p=0,002 and p=0,020, respectively). However pts with genotype FLT3-ITD+/NPM1+ were found to get to the group with an intermediate risk.We detected the significant adverse influence of CKIT mut on RFS (p=0,041). Mutations in NRAS didn't impact on prognosis; we only showed the tendency towards worsening of OS and RFS in group of pts with favorable cytogenetics (p=0,214 and p=0,160, respectively).Mutations DNMT3A R882 were investigated in group of 143 AML pts and were detected in 23 (16,1%) pts. Pts with DNMT3A R882 had higher WBC (p=0,001) and platelets (p=0,020) count at diagnosis and more frequently belonged to FAB groups M5 (p=0,003), as compared with DNMT3A wt. Of 23 pts who had AML with DNMT3A mutations, 17 had tumors with NK profiles (24,3% of a total of 70 cytogenetically normal samples) (p=0,009). Pts with isolated DNMT3A mutations were seen in 4 cases, whereas in the rest of pts they were detected simultaneously with mutations in genes FLT3, NPM1, NRAS and CKIT. DNTM3A mutations were significantly more prevalent in NPM1 mut (p=0,005) and FLT3-ITD (p=0,005) positive cases than wild type. DNMT3A mutations were associated with negative influence on pts OS and risk of relapse, compared with DNMT3A wt (р = 0,031 and р = 0,045, respectively).Summary. Mutations in FLT3 and NPM1 had a significantly higher incidence in the group of pts with a normal karyotype. FLT3 mutations showed the adverse prognostic value. Insertions in NPM1 were shownto be the favorable factor, correlating with prolonged RFS in all pts excepting pts with FLT3-ITD+/ NPM1+ genotype. CKIT mut was associated with higher relapse incidence in AML pts, while NRAS mut showed lack of prognostic significance. AML with DNMT3A mut represent the group, homogeneous on a number of clinical and laboratory parameters, associated with adverse prognosis and a high risk of the relapse. DisclosuresNo relevant conflicts of interest to declare.

Azacitidine in Older Patients with Acute Myeloid Leukemia (AML) and Adverse Karyotype. Subanalisis from the Alma Study

BackgroundAdverse karyotype and age are associated with poor prognosis in older AML patients (pts). Although complete remission (CR) can be achieved with intensive chemotherapy (IC) in pts with adverse cytogenetics, overall survival (OS) and leukemia free-survival (LFS) are poor (Knipp S, et al. Cancer 2007). In addition, low doses of ARA-C (LDAC) did not offer survival benefit in older pts with poor cytogenetics as compared to hydroxyurea and best supportive care (BSC) (Burnett A, et al. Cancer 2007). Azacitidine has shown a survival advantage in older pts with newly diagnosed AML in a recent phase 3 trial, as compared to conventional care regimens (BSC/LDAC/IC)(Dombret H, et al. EHA 2014).AimTo evaluate the role of azacitidine and factors associated with OS in pts with newly diagnosed AML and adverse karyotype from the ALMA study (Ramos F, et al. Blood 2012;120:abstract 3593).MethodsRetrospective, multicenter study, of pts with newly diagnosed AML and adverse karyotype who received front-line azacitidine in Spain. Response to azacitidine was evaluated by ELN-2010 criteria. Overall survival was evaluated by Kaplan-Meier method and log-rank test.ResultsThirty-nine pts were identified. Median age: 71y (52-83). Baseline characteristics are shown in table 1. All pts received azacitidine (75 mg/m2 sc x7 days) as first line treatment. Median time from AML diagnosis to therapy was 16 days (1-88). 56% of pts had bone marrow (BM) blasts >30% at diagnosis (median: 32%; range: 20-90). Five out of 39 (13%) pts had leucocyte count (WBC) >15x109/L and 20/39 (51%) had ECOG performance status >1. Complex karyotype (CK) and monosomal karyotype (MK) was present in 18/39 pts each (46%). Within the subset showing CK, 14/18 (78%) had MK. Complete remission (CR) and CRi was 23.1% and 5.1% respectively (ORR=28.2%). Median courses of therapy to best response: 3 (1-11). After 17m median follow-up, median OS (95% CI) was 7m (3.1-8.8). Estimated 1-year survival was 29.8%. There were no differences in median OS in pts with MK vs. rest of pts with CK (median OS 9m [95% CI: 5.3-12.6] vs. 6.5m [3.1-8.8], respectively; p=0.854). Monosomal karyotype, CK with >5 abnormalities, BM blasts >30% and ECOG status >1 did not achieve statistically significance in multivariate analysis. Only WBC at baseline (>10x109/L or >15x109/L; threshold not relevant) had an impact on OS in both univariate (3m [95% CI: 4.9-13] vs. 9m [4.9-13] if WBC <10x10e /L; p=0.014) and multivariate analysis (HR=3.3, [95% CI 1.1-9.5], p=0.025; Table 2). Most frequent causes of death were disease progression and infection (82%).Table 2Multivariate analysis for survivalParameterHR95% CIp-valueWBC >10x109/L3.341.17-9.580.025BM blast >30%1.080.46-2.540.855MK0.950.33-2.740.919CK1.610.58-4.510.361ECOG >11.840.81-4.170.144ConclusionAlbeit retrospective and non-comparative, azacitidine seems to improve median and 1y survival as compared to historic AML data in pts with adverse cytogenetics. An elevated WBC >10x109/L at diagnosis was the only parameter associated to adverse outcome in this set of pts.Table 1Baseline characteristicsAge, median (range)71 (52-83)ECOG performance status 0-1 2-319 (48.7%) 20 (51.3%)WBC (x109/L), median (range) WBC >10x109/L, N (%)2.2 (0.9-89.2) 5 (12.8%)BM blasts, median; (range) BM blasts >30%, N (%)32 (20-90) 22(56.4%)Complex karyotype (CK), N (%)18 (46.2)Monosomal karyotype (MK), N (%)18 (46.2%)Both CK and MK, N (%)14/18 (77.8%)Prior MDS, N (%)11 (28.2%)Karyotype, N (%) Complex >3 Complex >5 Chrom 7 abn Chrom 3 abn -7 only Chrom 5 and 7 abn Chrom 5 abn Other6 (15.4%) 11 (28.2%) 4 (10.3%) 4 (10.3%) 8 (20.5%) 2 (5.1%) 2 (5.1%) 2 (5.1%)*Excludes pts with chromosome 5 and 7 abnormality DisclosuresFalantes:Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30% This paper deals with both on-label and off-label use of azacitidine in AML. Xicoy:Celgene: Honoraria. Ramos:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

AB0692 Anti-C1Q antibodies in correlation with lupus nephritis in patients treated by rituximab

ObjectivesThe aim of the study was to assess the levels of the antibody to C1q complement component (anti-C1q) in the sera of patients (pts) with lupus nephritis (LN) in relation...

FLT3 Mutation Predicts Worse Clinical Outcome of Relapsed Acute Myeloid Leukemia (rAML) Patients (Pts): Mayo Clinic Experience.

AbstractAbstract 2525 Background:Patients with relapsed AML have a very poor outcome. The molecular signature at diagnosis has emerged as a significant marker for prognostic, and possibly therapeutic, values in newly-diagnosed AML. FLT3 mutations are found in about 25–30% of AML pts. In the absence of FDA-approved agents for FLT3, the prognostic value of FLT3 mutation on clinical outcome for relapsed AML (rAML) is not well documented. Aim:To study clinical implications of FLT3 status on rAML. Methods:All adult pts with AML diagnosed and treated at Mayo Clinic between 2003–2011were studied. Retrospective data collection included pts’ demographics, laboratory tests, bone marrow biopsies, FLT3 mutation (internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutation), and survival information. IRB approval was obtained in accordance with Helsinki declaration. Chi-Square and T-test were used for comparatives between groups and Kaplan-Meier test was applied for survival estimates using JMP 9.0 software. Results:A total of 192 pts with newly-diagnosed with AML were identified. Sixty percent (115) were males, 88% (168) were Caucasians, 26% (49) had antecedent hematological disease (AHD), and 13% (25) had previous exposure to chemo- or radiotherapy. Forty-seven percent had a normal chromosomal analysis, and 18% (35) had FLT3 mutation (28 ITD, 7 TKD). In FLT3-mutated pts, median WBC was 70 x109/L (p=0.0016), hemoglobin 9.5 g /dL, and platelets 48 x109/L, compared to 8.8 x109/L, 9.1 g/dL, 50 x109/L in the rest of pts, respectively. Peripheral blood blasts were elevated in FLT3-mutated group compared to rest of pts (p 0.0059).A total of 128 pts achieved complete remission (CR), with 79 (62%) subsequently relapsed. Of the relapsed patients, 93% (74) were Caucasians, 54% (43) males, 22% (17) had AHD, and 8% (6) had prior chemo- or radiotherapy. Cytogenetics were diploid in 49% (39) and complex in 15% (12). Hematopoietic stem cell transplantation was performed in 30% (24) of pts. Eleven of 79 (14%) pts were FLT3-mutated at relapse (Group 1); with 1 pt having TKD-mutation. Forty-eight percent (38) of pts had unmutated-FLT3 (Group 2), and 38% (30) pts were FLT3-unknown (Group 3).In group 1, median WBC was 9.9 x109/L, hemoglobin 10.55 g /dL, platelets 55 x109/L, compared to 3.2 x109/L (p=0.0034), 10.55 g/dL, and 58 x109/L in group 2, respectively. Peripheral blasts were significantly elevated in group 1 compared to group 2 (38% vs 4%, p <0.0001). Surprisingly, 3/11 pts (27%) with FLT3 mutation at relapse were unmutated at diagnosis. CR was achieved in 2/11 (18%) pts in group 1 compared to 15/38 (39%) in group 2 (p=0.19). Median overall survival in rAML was significantly lower in group 1 compared to group 2 (90 days vs 229 days, p 0.0076). This survival difference was statistically more significant in pts with diploid cytogenetics at relapse compared to the rest (p 0.0009 vs 0.48, respectively). Within 1.5 years, all pts in group 1 died, compared to 21% survived in group 2. Conclusion:FLT3-mutated AML pts had a significantly higher peripheral WBC and blasts at both diagnosis and relapse. Importantly, FLT3 at relapse was found to be mutated in one quarter of pts who were wild-type FLT3 at diagnosis; raising the importance of assessing FLT3 gene on all relapses. FLT3 mutation significantly predicted worse median overall survival in rAML raising the need for novel agents, such as FLT3 inhibitors, in this population. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A semi-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model of thrombocytopenia (TCP) characterizing the effect of trastuzumab-DM1 (T-DM1) on platelet counts in patients with HER2-positive MBC.

605 Background: T-DM1 is an antibody-drug conjugate in development for HER2-positive MBC. In clinical trials of single-agent T-DM1 for heavily pretreated patients (pts), TCP was the dose-limiting toxicity. TCP was generally transient, reversible and not associated with serious hemorrhage, with nadirs by day 8 post-treatment. In some pts, platelet (plt) time profiles drifted slowly down after multiple cycles of T-DM1, though development of grade ≥3 TCP was infrequent. Methods: A semi-physiologic population PK/PD model with transit compartments mimicking plt development and circulation was fit to the concentration-plt-time data from the phase I dose escalation study (TDM3569g; N=52) and a phase II study of single-agent T-DM1 (3.6 mg/kg q3w; TDM4258g; N=112). The rate and extent of plt drift was modeled as a time effect on the proliferation pool. NONMEM software was used for the modeling analyses, with a mixture model approach used to identify pt plt drifts. A separate phase II study (3.6 mg/kg; TDM4374g; N=110) was used for model validation. Results: The PK/PD model described the data well and predicted the 9% incidence of grade ≥3 TCP observed in the validation dataset (TDM4374g). The model also predicts that downward drifting plt profiles will eventually stabilize. In the model dataset, plt profiles from 25% of pts drifted downward much more rapidly than the rest of pts; these stabilized by 8 treatment cycles to typically 50% of the original baseline plt count. In 4374g, the overall plt response pattern was similar, with a subset of pts’ plt profiles drifting then stabilizing by 8 treatment cycles. Pt baseline characteristics were not significantly correlated with plt kinetics. Conclusions: The model accurately reflects clinical observations of plt counts during T-DM1 treatment and supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose, requiring minimal delays/reductions for TCP. In addition, the model supports partial depletion of the plt proliferation pool as a mechanism for the downward drift in plt count. Plt response to T-DM1 could not be predicted a priori from baseline characteristics.

Predicting the development of rheumatoid arthritis in patients with early undifferentiated arthritis

Diagnosis of rheumatoid arthritis (RA) at the beginning of the disease is a difficult task especially due to presence of a large group of pts with “undifferentiated arthritis” (UA) i.e. with inflammation of one or more joints which does not comply with a definite nosology. According to clinical experience UA is quite a serious condition which during a year transforms in definite RA in at least one third of pts. In 2007 Van der Helm-van Mil et al. proposed special criteria (“prediction rule”) allowing predicting transforming UA intoRA by counting prognostic index (PI). PI6 means low and PI8 - high probability of RA 37development during 1 year. Objective. To assess possibility of using prognostic criteria for determination of transforma- tion of UA into RA in Russian pts. Material and methods. 93 pts (84,9% - female) with early (disease duration no more than 12 months) UA were included. Mean age was 44,3±15,2 years, mean disease duration – 128,9±82,1 days (4,3±2,7 months). 59,1% of pts had olygoarthritis, 26,9% were rheumatoid factor seropositive, anti-cyclic citrullinated peptide antibodies (ACCP) were revealed in 29%. Examination with above mentioned methods to specify the diagnosis was performed trice during 12 months: at baseline, after 6 and 12 months. Results. During a year of follow up RA developed in 39(41,9%) pts. Mean value of PI was 5,18±2,48 (median 5,02 [3,01; 7,02]). PI values in pts with disease transformation into RA during a year were significantly higher (6,55±2,33) than in the rest of pts (4,18±2,1), p<0,0001. Analysis of discriminatory curve (ROC) was performed. Area under the curve statistics was 0,77 (SE 0,048, p=0,0001, 95% confidence intervals 0,68; 0,87). 64 (68,8%)pts had PI6, 17(18,3%) - PI≥8 and 12 (12,9%) – PI between 6 and 8. 17(26,6%) pts with PI≥6, 13 (76,5%) pts with PI≥8 and 9 (75%) pts with PI between 6 and 8 fulfilled criteria of RA in a year. Published data on European pts with UA cohorts analysis were compared with results of the present study. Conclusion. Using prognosis criteria for pts with UA in Russian pts gave satisfactory result. ROC analysis revealed PI level dividing transforming and not transforming into RA pts not around 8 as was demonstrated earlier but around 6. Differences between results of the present study and published data may be due to different factors including genetic features as well as clinical heterogeneity of pt groups from Western and Eastern Europe.