Letteratura scientifica selezionata sul tema "305.5/67/092 b"

9 Background: Men with PSA recurrence and fast PSA doubling time (PSADT) are at high risk of progression. While castration effectively decreases PSA and delays metastases, it compromises heath and quality of life without clear survival benefit. E2809 tested whether blocking Akt with MK alone or together with the AR using Bic, would be more effective than Bic alone to suppress AR activity without castration. Methods: 108 PSA-recurrent N0 M0, non-castrate PC patients (pts) with PSADT<12 months (mo) and PSA>2ng/mL; were randomized 1:1 to 11, 4-week (wk) treatment (tx) cycles (cy), up to18cy: arms (A) cy1-3, observation, cy 4-11, Bic 50 mg daily; (B) cy1-3 MK 200 mg once wk orally, cy 4-11 MK+Bic. Endpoints: Primary: proportion of pts with PSA <0.2 by cy11 (90% power to detect 45% vs. 20% using 0.1 level one-sided Fisher’s exact test); Secondary, PSA decline: ≥85%; nadir levels before and after Bic. Toxicity (Tox). Results: 54 pts/arm. Baseline characteristics (median (m) or %, A/B): age, 66/67 years; Gl>7 81/81%; >T2b 98/86%; prostatectomy, 81/75%; radiation, 30/31%; previous castration, 43/46%; testosterone, 302/333 ng/dL; PS 0, 94/93%; mPSA 5.1/6.1ng/dL; PSADT<9 mo, 87/81%, <3 mo 24/37%; Tox. Grade(G)/n: G4: A, 0; B, 2 (embolism, hyperglycemia). G3: A, 1(LFTs); B, 32, 60% (rash 20, hyperglycemia 5, low lymphs, 5; hypertension, 4). At 23.9 mo follow-up, 1 death B. Tx . A: 4 no tx; 14 (26%) started Bic early; 9 (16.7%) stopped <11cy without SAE’s; 41 (76%) completed 11cy, 23 (43%) 18cy. B: 7 (13%) started Bic early; 21 (39%) stopped <11cy due to AE’s in 14 (66%) cases; 32 (59%) completed 11cy, 14 (26%) 18cy. PSA<0.2 at 44wks (cy11): A, 6 (11.1%); B, 8 (14.8%), p=0.39. Among evaluable pts, PSA ≤0.2 occurred only after Bic: A: 10/49 pts (20.4%); B: 16/45 pts (35.6%), p=0.08. Conclusions: Overall, by intent to treat analysis at 44 wks, MK alone had no effect on PSA, nor did it increase response to Bic by any set criteria. High MK discontinuation due to rash before cy11 may have blunted the significance of a higher proportion of evaluable pts on MK+Bic achieving PSA ≤0.2ng/ml compared to Bic alone. Clinical trial information: 01251861.

Abstract Introduction. Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of both solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (HSCT). However, differences in clinical and biological characteristics between the two procedures are not well established. Methods. We retrospectively evaluated 84 consecutive patients diagnosed of PTLD at a single institution between 1993 and 2014. Results. Sixty-three cases occurred after SOT (25 hepatic, 20 renal, 10 cardiac, 9 pulmonary and 1 double-leg transplant) and 21 after HSCT (18 unrelated donor, 16 umbilical cord blood, 2 haploidentical and 2 HLA-identical sibling). There was a male predominance (73% in SOT and 62% in HSCT). Median age at transplant was 53 years (range, 11-76) in SOT and 43 years (range, 18-59) in HSCT (p=0.03). EBV serostatus before transplant was positive in 78% and 92% for SOT and HSCT recipients, respectively. Table 1 summarizes clinical and biological characteristics at diagnostic of PTLD. Briefly, HSCT patients had 89% of B symptoms compared to 60% in the SOT group (p<0.001). WaldeyerÕs ring, spleen and liver involvement was 25%, 45% and 45%, respectively, in the HSCT group; and 5% (p=0.03), 17% (p=0.03) and 13% (p=0.007), respectively, in the SOT group. There was a higher Ann Arbor stage in the HSCT group compare to the SOT group (p<0,05). Time from transplant to PTLD was 4 months (range, 1-27) and 60 months (range, 3-246) for HSCT and SOT group, respectively. Table 1. Clinical and biological characteristics at diagnostic of PTLD SOT HSCT p - value Time from transplant to PTLD (months), median (range) 60 (3 - 246) 4 (1- 27) <0.0001 Early onset, n (%) 14 (22) 19 (90.5) Late onset, n (%) 28 (44) 2 (9.5) Very late onset, n (%) 20 (32) 0 (0) B symptoms, n (%) 33 (60) 16 (89) <0.001 Nodal involvement, n (%) 33 (59) 12 (67) 0.75 WaldeyerÕs ring 3 (5) 5 (25) 0.03 Spleen 10 (17) 9 (45) 0.03 Extranodal involvement, n (%) 35 (58) 16 (80) 0.1 Bone marrow 8 (14) 6 (30) 0.2 Central nervous system 4 (7) 5 (25) 0.07 Liver 8 (13) 9 (45) 0.007 Gastrointestinal 13 (22) 2 (10) 0,4 Lung 7 (12) 1 (5) 0,7 Kidney 6 (10) 1 (5) 0,8 LDH (U/L), median (range) 568 (201 - 2415) 702 (328 - 1515) 0.24 ECOG 1 0-1 41 (87) 8 (89) 2-4 6 (13) 1 (11) Ann Arbor stage <0.05 I 12 (21.4) 1 (4.8) II 8 (14.3) 3 (14.3) III 8 (14.3) 0 (0) IV 28 (50.0) 17 (81.0) WHO classification, n (%) 0.2 Early lesion 0 (0) 0 (0) Polymorphic 7 (12.3) 4 (20) Monomorphic B 45 (79) 16 (80) DLBCL 36 (63.2) 16 (80) Others 9 (15.8) 0 (0) Monomorphic T/NK 3 (5.3) (0) Monomorphic E. Hodgkin 2 (3.5) (0) ND 6 (9.5) 1 (5) CD20+, n (%) 42 (86) 13 (68) 0.2 Most patients (95%) had received calcineurine inhibitors with other immunosuppressive agents. PTLD treatment was different between both groups (p=0.0001); in the SOT group, 22% received rituximab as monotherapy and 63% chemotherapy, as compared with 62% and 19% in the HSCT group, respectively. In SOT, 42 (70%) patients died at a median of 208 days (range, 0-4178) while in HSCT 19 (91%) patients died at a median of 26 days (range, 0-485) (p=0.002). Overall survival at 4 years was 35% for SOT and 7% for HSCT (p<0.0001). Most deaths were directly related to PTLD. Conclusions. PTLD after HSCT appears to be a different entity because of the earlier appearance after transplant, a more aggressive clinical presentation (B symptoms, nodal and extranodal involvement, higher Ann Arbor staging system) and a poorer survival outcome compared with PTLD after SOT. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2833 Introduction: In chronic lymphocytic leukemia (CLL), clonally expanded CD5+ B lymphocytes eventually overwhelm healthy immune cells, hindering normal immune function. To determine mechanisms fueling this expansion, gene expression data were gathered by microarray analysis of cells from CLL patients. Samples were grouped based on Ki-67 expression, an indicator of proliferation. To determine mechanisms correlating with B-cell proliferation and impacting on CLL B-cell biology, microarray profiles were compared using Gene Set Enrichment Analysis (GSEA) [Subramanian A, et al. PNAS 2005]. Methods: Samples were analyzed for intracellular expression of Ki-67 by flow cytometry and divided into 2 groups based on Ki-67 expression (cutoff at 5%). RNA was then purified from CD5+CD19+ CLL cells and gene expression microarray assays were performed using Illumina HumanHT12 beadchips. GSEA was carried out using a library of signatures by Dr. Louis Staudt [Shaffer AL, et al. Immunol Rev 2006] containing 305 gene sets encompassing 13, 564 genes biased towards hematopoietic signatures. Results: Of 61 cases, 14 were Ki-67high and 47 were Ki-67low. When time-to-first-treatment (TTFT) was compared between the groups, Ki67high patients had significantly shorter TTFT (2.76 yrs) compared to Ki-67low patients (23.46 yrs; P<0.0001). By GSEA, we determined 255/285 gene sets were upregulated in the Ki-67high group with 50 gene sets significantly enriched at a false discovery rate (FDR) <25%. For the Ki-67low group, 30/285 gene sets were upregulated with only one significant at FDR <25%. IGHV unmutated CLL (U-CLL) was enriched in only one gene set, termed CLLUNMUT-1, while mutated CLL (M-CLL) was only enriched in CLLMUT-1. CD38high and CD38low subsets were similarly enriched in these two gene sets, with 4 additional gene sets in the CD38high group, including MYD88UP-4 and IFN-2. Of the 50 significantly enriched gene sets in the Ki-67high group, 17 relate to signaling pathways, 16 to cellular differentiation, 6 to cellular processes, 4 to transcription factor targets, and the remaining 7 relate to cancer. Of these, the percentage of the signaling component is up 13% from its representation in the original Staudt library. The top 5 gene sets enriched in the Ki-67high group are: upregulated U-CLL compared to M-CLL (CLLUNMUT-1), myeloid tissue compared to other tissues (MYELOID-1), T cell cytokine induced proliferation (TCYTUP-8), BCR crosslinking CLL B cells (CLLBCRUP-1) and BDCA4+ dendritic cells compared to other hematopoietic cells (DC-1). The total number of genes enriched in these 50 sets is 769, with 217 genes shared in two or more gene sets. Twenty genes were enriched in the CLL BCR signature, CLLBCRUP-1 [Herishanu Y, et al. Blood 2011]. Of these, WARS, IRF4, MX1, OAS1, and NAMPT are also enriched in the T cell cytokine induced and T cell activation signatures. Only one gene set was enriched in the Ki-67low group, CLLMUT-1, upregulated in M-CLL compared to U-CLL. CD274 (PD-L1) was consistently elevated in the Ki-67low group in all the patients, irrespective of IGHV mutation status. Discussion: The observed GSEA profiles in Ki-67high patients correlated with gene signatures biased towards BCR signaling, signal transduction, and hematopoietic cancer, consistent with the Ki-67high group containing more (recently) proliferating cells influenced at least in part by BCR signaling. The profiles also suggest that additional cells (T lymphocytes and dendritic cells) may be involved. It is notable these gene sets were not observed for CLL patients subgrouped by IGHV mutation status or by CD38, and that these other subsets did not show as pronounced a distinction by GSEA profiling. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Chimeric antigen receptor T cell (CART) therapy has remarkably improved the outcome of patients (pts) with relapsed refractory B cell non-Hodgkin lymphoma. Anti-CD19 directed CART therapy have shown to yield durable remission in 40%-50% of patients with relapsed refractory (r/r) diffuse large B cell lymphoma (Neelapu et al. NEJM 2017; NCT 02348216). However, pts who had disease progression post CART therapy (non-responders) have poor outcomes. There is paucity of information regarding negative predictors for disease progression and outcome of non-responders post CART therapy. Methods We conducted a single center retrospective study of 11 patients with relapsed refractory large B cell lymphoma who underwent treatment with CART in our institution from December 2019 to June 2021 and further studied the baseline characteristics, and clinical outcome of 8 pts who were non responders to CART therapy. Results All patients received low dose fludarabine cyclophosphamide based lymphodepleting conditioning regimen followed by anti-CD19 directed CART cells using CD28 as costimulatory domain with a target dose of 2 x 10 6 cells /kilogram of body weight. Baseline characteristics as shown in [Table 1]. Median age at CART therapy was 61 years (range 49-71). Median ECOG score at CART therapy was 1. All patients had chemo refractory disease at time of CART therapy with 9 patients having refractory diffuse large B cell lymphoma and 2 patients had transformed large B cell lymphoma. Genomic studies showed high risk disease in 4 patients with double hit lymphoma, 3 patients with complex cytogenetics with one having 17 p deletion and 2 patients with double expressors of c-myc and bcl2. Only 5 patients had available Ki-67 score &gt; 80%. All patients had stage III-IV disease at the time of CART therapy. Seven pts had extra nodal disease and one patient had CNS involvement. Median R-IPI score at time of CART therapy was 3 (range 2-4). Median LDH, serum ferritin and serum CRP at the time of CART therapy was 388 (range 136-1489); 831 (range 116.9-1503); and 28.1 (range 7.4-226) respectively. Median number of prior therapies were 3 (range 2-9). One patient had prior autologous stem cell transplant. Median absolute lymphocyte count (ALC) and platelet count at CART therapy was 0.01/ul (range 0.01-2.5) and 89 x 10 3/ul (range 10-385) respectively. Median time from last salvage chemotherapy to CART therapy was 62 days (range 28-492). Total six pts had cytokine release syndrome (CRS) with median time for CRS onset was 3.5 days (range 1-8) with all of them having grade 1-2 CRS. Total seven pts had neurotoxicity with median time for onset was 5 days (range 1-41) post CART with 4 pts having &gt; grade 3 immune effector cell associated neurotoxicity syndrome (ICANS). Overall, six and seven pts received tociluzumab and steroids respectively for treatment of CART related CRS and ICANS. Day 30 PET/CT scan showed three responders (2CR,1PR) and eight non responder patients with disease progression. Non responder pts to CART, when compared with responders had higher value of median LDH (438 vs 300; p = 0.92); median CRP (29 vs 13; p = 0.497) ; higher extra nodal involvement ( 6 pts vs one), median R-IPI score at the time of CART ( 4 vs 3), median number of prior therapies (4 vs 3), and median time from last salvage therapy to CART ( 73 days vs 50 days ; p = 0.91). No difference in baseline ALC count and platelet count was noted between the two groups. Compared to responders, non-responder pts had lower incidence of CRS (100% vs 37.5%) and ICANS (100% vs 50%). Post CART therapy, non-responder pts were treated with Nivolumab based immunotherapy in 5 pts, Ipilimumab based therapy in 1 pt, Selinexor in 1 patient and Polatuzumab based therapy in 2 pts. Median progression free survival and overall survival of non-responders was only 30.5 days and 94 days respectively. 5 out of 8 non responder pts died (4 due to disease progression and 1 due to sepsis). All three responder pts were alive and disease free at the end of study. Median follow up of our study was 108 days (range 32- 561). Conclusions Despite smaller sample size, our study showed dismal outcome of pts who don't respond to CART therapy, showing an unmet need for better salvage therapies in such pts. Refractory lymphoma pts with extra nodal disease involvement, higher LDH and CRP at the time of CART therapy could be negative predictors for response. Further prospective studies with larger sample size required to further validate these findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

e14018 Background: Cancer survival rates are improving. Therefore, management of cardiovascular complications has now become a crucial clinical concern. Cardio-oncology is the sub-specialty that assists in the overall management of cancer patients in a multi-disciplinary manner. Mayo Clinic cardio-oncology practice was initiated to work closely with our oncology colleagues for early detection of cardiovascular complications in response to cancer-therapy. Majority of the patients visit our cardio-oncology clinic once, we thought it is important to study the group of patients that visited frequently due to cardiovascular complications. Aim: To evaluate the most common cardiovascular complication in patients with 2 or more visits to our cardio-oncology clinic. Methods: From 2012-2017, there were > 2500 patients visits to our clinic, with 24 patients having 2 or more visits. Data including patients’ demographics, ethnicity, chemotherapeutic medications, primary cancer type, cardiovascular risk factors, echocardiography and clinical outcomes were collected. Cardiotoxicity was defined as the decrease in left ventricular ejection fraction (LVEF) of > 10% to a value of < 53%. Heart failure was diagnosed based on Framingham’s criteria or by a cardiologist. Results: There were 19 women (80%) and 5 men (20%). Median age at the time of diagnosis was 56 years [19-76]. The most common malignancy was breast cancer (70%), followed by B-cell lymphoma (12%) and acute myeloid leukemia (8%). Thirty percent had > 2 risk factors for cardiovascular disease. 75% of the patients had an LVEF of < 53, of these 67% developed heart failure with 58% preserved and 42% reduced ejection fraction. Those with heart failure had received a mean anthracycline dose of 305 ± 91.8mg/m2. With initiation of ACEI, B-Blockers, and diuretics (GDMT) 79% showed recovery of LVEF to ≥53 during the follow up. Conclusions: In our experience, most patients who were seen at least twice in the cardio-oncology clinic for heart failure had received a dose of > 300mg/m2 anthracycline. With GDMT over 75% of the patients recovered. Care in the cardio-oncology clinic plays a key role in optimizing these clinical outcomes.

e19041 Background: VEN is a selective orally bioavailable BCL-2 inhibitor. The dose-escalation Phase 1 study of VEN in 106 patients (pts) with relapsed/refractory NHL reported an ORR of 44%. Most pts had diffuse large B-cell/follicular lymphoma; we report on updated results in pts with less common NHL subtypes. Methods: VEN was administered and continued until progressive disease (PD)/unacceptable toxicity, in dose cohorts ranging from 300–1200 mg. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and response by 2007 Cheson IWG response criteria, utilizing CT scans beginning at wk 6. Results: 35 of 106 pts had mantle cell lymphoma (MCL, n=28), marginal zone lymphoma (MZL, n=3) or Waldenström macroglobulinemia (WM, n=4). Most common all grade treatment emergent AEs were nausea (51%), diarrhea (49%) and fatigue (34%); grade 3/4 AEs in >10% of pts were neutropenia and anemia (17% each). Laboratory TLS was reported in a single pt (bulky MCL). MCL pts (median age: 72 years) had received a median of 3 (1–7) prior treatments (tx). Median time from start of prior tx to start of VEN was 13 mo (2–148) and time on VEN was 11 mo (0.2–42). ORR was 75%, 6 pts (21%) achieved CR and remain on study (DORs: 25–40 mo). One pt with a PR proceeded to elective allogeneic stem cell transplant and remained disease free at last protocol defined follow-up (24 mo after coming off study). Median PFS was 11 mo and DOR was 15 mo. MZL pts (median age: 63 years) had received a median of 4 (2–6) prior tx. Time from start of prior tx to start of VEN was 8, 14, 73 mo and time on VEN was 5, 1, 35 mo. One pt (6 prior tx) received VEN for <1 mo due to progressive cytopenias; 1 pt (4 prior tx) achieved a PR with VEN at wk 6 but had PD at wk 16; 1 pt (2 prior tx) achieved PR at wk 6 and is the only pt to remain on study (DOR:32 mo). WM pts (median age: 67 years) had a median of 4 (3–5) prior tx. Time from start of prior tx to start of VEN was 5, 18, 33, 67 mo and time on VEN was 42, 17, 54, 20 mo. All pts achieved PR (at wks 6 [n=2], 16 and 36), with DORs of 11, 12, 38 and 50+ mo (latter is ongoing and remains on study). Conclusions: VEN monotherapy has a tolerable safety profile in MCL, MZL and WM pts. ORR were high and most responses durable; median PFS and DOR suggest significant activity in MCL pts. Further investigation of VEN in each disease is indicated. Clinical trial information: NCT01328626.

Abstract Abstract 1554 Poster Board I-577 Introduction The International Prognostic Factor Project Score (IPS) is the most widely utilized risk stratification index for Hodgkin lymphoma (HL) (Hasenclever, N Engl J Med, 1998). Based on patients treated before 1992, it incorporates 7 adverse risk features (male gender, age ≥45 y, stage IV, hemoglobin <105 g/L, WBC ≥15 × 109/L, lymphocyte count <0.6 × 109/L or <8% of differential, albumin <40 g/L) and predicts for a 5-year freedom-from progression (FFP) ranging from 42-84%.The IPS has not been validated in a more recently treated population, where more accurate pathologic diagnosis, routine use of growth factors and enhanced supportive care may have improved outcomes compared with historic results. Methods This retrospective population-based analysis used the British Columbia Cancer Agency Lymphoid Cancer Database to identify all patients ages 15-65 y diagnosed from January 1st,1990 to June 30th, 2008 with advanced stage HL (stage III/IV, or stage I/II with B symptoms or bulky disease ≥10 cm), who were treated with curative intent with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or an ABVD-equivalent regimen and had complete information including all IPS variables. Primary endpoint was FFP, defined as the interval from diagnosis to first progression or relapse or death due to treatment toxicity; deaths from unrelated causes were censored. Results 579 patients were identified. Median age was 29 y (range 15-65); 11 (2%) stage I, 239 (41%) stage II, 202 (35%) stage III and 127 (22%) stage IV; 245 (42.3%) had bulky disease; and 359 (62%) had B symptoms. Histologies included: 455 (79%) nodular sclerosing, 35 (6%) mixed cellularity, 7 (1%) lymphocyte-rich, 11 (2%) lymphocyte depleted, 13 (2%) nodular lymphocyte predominant, 58 (10%) HL NOS. 161 (28%) patients received IFRT with primary treatment. Adverse prognostic factors were present as follows: 119 (21%) age≥45, 375 (65%) albumin <40 g/L, 88 (15%) WBC ≥15 × 109/L, 116 (20%) hemoglobin <105 g/L, 57 (10%) lymphocyte count <0.6 × 109/L or <8%, 302 (52%) male, 127(22%) stage IV. Only 37 (6.4%) patients had a prognostic score ≥5. With a median follow-up of 73 months (range, 1-222), 512 (88.4%) patients were alive and 67 (11.6%) had died (39 with HL, 7 due to toxicity and 21 from unrelated causes). Five year FFP and overall survival (OS) were 79% and 91%, respectively. The IPS was prognostic for both FFP (p=.0035) and OS (p<.0001), with 5-y FFP ranging from 66% to 86% and 5-y OS ranging from 74% to 98% (Table 1). In univariate analysis only stage IV (p=.003) and hemoglobin (P=.001) were prognostic for FFP. Albumin (p=.054), age (p=.082) and WBC (p=.094) were borderline significant, but gender (p=.329) and lymphocyte count (P=.496) appeared to have a weaker prognostic value for FFP. Only stage IV (HR=1.63, CI 1.10-2.40, p=.014) and hemoglobin (HR=1.73, CI 1.17-2.57, p=.006) were prognostic for FFP in a multivariate Cox regression. Conclusion The IPS remains prognostic for patients with advanced stage HL treated in a more modern era. However, it does not identify risk groups with sufficiently good or poor outcome to justify deviation from standard therapy. Identification of truly low or high risk populations will require supplementation with molecular markers and/or the use of early PET scanning. Caution should be used when comparing results from current clinical trials to historic controls, since more recent outcomes with standard therapy are clearly superior to those previously reported. Disclosures No relevant conflicts of interest to declare.

Abstract Background Pretreatment cytogenetic analysis is frequently used to predict response and outcome in hematologic malignancies. Hypodiploidy is associated with a poor prognosis in childhood ALL. Similarly, complex cytogenetics is a known adverse prognostic factor in myeloid malignancies. The impact of hypodiploidy and complex cytogenetics has not been extensively assessed in adult patients with ALL. To address this issue, we have conducted a retrospective analysis of all adult patients with ALL treated with frontline Hyper-CVAD based regimens at our institution. Methods We reviewed 332 adult patients treated between May 2000 and March 2015. Patients with Philadelphia-positive ALL and those with t(4;11) were excluded. Hyodiploidy was defined as 45 or less chromosomes. Hyperdiploidy was defined as 47 and more chromosomes. Complex karyotype was defined as having 5 or more chromosomal abnormalities (Moorman et al., Blood 2007). We analyzed the clinical outcomes based on the cytogenetic risk groups. Chi-square test was performed to evaluate differences in response rates. Survival was calculated using Kaplan-Meier estimates and compared using the log-rank test. Results Patient characteristics, responses to therapy, and outcomes are summarized in Table 1. Thirty-five patients (10%) were hypodiploid, 67 (20%) were hyperdiploid, and 71 (21%) had a complex karyotype. With a median follow-up of 28 months (range 0.5 - 176 months), the median survival was 61, 69, and 45 months for patients with diploid, hypodiploid, and hyperdiploid cytogenetics respectively. The 3-year survival rates were 63%, 59% and 53%, respectively (p=0.18). Similarly, having a complex karyotype did not affect survival when compared to diploid cytogenetics with a median survival of 58 and 61 months respectively. The 3-year survival rates were 63% and 59%, respectively (p=0.27). Conclusion Unlike what has been described in childhood ALL, the prognosis of adult ALL patients with a hypodiploid or complex karyotype treated with Hyper-CVAD based regimens is similar to patients with a diploid karyotype. This could be attributed to a different biology of the disease or could be related to the treatment given in this population. The use of genomics combined with cytogenetic analysis could perhaps constitute a better predictive biomarker. Table 1. Characteristics (n total=332) Diploid (n=147) Hypodiploid(n=35) Hyperdiploid(n=67) Complex (n=71) Median age, y (range) 44 (16-83) 58 (20-80) 54 (18-85) 58 (18-85) Sex no. (M/F) (182/150) 95/52 14/21 34/33 39/32 WBC, median x 109/L(range) 3.85 (0.4-216) 3.6 (0.7-420) 3.9 (0.6 -134) 3 (0.5-87) Hg, median g/L (range) 9.3 (3.5-16) 8.9 (4-11.9) 9.2 (4.5-14) 9.2 (5-14) Platelets, median x 109/L (range) 64 (1-626) 32 (7-233) 36 (7-271) 32 (7-233) Creatinine, median mg/dL (range) 0.9 (0.3-4) 0.8 (0.45-1.5) 0.8 (0.5-2.3) 0.8 (0.4-2.3) Bilirubin, median mg/dL (range) 0.5 (0-8) 0.6 (0.2-5.6) 0.5 (0.2-11) 0.5 (0.2-5.4) LDH, median IU/L (range) 839 (268-32029) 1460 (172-6408) 1177 (345-8953) 1241 (172-8953) Blasts in BM, median % (range) 78 (0-99) 88 (60-98) 83 (26-100) 84(26-97) Blasts in PB, median % (range) 12 (0-99) 36 (0-92) 26 (0-96) 26(0-100) B-ALL (n=282) n 120 33 63 65 T-ALL (n=50) n 27 2 4 6 Complete response (%) 92 88 88 88 3-year survival rate (%) 63 59 53 56 Disclosures DiNardo: Novartis: Research Funding. Cortes:Teva: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Abstract Background: The SAKK 22/99 is a phase III randomized clinical trial launched by the Swiss Group for Clinical Cancer Research and the European Institute of Oncology in Milan in 99 for women with HER2-positive advanced breast cancer (ABC). 175 patients were randomized 1:1 from Sept 99 to Jan 2013 to receive first-line trastuzumab (T) alone followed at disease progression by the combination with chemo (Arm A) vs the upfront combination of T and chemo (Arm B). The results were published in 2017 (O. Pagani et al Ann Onc 28: 305–312, 2017). The outcome was similar for sequential T-chemo or upfront combination The patients’ treatment and FU continued until March 2022 and we now report the safety data after 135.2 months of median FU. Patients and methods: at the time of study termination 1 patient with SD was still receiving T alone in the study and T was continued after trial closure. The safety analyses include 86 pts allocated to arm A and 88 to arm B. 1 pt did not receive any trial treatment and was excluded from this analyses. 19 of the 86 patients in arm A stopped trial treatment after T alone, 67 continued with T+ chemo. Baseline characteristics were well balanced and are summarized in Table 1. Treatment The T loading dose of 4 mg/kg/iv was followed by 2 mg/kg/iv weekly. In the 1st-line population (84) chemo was weekly paclitaxel (90 mg/m2/iv-3/4 weeks). After amendment 1 chemo was at investigator’s choice (taxanes, vinorelbine, platin) according to label indications and could be stopped after 24 weeks (6–8 cycles) in responding patients or after unacceptable toxicity. Results: 7 patients in arm A (8%) and 11 in arm B (13%) stopped trial treatment due to toxicities (Fisher’s exact test, p=0.46). 3 of the 7 patients in arm A stopped under T alone and 4 under T+chemo (all paclitaxel weekly) Treatment durations of these 7 and 11 patients were 7.7 months (range 0.5 – 49) in arm A and 5.5 months (range 0.6 – 31 months) in arm B, respectively. Cardiovascular toxicities: The most common toxicities were thromboembolic events, blood pressure disorders and arrhythmia. 6 patients (7%) in arm A and 10 (11%) in arm B had cardiac events (Fisher’s exact test, p=0.43). G1-3 toxicities occurred in 2 (2%), 2 (2%) and 2 (2%) patients of arm A and in 5 (7%), 2 (2%) and 3 (3%) of arm B. We observed no grade 4 events. Split by treatment phase in arm A, G1-3 toxicities were seen in in 1 (1%), 2 (2%) and 1 (1%) patient under T alone (N=86) and in 1 (1%), 0 (0%) and 2 (3%) under T+chemo (N=67). LVEF-decline: 78 patients in arm A and 74 in arm B had sequential LVEF measurements. A decline ≥ 10% was found in 35 patients (45%) in arm A and in 20 (27%) in arm B (Fisher’s exact test, p=0.028). Among the 35 patients in arm A, 12 had the decline under T alone, 14 under T+chemo, and 9 under both T alone and T+chemo. A decline ≥ 20% was found in 10 patients (13%) in arm A and in 3 (4%) in arm B (Fisher’s exact test, p=0.08). Among the 10 patients in arm A, 7 had the decline under T alone, 3 under T+chemo. Sensory neuropathy 43 patients (50%) in arm A and 48 (54%) in arm B had neuropathy (Fisher’s exact test, p=0.65). G1-3 toxicity in arm A was developed by 26 (30%), 11 (13%) and 6 (7%) patients, respectively; in arm B 30 (34%), 12 (14%) and 6 (7%). No grades 4 events occurred. Conclusion: After more than 11 years of follow-up, no relevant toxicities were found in these patients receiving T for ABC. In particular, the incidence and grade of cardiac toxicity was low. The decline in LVEF was numerically higher in the arm A and in particular in the T alone group, but was not clinically relevant. Our data potentially suggest that T+chemo followed by T maintenance could have less cardiotoxicity than T followed by T+chemo. The possible causes for the difference in LVEF decline between the two arms are unclear, but could be related to treatment duration. The women in Arm A shows a trend to longer therapy: Median treatment duration (months) in Arm A was 7.92 (0.46 - 135.98) vs 6.62 (0.56 - 71.28) in Arm B. This long-term analysis confirms the favorable safety and good tolerability of the reported regimes. Table 2: Treatment duration Citation Format: Manuela Rabaglio, Daniel Dietrich, Bernhard Scheibe, Thomas Ruhstaller, Franco Nole, Serenella Eppenberger, Christian Oehlschlegel, Dagmar Hess, Christoph Mamot, Elisabetta Munzone, Bernhard Pestalozzi, Stefan Aebi, Marcus Vetter, Beat Thuerlimann, Roger von Moos, Khalil Zaman, Olivia Pagani. Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer [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 P4-01-25.

The aim of this paper was to identify which psycholinguistic variables are better predictors of performance for healthy participants in a picture naming task and in a picture categorization task. A correlation analysis and a Path analysis were carried out. The correlation analysis showed that naming accuracy and naming latency are significant and positively correlated with lexical frequency and conceptual familiarity variables, whereas they are negatively correlated with H index. Reaction times in the categorization task were negatively correlated with lexical frequency and conceptual familiarity variables and positively correlated with visual complexity variable. The Path analysis showed that subjective lexical frequency and H index are the better predictors for picture naming task. In picture categorization task, for reaction times, the better predictor variables were subjective lexical frequency, conceptual familiarity and visual complexity. 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