Of Survival Research Articles

Tumor inflammatory microenvironment contribution to survival in resected upstaged adenocarcinomas

IntroductionTumor Inflammatory microenvironment (TIME) encompasses several immune pathways modulating cancer development and escape that are not entirely uncoded. The results achieved with immunotherapy elicited the scientific debate on TIME also in non-small cell lung cancer (NSCLC). We aimed to investigate whether TIME (in terms of PD-L1 expression and/or Tumor Infiltrating Lymphocytes - TILs) played a separate role in terms of survival (OS) in resected upstaged lung adenocarcinomas (ADCs), excluding other perioperative variables as confounders. Materials and methodsThis retrospective study included 50 patients with a clinically resectable lung ADC, undergoing surgery (lobectomy or segmentectomy) at the Thoracic Unit of Padova University Hospital between 2016 and 2022 and receiving an unexpected pathological upstaging (IIB or higher). ResultsDespite microscopical variables increasing from IIB to IIIB, survival was not significantly related to them. OS was better in TIME-active patients (defined as the presence of positive PD-L1 and/or TILs>10 %) than double negatives (PD-L1-/TILs-) (p = 0.01). In IIB or higher ADCs, TIME-active patients showed an improved survival compared to double negatives, merging the current TIME theories. ConclusionTIME seems to be associated with survival independently from other microscopical parameter, even in case of resected upstaged adenocarcinomas.

Radiotherapy Dose as a Predictor of Outcomes Following Cardiac Radioablation for High-risk Refractory VT

Cardiac radioablation (CRA) is an emerging treatment for high-risk refractory ventricular tachycardia (VT). Despite a fixed prescription dose to the planning target volume (PTV) there is still considerable heterogeneity in the radiotherapy dose distribution due to planning technique, proximity to organs at risk, and radiation oncologist preference. The hypothesis is that plans with an inherently "hotter" internal dose to the PTV may lead to improved VT outcomes. Single-center, IRB-approved retrospective case series of patients with refractory VT who had failed at least one prior CA (or were unfit for CA) treated with CRA. All patients were treated with a single fraction of 25 Gy prescribed to the PTV. Maximum dose to PTV was collected from each plan and stratified as high vs low above and below the median. Maximum dose was defined as the highest dose delivered to the "hottest" 0.035 cc of the PTV to avoid known variability in reporting of dose to single voxels within the treatment planning system. Rates of survival (OS), freedom from shock and/or storm (FFSS), and freedom from death, shock, and/or storm (FFDSS) were collected, and stratified by maximum dose to the PTV. Formal statistical comparisons were not performed due to limited patient numbers. From 2015-2020, 22 patients were treated with CRA (18 with prior CA, 4 unfit for CA) for high-risk refractory VT. Median age was 64.5 years (range, 49-84), and 90.9% were male. 50% had ICM, with a median NYHA class of 3 (range, 1-4) and median EF of 25% (range, 15-58%). Median follow-up was 31.3 months. 2-year OS was 54.5%, FFSS was 42.4%, and FFDSS was 27.3%. Median maximum dose to the PTV was 42.2 Gy (range, 29.2-45.8 Gy). PTV maximum dose (high vs low) discriminated 2-year OS (63.6% vs 45.5%), FFSS (50% vs 30%) and FFDSS (36.4% vs 18.2%). For all endpoints, Kaplan-Meier curves overlapped for the first 6 months, and then diverged. In patients with high-risk refractory VT treated with CRA, survival and VT outcomes were similar between both groups out to 6 months, with improved OS and VT control noted after that with higher maximum doses. With a prescription dose of 25 Gy to the PTV, adjusting planning parameters to maintain maximum doses > 42 Gy may improve durable outcomes and requires validation in a larger cohort.

PO-05-064 UTILITY OF CATHETER ABLATION VT RISK SCORES IN PREDICTING OUTCOMES FOLLOWING CARDIAC RADIOABLATION FOR HIGH-RISK REFRACTORY VT

Cardiac radioablation (CRA) is an emerging treatment for high-risk refractory ventricular tachycardia (VT). Validated risk scores (I-VT, PAINESD) exist for prediction of outcomes following catheter ablation (CA) for VT but have unclear utility in patients undergoing CRA. Examine outcomes for high-risk refractory VT treated with CRA at a high-volume center stratified by I-VT and PAINESD scores. Single-center, IRB-approved retrospective case series of patients with refractory VT who had failed at least one prior CA (or were unfit for CA) treated with CRA. I-VT and PAINESD scores were calculated for each patient. Rates of survival (OS), freedom from shock and/or storm (FFSS), and freedom from death, shock, and/or storm (FFDSS) were collected, and stratified by I-VT and PAINESD score. Formal statistical comparisons were not performed due to limited patient numbers. From 2015-2020, 22 patients were treated with CRA (18 with prior CA, 4 unfit for CA) for high-risk refractory VT. Median age was 64.5 years (range, 49-84), and 90.9% were male. 50% had ICM, with a median NYHA class of 3 (range, 1-4) and median EF of 25% (range, 15-58%). Median follow-up was 31.3 months. 2-year OS was 54.5%, FFSS was 42.4%, and FFDSS was 27.3%. A total of 63.6% and 68.2% had high risk I-VT and PAINESD scores, respectively. I-VT (low vs high) discriminated 2-year OS (75% vs 42.9%), FFSS (Figure 1B, 57.1% vs 34.6%), and FFDSS (37.5% vs. 21.4%). PAINESD (low/moderate vs high) discriminated 2-year OS (71.4% vs 46.7%), but not FFSS (Figure 1B, 42.9% vs 43.1%), or FFDSS (28.6% vs 26.7%). In patients with high-risk refractory VT treated with CRA, I-VT was a promising predictor of survival and VT outcomes while PAINESD only predicted survival. Use of I-VT risk stratification may serve as a useful metric when selecting patients mostly likely to benefit from CRA in future studies and requires validation in a larger cohort.

Proteomic Profiling Based Classification of CLL Provides Prognostication for Modern Therapy and Identifies Novel Therapeutic Targets

The availability of targeted therapy and improved molecular characterization of Chronic Lymphocytic Leukemia (CLL) require a re-evaluation of treatment paradigms. As CLL heterogeneity is dependent on molecular and environmental factors, there is a need to create a new classification based on the integration of several factors. Here, we accomplish this goal by identifying CLL signatures using Reverse Phase Protein Array. Protein expression for 384 total and post translationally modified proteins was assessed in 871 CLL and Mature Small B Cell Leukemia (MSBL: HCL, HCLV, LGL-T, MCL, MZL, PLL, Richter's, T-Cell PLL) patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteins were categorized into 40 protein functional groups (PFGs) based on literature and intra-dataset protein correlations and patients clustered based on PFG expression patterns into 6 recurrent protein expression signatures (PES) (Figure 1A). Individual protein expression (58/384 proteins), PFG expression (32/40) and overall PES were all highly prognostic of survival (OS) and time to first or second treatment (TTFT, TTST) (Figures 1B-C). The adhesion, apoptosis-occurring, apoptosis-regulating, heat shock, histone1 (marks), histone 2 (modifiers) and the STP-regulation PFGs were prognostic for all 3 outcome measures. Notably SG-A contained most of the MSBL and 15/16 cases of hairy cell leukemia, but the CLL cases within this SG fared very poorly. For OS, groups A and C had markedly inferior survival (P<0.0001) (10.3 and 20.3 median years) relative to the other 4 groups, which were statistically similar to each other. First treatment occurred sooner for Groups A and C (5.8 and 5.23 median years). Additionally, the TTST was also inferior for Group A (median 3.5 years). There were significant differences in age, hemoglobin, platelets, % BM and PB lymphocytes and β2M between the SG, but not for race (p = 0.84) or gender (p = 0.72). , Historically adverse cytogenetic aberrations del 11q and del17p events (23% overall) were less common in SG A, B, D and E (15, 14, 16, 17%) and overrepresented in SG C (32%), while historically favorable 13q changes were seen across all groups as was Trisomy 12 (14% overall), although SGs A and E were enriched (25%, 22%) while SG-F was low (5%) for Trisomy 12. SG membership superseded other traditional prognostic factors (Rai Staging, IGHV Status) and were prognostic for modern (BTK inhibition) and older CLL therapies. SGs A and C responded poorly to chemotherapy regimens compared to the other groups, whereas all groups responded well to BTK inhibitors except for SG-A. SGs and PFGs membership provided novel drug targets (see our other abstracts on TP53BP1 and ASNS) and defined optimal candidates for Watch and Wait (WaW) vs. early intervention. A model based on the accumulation of irregularities in ANXA1, TFRC, and SMAD2.p245 expression, optimally predicted TTFT overall and in early stage CLL patients. Patients with < 1 negative level of either of the 3 proteins, have a median TTFT of 14.59 years, whereas patients having 2-3 have a median of 5-6.27 years (P<0.0001). CHEK1.pS345, GAB2, IGFBP2, S100A4, WEE1.pS642, and ZAP70 were universally overexpressed by all SGs, suggesting them as ideal targets for inhibition. Collectively proteomics demonstrates promise for improving classification, therapy strategy determination, and identifying novel therapeutic targets. [Display omitted] DisclosuresFerrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Burger: Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Wierda: Xencor: Research Funding; Karyopharm: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Janssen: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding.

Evaluation of Novel Endpoints As Treatment Outcome in Allogeneic Hematopoietic Stem Cell Transplantation: A Comparison of “Classical” and “Refined” Definition of Graft-Versus Host Disease Free and Relapse Free Survival for Registry-Based Studies

Allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Holtan et al. (Blood 2015) proposed GVHD free/relapse free survival (GRFS), as a composite endpoint to analyse transplant associated morbidity. This endpoint considers as events grades III-IV acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse, or death for any cause. Although it could be a good indicator in prospective trials, since it seems to characterize the survival without mortality or ongoing morbidity, it might be difficult to use in retrospective setting. A “refined” GRFS (considering grade III-IV acute GVHD, extended/severe chronic GVHD, relapse and death for any cause) was proposed by Ruggeri et al (BMT 2016) to adapt this endpoint also to registry-based studies.To compare definitions of this composite endpoint we retrospectively analyzed “classical” and “refined” GRFS on 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital in Paris (n=840) between 2007 and 2014. Data collection is based on the European Group of Blood and Marrow Transplantation (EBMT) registry via the central data processing system “Project Manager Internet Server” (ProMISe), considering the MED-A and MED-B forms for patients registered in those two centers. A MED-C form was built for all patients who developed chronic GVHD.Median age of patients at transplant was 41 (range 4-64 years) whereas median duration of follow-up for survivors after HSCT was 38 months (range: 0-97.7 months). Characteristics of patients were reported in table 1. Cumulative incidence (CI) at day 100 of grade II-IV and grade III-IV acute GVHD were 41.1% (95%CI 37.9-44.3%) and 15.6% (95%CI 13.4-18), respectively. CI of chronic GVHD requiring systemic treatment and diagnosed according to NIH criteria was 22.3% (95%CI 20.7 -26.3) at 1 year and 32.6 % (95%CI 29.5-36.0) at 3 years. CI of severe/extended chronic GVHD (as reported in ProMise registry) was estimated at 16.6% (95%CI 14.1-19.5) at 1 year and 22.5% (95%CI 19.4-26.0) at 3 years. CI of relapse was 18.7% (95%CI 16.3-21.5%) at 1 year, 25.1% (95%CI 22.3-28.2%) at 3 years and 26.7 (95%CI 23.7-30.0) at 5-years. Probability of survival (OS) of the whole population at 1, 3 and 5 years was respectively: 75% (95%CI 73.0-76.9), 62% (95%CI 58.0-65.8), and 57% (95%CI 55.0-58.9). Event free survival (EFS) was 64% (95%CI 48.0-56.9) at 1 year, 53% at 3 years (95%CI 49.1-56.9) and 50% at 5 years (95%CI 48.0-52.0). Global classical GRFS was 71% (95%CI, 69.0-72.9) at 1 years, 52% (95%CI 48.1-55.9) at 3 years and 35% (95%CI 31.2-39.0) at 5 years, whereas refined GRFS was 71% (95%CI, 69.0-72.9), 53% (95%CI 49.1-56.9) and 38% (95%CI 34.2-42.0) at 1, 3, and 5 years respectively. Six hundred twenty-eight subjects were censored by classical GRFS whereas 546 patients have been identified as reporting at last one event according to refined GRFS. Chronic GVHD and relapse represented the major components of classical GRFS (35.7 and 35.2% respectively) whereas relapse (40.5%) and III-IV acute GVHD (25.6%) were major constituents of refined GRFS (Figure 2). According both definitions several risk factors were identified in univariate and multivariate analysis. Particularly, transplants performed after 2010, diagnosis of acute leukemia and RIC regimens had a significant impact on survival without GVHD and relapse (both in classical and in refined GRFS) whereas age, stem cell source, disease risk group (identified as influencing factors in univariate analysis) did not impacted on GRFS in multivariate model. Transplants from non-matched unrelated donors showed a significant impact only on classical GRFS in COX regression. The multivariable c-statistics were 0.609 for classical and 0.614 for refined GRFS.Our data support the use of both composite endpoints to describe HSCT outcomes. Classical GRFS could represent the ideal endpoint following HSCT in prospective setting, whereas refined GRFS could be used as good surrogate of GRFS in retrospective studies. However, attention need to be paid concerning the use of refined indicator because of the risk of underestimation of censored events, since it may not reflect the real impact of chronic GVHD on population in study. [Display omitted] DisclosuresPeffault De Latour:Amgen: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Socié:Alexion Pharmaceuticals, Inc.: Consultancy.

The Two-Step Approach to Haploidentical Hematopoietic Stem Cell Transplantation (HI HSCT): 15 Years of Transplants in Patients 19-78 Years Old

Background/Methods: The two-step approach to HI HSCT was developed in 2005 with the first patient treated on clinical trial in early 2006. In this approach, after myeloablative [MA- 12 Gy total body irradiation (TBI)], reduced intensity (RIC- fludarabine, 2 Gy TBI and cytarabine, OR thiotepa, OR busulfan), or nonmyeloablative (NMA-fludarabine and 2 Gy TBI) conditioning, patients receive a fixed dose of unmanipulated donor lymphocytes (DLI) containing 2 x 108/kg CD3+ cells (Step 1). Two days later, cyclophosphamide (CY) 60 mg/kg/day x 2 is infused for bidirectional T cell tolerization. One day after the completion of CY, a CD34-selected stem cell product is infused (Step 2). All patients receive tacrolimus and mycophenolate mofetil starting at d-1. The two-step approach avoids stem cell exposure to CY, allows a growth factor-naïve fixed dose of donor T-cells to be infused increasing uniformity for outcomes analysis, and permits easier manipulation of both T-cell and CD34 cell dosing. In later protocols, the timing of the DLI after conditioning and the CD34 cell dose have been manipulated with the goal of reducing relapse, and age-based comorbidity and performance status indices were added to eligibility criteria to reduce non-relapse mortality (NRM). Results: We analyzed all 283 patients treated on a two-step HI HSCT clinical trial at our institution. The median follow-up is 63 (range 1-165) months. Diagnoses were AML (n=118), MDS (n=43), myeloproliferative disorder (n=7), CMML (n=3), B-ALL (n=21), Ph+ ALL (n=15), multiple myeloma (n=14), T cell ALL (n=9), aggressive lymphoma (n=15), CLL (n=8), Hodgkin (n=7), aplastic anemia (n=5), and lymphoma-other (n=18). Patients had high (45%), intermediate (43%), very high (5%), and low (4%) risk disease per the Revised Disease Risk Index. Median age of the group is 58 (19-78) years and 21% of patients were &amp;gt;age 65. Conditioning was MA in 56%, RIC in 37%, and NMA in 7%. All patients received 2 x 108/kg CD3+ cells in step 1 of the HSCT except for 1 early patient who received 1.7 x 108/kg CD3+ cells. Median CD34 cell dose was 6.3 (range 1.0-20.0) x 106/kg, median non-CY-exposed T cells in the CD34 product was 2.88 (range 0.33-50.0) x 103/kg. Patients developed a haploimmunostorm manifested by high grade fever, diarrhea and rash within 24 hours of receiving DLI. These symptoms effectively resolved after the administration of CY. Median peak fever of patients during the haploimmunostorm was 103.6 (range 98.6-106.1). No patients died as a consequence of the haploimmunostorm. Cumulative incidence (CI) of donor engraftment was 97%. Median time to neutrophil and platelet engraftment was 11 (8-21) days and 17 (10-173) days respectively. All results at 2 years: CI of relapse and NRM were 25% each. CI grades 2-4 and 3-4 acute GVHD were 39% and 7% respectively, and CI chronic GVHD was 15%. Probability of survival (OS) was 55% in the total cohort and 34% in patients &amp;gt;65 years. In patients with AML which represented the largest subgroup of patients, OS was 51% in the total cohort and 40% in patients &amp;gt; 65. Conclusion: HI HSCT using the two-step approach is an effective treatment for a variety of hematologic malignancies and dyscrasias. Despite older age, over 1/3 of patients &amp;gt;65 years were alive 2 years after HI-HSCT. Disclosures Flomenberg: Tevogen: Consultancy, Honoraria.

Encouraging Results of Haploidentical Transplantation in Older Patents Using the Two-Step T Cell Tolerization Platform - Results of a Prospective Trial

Background: Hematologic malignancies arise in the 5th through 7th decades of life resulting in the need for aggressive treatment in an aging population with inherent comorbidities. We previously reported on the efficacy of a myeloablative two-step haploidentical hematopoietic stem cell transplant (HI HSCT). Herein, we report the results of our prospective trial utilizing a reduced intensity conditioning (RIC) HI-HSCT two-step platform in older patients. Methods: The RIC regimen consisted of fludarabine, thiotepa (33%) OR busulfan (67%), and 2 Gy total body irradiation (TBI). An unmanipulated donor lymphocyte infusion (DLI) containing 2 x 108/kg T cells was infused three days after the completion of the conditioning regimen. Two days later, cyclophosphamide (CY) was administered for bidirectional tolerization of the donor lymphocytes, followed one day later by a CD34 selected stem cell infusion. In the current clinical trial, three rest days were added between the completion of the conditioning regimen and the administration of the DLI. We hypothesized that the extra days would allow further conditioning-related tumor burden reduction, less alloreactive tumor-specific T cells activation and thus avoid eradication by CY. Patients were enrolled from 2013-2020. Due to higher than expected non-relapse mortality (NRM), the protocol was amended in 2015 to require that patients age ≤ 60 years have ≤5 HCT-CI points and KPS ≥ 80%, age 60-65 have ≤4 HCT-CI points and KPS ≥80%, age 65-69 have ≤3 HCT-CI points and KPS ≥90%, and ≥ 70 have ≤2 HCT CI points and ≥KPS 90%. The study was approved by the Jefferson IRB and all subjects were consented according to the Declaration of Helsinki. Results: Forty-two patients with AML (14), MDS (7), Hodgkin Disease (5), myeloproliferative disorder (4), multiple myeloma (3), diffuse large cell lymphoma (3), mantle cell lymphoma (2), CMML (1), Ph+ ALL (1), T cell NHL (1), and marginal zone lymphoma (1), were treated from 2013 to 2020. Median age and KPS were 60 (range 22-74) years and 90% (range 80%-100%) respectively. At a median follow-up of 42 (range 2-78) months, the 2-year probability of survival (OS) was 41%, and cumulative incidence (CI) of relapse and NRM were 23% and 41%. CI of acute and chronic GVHD were 44% and 16% respectively. Fifteen patients (36%)-"Pre∆ group", were treated from 2013-2014 and twenty seven patients (64%)-"Post ∆ group" were treated from 2015-2020. Univariate comparisons revealed no significant differences between the Pre∆ and Post∆ groups in terms of age (p=0.53), diagnoses (p=0.72) or Revised Disease Risk Index category (p=0.14). Median HCT-CI score was 3.0 vs 2.7 in the Pre∆ and Post∆ groups (p=0.21) respectively, and the median KPS in both groups was 90% (p=0.62). OS was 20% vs 55% in the Pre∆ and Post∆ groups (p=0.044), CI of relapse was 27% vs 20% (p=0.60) and CI of NRM was 53% vs 31% (p=0.34) respectively. CI of acute GVHD and chronic GVHD was 33% vs 51% (p=0.41) and 20% vs 13% (p=0.92) in the Pre∆ and Post∆ groups respectively. Conclusion: Haploidentical transplantation using the two-step T cell tolerization approach is feasible and encouraging in older patients. An adjusted risk model incorporating age, HCT-CI and KPS should be utilized in selecting older patients who are candidates for transplant. Disclosures Gergis: Incyte: Speakers Bureau; Merck: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Mesoblast: Other: Ad Board; Jazz: Other: Ad board, Speakers Bureau. Flomenberg:Tevogen: Consultancy, Honoraria.

Real-world evaluation of the impact of radiotherapy and chemotherapy in elderly patients with glioblastoma based on age and performance status.

This retrospective study investigated the impact of, in addition to age, the management and outcomes of elderly patients with glioblastoma (GBM). The National Cancer Database was queried between 2004 and 2015 for GBM patients age 60 years and older. Three age groups were created: 60 to 69, 70 to 79, and 80 years and older, and 4 age/KPS groups: "age ≥ 60/ KPS < 70" (group 1), "age 60 to 69/KPS ≥ 70" (group 2), "age 70 to 79/KPS ≥ 70" (group 3), and "age ≥ 80/KPS ≥ 70" (group 4). Multivariable (MVA) modeling with Cox regression determined predictors of survival (OS), and estimated average treatment effects analysis was performed. A total of 48 540 patients with a median age of 70 years (range, 60-90 years) at diagnosis, and a median follow-up of 6.8 months (range, 0-151 months) were included. Median survival was 5.0, 15.2, 9.6, and 6.8 months in groups 1, 2, 3, and 4, respectively (P < .001). On treatment effects analysis, all groups survived longer with combined chemotherapy (ChT) and radiation therapy (RT), except group 1, which survived longer with ChT alone (P < .001). RT alone was associated with the worst OS in all groups (P < .01). Across all groups, predictors of worse OS on MVA were older age, lower KPS, White, higher comorbidity score, worse socioeconomic status, community treatment, tumor multifocality, subtotal resection, and no adjuvant treatment (all P < .01). In elderly patients with newly diagnosed GBM, those with good KPS fared best with combined ChT and RT across all age groups. Performance status is a key prognostic factor that should be considered for management decisions in these patients.

Real Life CNS-IPI Score Validation: A Retrospective Analysis of Two Centers in Brazil Outside of Clinical Trial

Introduction:Diffuse large B cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma (NHL). Treatment has improved over the years and can achieve 70% of survival (OS) in five years. Despite all progress in this field, central nervous system infiltration (CNSi), which is a devastating complication, still occurs with an incidence of 2-10%. Therefore, defining high-risk patients who consequently need prophylaxis seems to be the most adequate approach. Objective: Evaluate central nervous system international prognostic index (CNS-IPI) score regarding reproducibility and validity of the model in a heterogeneous cohort outside of clinical trial. Patients and methods: This retrospective research study was approved by the Santa Casa de Misericórdia de São Paulo Medical School (SCMSP) and Ac Camargo Cancer Center (ACCC) Ethics Committee. Patients were eligible if they were sequentially diagnosed with primary DLBCL, between January 2007 and January 2016. Also, if patients had complete chart data, pathological review and had started treatment at the respective institution (SCMSP or ACCC). Lymphoma staging was defined according tothe Ann Arbor system and patients were also categorized by the international prognostic index - IPI at baseline All patients were treated with rituximab-based chemotherapy, mostly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).CNSi was diagnosed by liquor (positive cytology and/or immunophenotype), computerized tomography, magnetic resonance image and/or fluorodeoxy-glucose-positron emission tomography, requested only in symptomatic patients when CNSi was clinically suspected. Confirmed cases were classified as parenchymal, leptomeningeal or both. Validation of the CNS‐IPI was assessed by graphical comparison between our results of Kaplan‐Meier curves (risk stratification groups: low, intermediate and high risk) and those previously defined by CNS‐IPI. Results:After inclusion and exclusion criteria 322 patients were available for the analysis (55% at ACCC vs. 46% at the SCMSP). Median follow-up was 60 months and median age was 58 years. There was similar distribution between male and female (47.8 vs. 52.2, respectively), and also similar distribution between localized (stage I-II) and advanced disease (stage III-IV), 47.2 vs. 51.2%, respectively. More than half of patients were low or low-intermediate IPI (59.6%) and low and intermediate CNS-IPI 0-3 (77.6%). The minority was submitted to CNS prophylaxis (19.9%), and the majority achieved complete response at the end of therapy (73.3%). Seven patients experienced CNSi, characterizing an incidence of 2.17% (7/322). The median time from diagnosis of DLBCL to CNSi was six months (range 2-52 months), while the median time of CNSi to death was 19 days (range 0 days -9.3 months). In our cohort, given the small number of events (7/322), an univariate model for risk factors was not possible, even though we statistically compared the groups of patients without and with CNSi. In univariate analysis at baseline LDH, number of extranodal sites, IPI, kidney/ adrenal were statically different in patients without and with CNSi (Table 1). Furthermore, regarding treatment, absence of complete response was also statistically different. CNS-IPI model stratified patients in a three-risk group model (low [0-1 points], intermediate [2-3 points] and high risk [4-6 points]) and demonstrateda 2-year rate of CNS relapse of 0.6%, 3.4% and 10.2%, respectively. In our cohort, using the same stratification, we obtained the2-year rate of CNS relapse of 0.0%, 0.8% and 13.8%, respectively. There was a statistical survival difference between the cohort of patients without or with CNSi. Median OS for patients without CNSi was not reached (average: 9.0 years [95% CI:8.5-9.5]) while median OS for patient with CNSi was of 8 months (95% CI: 2.8- 13.1). Log-rank p=0.000. Conclusion:CNSi in patients with DLBCL treated with rituximab based chemotherapy remains a rare but devastating complication. Our study reinforces the validity and reproducibility of CNS-IPI, specific outside of clinical trials. Also guarantee the safety of CNS-IPI use in daily practice. Our results demonstrate that almost 80% of patients are low or intermediate risk of CNSi with no need of interventions. Those considered high risk would benefit from more intensive diagnosis and prophylaxis approach. Table 1 Disclosures No relevant conflicts of interest to declare.

S1620 NELARABINE AS SALVAGE THERAPY AND BRIDGE TO ALLOGENEIC STEM CELLS TRANSPLANTATION IN 118 ADULT PATIENTS WITH RELAPSED/REFRACTORY T‐ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA. A CAMPUS‐ALL, PHASE 4, STUDY.

Background:The overall outcome of relapsed/refractory T‐Lymphoblastic leukemia/lymphoma (T‐ALL/T‐LBL) in adults is poor with less than 10% of patients surviving at 5 years. There is no agreed standard of care in this setting and there are very limited clinical trials including this patient population. Nelarabine is the only recent drug that is specifically approved (as an orphan drug) in relapsed/refractory T‐ALL/T‐LBL but the informations to support its indication of use are based on limited available data.Aims:The aim of this observational, phase 4, study was to provide recent additional data on the efficacy and safety of Nelarabine in adults with relapsed/refractory T‐ALL/T‐LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cells transplantation (Allo‐SCT) after Nelarabine salvage therapy.Methods:Inclusion criteria were: age ≥ 18 years, diagnosis of relapsed or refractory T‐ALL/T‐LBL and treatment with at least one complete cycle of Nelarabine. The primary endpoints were the overall response rate (ORR) and the probability of Survival (OS). Additional endpoints were safety (graded according NCI CTCAE v3.0), Allo‐SCT rate and post‐transplant OS. Between May 2007 and November 2018, 118 patients with relapsed/refractory T‐ALL/T‐LBL received salvage therapy with Nelarabine in 27 Italian hematologic sites and were included in this study. The median age was 38 years (range, 18–81); 73 % were male; 77 had diagnosis of T‐ALL and 41 diagnosis of T‐LBL; 65/118 (55%) had received ≥ 2 of prior chemotherapy regimens and 18/118 (15%) relapsed after Allo‐SCT.Results:The median number of Nelarabine cycles was 2 (range, 1–4). All cases were evaluable for response and 43/118 (36%) of patients achieved complete remission (CR), 16 partial remission (14%), and 59 (50%) were refractory. The ORR was 50%. A total of 47 (40%) patients received an Allo‐SCT after salvage therapy. The probability of Overall survival from the first dose of Nelarabine for the entire population was 37% at 1 year (18% at 5 years) with a median survival of 8 months. The OS at 1 year was significantly better for patients who underwent an Allo‐SCT after Nelarabine salvage treatment (58% vs 22 %, log‐rank P = 0,0001)‐Figure 1. In multivariate analysis the favourable independent predictive factors for OS were: age less than 55 yrs and Allo‐SCT after Nelarabine therapy. Probability of OS at 2 and 5 years from transplant was 46% and 38%, respectively. Seventy five patients (64%) experienced one or more drug related adverse events (AE). Neurologic toxicities of grade III‐IV were observed in 9/118 (8%) of patients and mild neurologic AE (grade I‐II) was reported in 7/118 (6%) of cases. Thrombocytopenia or/and Neutropenia (grade III‐IV) was reported in 41% and 43% of cases, respectively. There were 3 cases of AE related deaths (2 septic shock and 1 aspergillosis). Hepatic toxicity (grade II) was observed in 4/118 cases (3%).Summary/Conclusion:This is one of the largest cohort of adult patients with relapsed or refractory T‐ALL/T‐LBL treated in real‐world with Nelarabine. Taking into account the poor prognosis of this population Nelarabine can be considered as an effective option providing an ORR of 50% and a CR rate of 36%. In addition, 40% of cases who received Nelarabine salvage therapy underwent an Allo‐SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. Overall, the safety profile of Nelarabine was acceptable with only 8 % of cases with grade III‐IV neurological AE.image

A randomized phase II study assessing an optimized schedule of oregovomab (O) anti-CA125 vaccination with carboplatin paclitaxel (CP) relative to CP alone in front-line treatment of optimally cytoreduced stage III/IV ovarian cancer (EOC).

5536 Background: In a phase II study of vaccination schedule in front-line combinatorial treatment of EOC (Braly JIT 2009), simultaneous day infusion dramatically enhanced the magnitude of induced immunity relative to a one week delayed schedule &amp; other schedules historically evaluated. The current study is exploring the clinical &amp; biological effects of the optimized 4 vaccine schedule relative to CP alone. Methods: Stage III/IV EOC patients (pts) optimally debulked to &lt;1cm residual disease with CA125 &gt;2x ULN were randomized to CP+O (cycle 1,3,5, &amp; C5 +12 weeks) vs CP and followed for clinical outcomes and immune reponse. A total of at least 80 evaluable pts were required for 80% power to detect a difference of 45% vs 15% for a primary comparative analysis of induced CA125 specific T cell immunity using an IFN-γ ELISpot. Clinical evaluations and safety were considered secondary endpoints. Results: 97 pts (47 OV+SOC &amp; 50 SOC) were accrued at 13 centers in US &amp; Italy. Analysis of immune markers and long term clinical outcomes is ongoing. The median duration of follow up at time of this analysis was 26 months (m). There was no difference in safety outcomes between the treatment groups. Grade 3-4 toxicity was observed in 24 (52%) CP+O vs 28 (58%) C-P pts. Toxicities were typical of standard IV C-P chemotherapy. K-M Analysis of recurrence free survival (RFS) showed median RFS not estimable for CP+O [95% CI: 21.3, NE] vs 15.4 m [10.9,19.3] for CP (p=0.0009 log rank). In the interim analysis of survival (OS), 4 deaths have been observed in CP+O vs 16 in CP (log rank p=0.0025). Cox proportional hazard analysis finds consistent results across centers, and no imbalance in identified risk factors explanatory for the emerging outcome Conclusions: This study suggests simultaneous day vaccination with O on alternate cycles of front line CP leverages CP associated temporal change in the tumor microenvironment permitting an immune treatment effect to enhance the outcomes achievable with CP alone. This observation will be further characterized in ongoing translational studies and confirmed in a future phase III study. Clinical trial information: NCT01616303.

Conditional probability of survival in gallbladder carcinoma as a prognostic tool for long term survivors.

455 Background: Gallbladder carcinoma (GBC) often presents in an advanced stage and despite radical resection and nodal harvest, prognosis remains poor. Conventional survival statistics do not account for time elapsed from diagnosis and may not carry relevant prognostic information for long term survivors. This study sought to estimate the conditional probability of survival (CS) in patients of GBC. Methods: Patients with GBC were identified from the Surveillance, Epidemiology and End Results (SEER) database (1988-2012). Overall probability of survival (OS) was estimated using Kaplan-Meier method. Cumulative incidence method was employed to calculate CS. Results: Of 15,046 GBC patients identified, Stage IV disease was the most common presentation (n = 5625). Surgical intervention was reported in 9,720(65%) patients with cholecystectomies (n = 8254) outnumbering radical resections (n = 1116). 3-year OS for all stages was 18% and conditional probability of surviving additional 3 years (CS3) at 1, 2 and 3 years from diagnosis was 42%, 57% and 66% respectively. Stage III and IV disease had 3-year OS rates of 19% and 3% respectively while CS3 increased progressively with each year survived(33% and 17% at 1 year, 51% and 34% at 2 years, 60% and 56% at 3 years). Conclusions: Conditional probability of survival is favorable in patients surviving one year from diagnosis and shows an increasing trend with time. Improvements in survival are more substantial in patients with adverse initial prognosis. Conditional survival provides valuable information on prognosis to patients after curative surgery and can be the basis of follow-up guidelines.

The Prognostic Impact of the Mutational Profile in Patients with Myelofibrosis in the Era of the JAK1/JAK2-Inhibitor Ruxolitinib

In retrospective studies, CALR mutation is found to be a favorable prognostic variable in myelofibrosis (MF) compared with JAK2, or MPL mutations. With the availability of the JAK1/JAK2 inhibitor ruxolitinib (RUX) for treatment of MF, it is not yet known whether response varies across mutational subgroups and whether the prognostic implication of the driver mutations in terms of survival (OS) changes under RUX. We studied the prevalence and prognostic weight of clinical parameters in the IPSS and DIPSS-plus and the impact of RUX on OS in the context of mutation status.Patient and Methods: As of November 2009, RUX for treatment of splenomegaly and/or constitutional symptoms became an option at the University of Leipzig. All patients (pt) with MF seen since then were included (n=127; f=43%, median age 58 years) with the exception of pt with MPL mut+ because of small number. Screening for the JAK2V617F and CALR mutations was performed as previously published. Cytogenetic-risk categorization was conducted as published (Caramazza et al. Leukemia 2011).Results: JAK2 mut+ (group A; 60.6%) constituted the largest group, followed by CALR mut+ (group B; 19.7%), and “triple-negative” (group C; 19.7%). The median duration of MF was 22 months with no difference in the 3 groups. Higher-risk IPSS was present in the majority [Int-II 34.4%; high-risk 42.4%]. Constitutional symptoms were present across all groups, although more frequent in group A which was also characterized by prominent splenomegaly (Table). Group B pt were younger with low WBC in contrast to goup C pt who were older, anemic, with high WBC and low platelets, unfavorable cytogenetics and high-risk IPSS. Hb < 100 g/L (54%), and transfusion-dependency (32%) were frequently present in group B and was similar to group A. RUX was given to 72 (57%) pt [graoup A (66%), group B (56%), group C (29%)] with a median exposure of 8 months. The response of 80% was not influenced by the mutation status, cytogenetics, or IPSS variables. Leukemic transformation was documented in 22 pt [14 (64%) pt had no RUX exposure] after a median of 18 months after diagnosis. The incidence was highest in group C (36%) and lowest in group B (4%) (p=0.004). Unfavorable cytogenetics were 75%, and 27% in group C and A respectively.After a median follow-up of 31 months, OS at 3-years was 82% and worst in group C (72%) vs 80% for group A (p=0.05) vs 96% in goup B (p=0.003). In univariate analysis, non-mutated status (p=0.02), Int-2/high-risk IPSS (p=0.06), anemia (p=0.03), transfusion dependency (p=0.04), and platelets < 100 x109/L (p=0.06) but not unfavorable cytogenetics were associated with an inferior OS. In multivariate analysis, advanced IPSS only (p=0.04) but not the mutation status (p=0.4) retained its negative impact on OS. Generally, in group A pt treated with RUX (n=50), OS was only marginally inferior to group B (p=0.08). In pt with int-2/high-risk IPSS, OS in group A with RUX (n=41) was similar to that of group B (p=0.4).Conclusions: The mutation status in MF bestows distinct clinical phenotypes and has crucial prognostic and therapeutic implications. Patients with non-mutated MF had the worst prognosis, unfavourable cytogenetics, and the highest rate of leukemic transformation. Although the IPSS retains its value, the prognostic power of certain factors such as anemia and constitutional symptoms in CALR-mutated pt needs to be re-evaluated. Response to ruxolitinib seems to be independent of the mutation status. More importantly, a JAK1/JAK2 inhibition appears to be capable of attenuating the prognostic implication of the different mutation profiles by improving the less-favorable survival associated with non-CALR-mutated MF through a disease-modifying effect. The full potential of a sustained JAK1/JAK2 inhibition in modifying survival in the context of the various mutational profiles needs to be further studied in a larger cohort of patients.TableClinical variables in patients with different driver mutationsVariableJAK2 mut+CALR mut+Triple-negativepN (%)77 (60.6)25 (19.7)25 (19.7)Median age (years)5951610.02Constitutional symptoms (%)6952460.08Median palpable spleen (cm)10430.001Int-2/high-risk IPSS (%)7952960.01WBC > 25 x109/L (%)2111.5440.008Median peripheral blasts (%)10.52nsMedian Hb (g/L)10699860.008Hb < 100 g/L (%)4254800.03Transfusion dependency (%)3332670.009Platelets < 100 x109/L (%)308520.04Unfavorable cytogenetics (%)3114480.06 DisclosuresAl-Ali:Novartis: Honoraria, Research Funding. Jaekel:Novartis: Honoraria. Lange:Novartis: Honoraria. Roskos:Novartis: Honoraria. Niederwieser:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Salvage therapy with ARA-C and gemtuzumab ozogamicin in AML patients relapsing after stem cell transplantation.

Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, especially after allogeneic stem cell transplantation (Allo-SCT). In patients relapsing early after SCT treatment, options are further limited by the fear for increased toxicity. We report our experience with ARA-C and gemtuzumab ozogamicin (GO) combination in relapsed post-SCT AML patients. Therapy consisted of ARA-C (1 gr/m(2)) for 4 days followed by one dose of GO 9 mg/m(2) on day 5 and was supported by donor stem cells when possible. Responding patients not developing graft versus host disease (GVHD) were eligible for immunotherapy with donor lymphocyte infusion (DLI) or a second Allo-SCT. Sixteen patients, median age 53 years (range 31-63), are included in this analysis. Patients underwent SCT for high-risk AML (n = 11) or AML relapse (n = 5), and 81 % had an early post-SCT relapse. Responses were achieved in 60 % of evaluable patients (CR-5 CRp-4). Median probabilities of survival (OS) and event-free survival (EFS) in the entire cohort, responding and non-responding patients were 103 and 76 days, 183 and 97 days, and 79 and 16 days, respectively. At 1-year follow-up, 25 % of patients were alive; however, all had relapse. Treatment resulted in grade 3-4 neutropenia and thrombocytopenia in all patients, and 27 % each had grade 3-4 hyperbilirubinemia or elevation of liver enzymes. One patient died during treatment due to intracranial hemorrhage. Of the six patients proceeding to second SCT or receiving DLI, three patients developed mild veno-occlusive disease (VOD). Combination therapy with ARA-C and GO after SCT results in short-term disease control and limited toxicity and could be considered for patients who are candidates for further immunotherapy.

Allogeneic Stem Cell Transplantation In Adults With High Risk Acute Lymphoblastic Leukemia (ALL) In 1. Remission (CR1): Promising, But Strongly Influenced By ALL Subtypes

Stem cell transplantation (SCT) has contributed to improved overall survival particularly in high risk adult ALL patients and the indication for SCT is a matter of ongoing discussion. We report the results obtained over a period of 18 years in a large center. Patients received first line treatment according to three consecutive trials of the German Multicenter Study group for Adult ALL (GMALL) and risk stratification was performed accordingly. In the most recent trial patients with high risk and very high risk factors are candidates for allogeneic stem cell transplantation (SCT) in CR1 from matched sibling or unrelated donors. The risk factors are: very high risk (VHR): Philadelphia chromosome positive ALL (Ph+ALL); high risk group (HR) of B-lineage ALL (HR-B): leukocytes > 30/nl at diagnosis and/or delayed CR > 3 weeks (other B) or pro B-ALL and of T-lineage ALL (HR-T): early-T-All and mature T-ALL. In addition standard risk patients were candidates for SCT in case of molecular failure or molecular relapse (SR-Mol). 106 high risk ALL patients in CR1 underwent allogeneic SCT between 1995 and 2012 at our center. Median age was 38 years (17 – 67). 40/106 patients had Ph+ALL (VHR), 57/106 patients were HR patients (HR-B n = 32: pro-B-ALL n = 15, other B n = 17; HR-T n = 25: early T n = 17, mature T n = 4, thymic n = 4). 9/106 patients belonged to the SR-Mol group. Stem cell donors were matched related donors (MRD) in 42 patients and compatible unrelated donors in 64 patients. The conditioning regimen was 12 Gy TBI ± Cyclophosphamide or VP16 in 86 patients, other n = 1, and in patients > 55 years 8 Gy TBI + Fludarabine (n = 5) or Fludarabine + Busulfan (n = 14). ATG as GvHD and rejection prophylaxis was given since 5/2005 in all patients with unrelated SCT and in reduced intensity conditioning regimens (RIC). Results60/106 (57 %) patients with high risk ALL transplanted in CR1 are alive, 46/106 (43 %) patients are dead. The median follow-up of the surviving patients is 64 months (5 – 172). Causes of death were leukemia in 16/106 patients (15%) and transplant-related mortality (TRM) in 30/106 patients (28%), mainly infections ± GvHD (n = 24), secondary malignancies (n = 2) and other (n = 4). In Ph+ALL 19/40 patients (47 %) are alive in CR (CCR), 12/40 are dead due to TRM and 9/40 due to leukemia. In HR-B ALL 23/32 patients (71 %) are in CCR, 8/32 are dead due to TRM and 1/32 due to leukemia. In HR-T ALL 11/25 patients (44 %) are in CCR, 10/25 died due to TRM and 4/25 due to leukemia. In SR-Mol patients 7/9 patients (77 %) are in CCR, 2/9 died due to leukemia. Probability of survival (OS) for all patients at 96 months is 0.48, probability of disease free survival (DFS) at 96 months is 0.47, probability of TRM at 96 months is 0.34. OS was 0.50 for patients with myeloablative conditioning (MAC) (n = 86) and 0.38 for patients with RIC (n = 19), n.s. OS was different for the 4 risk groups: VHR 0.42, HR-B 0.67, HR-T 0.27, SR-Mol 0.74, but not significant (0.095). DFS: VHR 0.42, HR-B 0.68, HR-T 0.24, SR-Mol 0.76 (0.041) and TRM: VHR 0.34, HR-B 0.26, HR-T 0.58, SR-Mol 0. (0.026). In HR-B OS was better for pro-B-ALL than other B-lineage (0.73.vs. 0.66, resp.). OS was lower in early-T-ALL (0.24). In mature T-ALL 3/4 patients are dead, in thymic ALL 1/4 patients. In ConclusionLong term survival and probably cure can be reached in high risk ALL patients after allogeneic stem cell transplantation in CR1. OS in pro-B-ALL and B-lineage-HR-ALL patients is better than in Ph+ALL or in HR-T-ALL due to lower relapse rate and lower TRM. Whether the quality of remission before allogeneic SCT could be improved in Ph+ALL and HR-T-ALL, has to be studied. Allogeneic SCT in SR with molecular failure or relapse show promising data, though in a small patient cohort. For all patients the TRM-rate due to GvHD and infection has to be improved due to better supportive care. Disclosures:No relevant conflicts of interest to declare.

Plasma osteopontin and the prognosis of pleural mesothelioma.

11109 Background: Cytoreductive surgery for malignant pleural mesothelioma (MPM) should be reserved for patients with favorable tumor biology. Osteopontin (OPN) and the ratio of absolute neutrophil to absolute lymphocyte counts (NLR) have been reported as possible prognostic biomarkers. These were studied with other clinical/ laboratory variables in a mixed surgical/non-surgical MPM population to define independent predictors of survival (OS) and progression (TTP). Methods: Forty-four MPM patients (12 F, 32M; 26 cytoreduction, 18 no cytoreduction; 31 epithelial, 13 non-epithelial; 15 Stage I/II, 29 Stage III/IV) were examined with regard to pretreatment plasma OPN (ELISA, R&amp;D, Minneapolis, MN), NLR age, gender, therapy, histology, stage, platelet count and WBC count. Cut points for age, OPN, NLR, platelets, and WBC were determined by X-tile Software (Yale, New Haven, CT) and univariate/multivariate Cox analyses performed. Results: Median OS were 11 m, 21m, and 8m for all 44 MPMs, cytoreduced and non-cytoreduced MPMs, respectively. Of platelet count, WBC, NLR, and OPN, only OPN was statistically significant between Stage I/II and Stage III/IV (80.3 ng/ml vs 148 ng/ml, p&lt;0.018). The only independent covariate predictive of OS was plasma OPN. For TTP in cytoreduced patients, only age, stage, platelet count, and OPN were significant in univariate analysis, and multivariate modeling retained stage (p=0.04, HR=2.75, 95% CI=1.0517 to 7.1879) and OPN (p=0.0008, HR=17.471, 95% CI=3.3054 to 92.3461). Conclusions: Plasma OPN is promising for the stratification of tumors into good or bad risk categories and to help select potential candidates for cytoreduction and further postoperative therapy. [Table: see text]

Efficacy of tyrosine kinase inhibitors in routine clinical practice: Epidermal growth factor mutations and their implications

Activating mutations in the epidermal growth factor (EGFR) gene confer sensitivity to the tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). TKI treatment efficacy and EGFR mutation implications were evaluated in clinically selected advanced NSCLC patients treated with TKIs in routine clinical practice. A retrospective chart review for clinicopathological characteristics and mutation status (EGFR, KRAS) analysis of 40 consecutive patients treated with TKIs between 2005 and 2010 was performed. PFS and OS were estimated by the Kaplan-Meier method, the log-rank test was used to test for differences. The strength of the associations between the EGFR mutation status and clinicopathological characteristics were tested with the Mann-Whitney U-test or the Kruskal-Wallis H-test. The prevalence of EGFR mutations was 45% with a predominance of deletion mutations in exon 19 (55.5%). Significant correlations between gender, histology, and EGFR mutations were observed. Median progression-free survival (mPFS) for the entire group of patients was 8.7 months and median overall survival (mOS) was not yet reached. Patients with EGFR mutant tumors derived significantly higher benefit from TKI therapy compared to patients with mutation-negative disease; with mPFS of 22.0 vs. 3.2 months (HR: 3.9, 95% CI 1.56-9.89) and with a trend towards better OS (probability of survival at 12 months 82.0 vs. 63.0%, P = 0.080). We demonstrated that screening for EGFR mutations is reliable in a routine clinical setting and might allow for a better selection of NSCLC patients for anti-EGFR TKI therapy.

A 2 Step Approach to Myeloablative Haploidentical Hematopoietic Stem Cell Transplanation (HSCT): Report of a Phase II Trial With 18 Months of Follow-Up for All Patients

Haploidentical HSCT using post transplant cyclophosphamide (CY) for elimination of alloreactive lymphocytes has been reported as a safe option for patients lacking an HLA identical donor. We report an alternate approach with the following salient differences: myeloablative vs non-myeloablative conditioning, peripheral blood rather than marrow stem cell source, no exposure vs exposure of HSC to cyclophosphamide, higher fixed number of CD3 cells versus a lower variable number of CD3 cells in each graft. Results are reported now with a followed up of 18-46 months.Table 1Patient Characteristics-2 Step ApproachAge52 (19-67)AML16Remission7Resistant/PIF9Biphenotypic Leukemia (Active Disease)1ALL4CR2 (ph-)3Persistent Disease (PH+)1MDS2NHL Resistant3SAA1HLA MM (GVH Direction)4133112201 Open table in a new tab Patients received 12 Gy of total body irradiation (TBI), followed by a donor lymphocyte product (DLI) containing 2 × 10e8 CD3+ cells/kg (Step 1). This large dose of haploidentical lymphocytes resulted in fever (median temperature 103.8°f), diarrhea and rash. CY 60 mg/kg was given on days -3 and -2 resulting in resolution of symptoms. Tacrolimus and MMF were begun on day-1. A CD 34 selected donor product was infused on day 0 (Step 2). Two of the 27 patients died of toxicity and infection before day 14. Of the remaining 25 patients, 23 had complete engraftment while two with pre-existing anti-donor HLA antibodies failed to engraft. Only 2 of 25 (8%) patients developed severe acute GVHD, 3 of 25 (12%) developed limited chronic GVHD, and no patient died of GVHD. Only two of 25 patients (8%) died of infection. Of 16 disease-free patients surviving 6 months from HSCT, median CD4+ count at day 100 was 105 cells/μl (range 10-403). Eight of 25 (32%) patients relapsed after HSCT. Probability of survival (OS) at 1 and 3 years post transplant is 52% and 48% respectively. All surviving patients are disease-free. OS at 3 years is 75% for patients transplanted in CR, but only 27% for patients transplanted with active disease. KIR mismatching was not correlated with relapse rates. In contrast, child to mother transplants for AML appear to be relapsing at higher rates than other combinations (66% vs 14%). In the context of CY tolerization, a dose of 2 × 10e8/kg T-cells resulted in consistent engraftment, prompt immune reconstitution, little severe GVHD, acceptable toxicity, and encouraging overall survival, particularly in patients transplanted in CR. Using this 2-step platform allows us to explore the use of alternate agents for the elimination of alloreactive lymphocytes, increase the length of time between DLI and CY, and to employ two donor strategies to improve outcomes in high risk patients.

Life after Fludarabine, Cyclophosphamide, & Rituximab (FCR) - the Clinical Outcome of Patients with Chronic Lymphocytic Leukemia Who Receive Salvage Treatment after Frontline FCR.

The FCR regimen is the most active treatment program in CLL, with 72% of frontline patients achieving a complete remission (CR) lasting a median of 7 years. However, most patients are not cured and will eventually relapse with CLL. In order to evaluate how these patients should be subsequently managed, we analyzed our institutional experience with 300 patients treated with frontline FCR (Blood 112:975). After a median follow-up of 6 years, 116 patients (39%) had failed FCR therapy with 13 primary refractory disease and 103 relapses from partial remission (PR), nodular PR (nPR) or CR. Compared with patients in ongoing remission, relapsed/refractory patients had more adverse baseline characteristics including a greater proportion with performance status ≥ 1 (71% vs 53% p=0.002), elevated β2m (54% vs 36% p=0.002), white cell count ≥ 150 x 10^9/L (25% vs 12% p=0.003), unmutated IgVH (81% vs 44% p<0.001) and ZAP-70 positivity (78% vs 49% p<0.001). The aim of the current analysis was to determine the duration of survival (OS) following second-line therapy in 97 patients who had completed salvage treatment. The median follow-up was 32 (range 3 – 69) months, and the median OS (mOS) was 32 months. Characteristics associated with favorable OS were: (1) previous best response to FCR of nPR/CR lasting ≥ 18 months (mOS 47 months, vs 13 months for primary refractory disease, PR or nPR/CR lasting <18 months p=0.002); (2) β2m < 3.0 mg/L (mOS not reached, vs 17 months p=0.0003) and (3) platelets ≥ 100x10^9/L (mOS 47 months, vs 15 months p=0.004). Poor risk cytogenetic abnormalities were common at FCR failure: among 38 assessable patients, 7 (18%) had 17p- and 18 (47%) had 11q- by conventional karyotyping and/or FISH. Although patients with 17p- or 11q- had an inferior survival, this survival disadvantage was confined entirely to those who also had an elevated β2m ≥ 3.0 mg/L. Surprisingly, patients relapsing after durable FCR remissions (≥ 5 years) and patients with slowly progressive relapse (time to salvage ≥ 12 months after FCR failure) had similar OS as their more adverse counterparts (p=0.76 and 0.86 respectively). A prognostic model comprising β2m and platelet count effectively divided patients into low, intermediate and high risk categories with mOS of >45, 32 and 13 months respectively (p<0.0001). Patients received treatment chosen at the discretion of individual treating physicians and the CR rate of second-line therapy were: FCR (n=30), 17%; rituximab (n=25), 4%; alemtuzumab ± rituximab (n=16), 31%; FCR & alemtuzumab (CFAR, n=9), 56%; lymphoma-type chemotherapy (n=5), 0%; other treatment (n=12), 0%. The CR rate for CFAR was significantly higher than that of FCR (p=0.03), although the median remission duration (30 vs 20 months) and OS (44 vs 32 months) were similar (p=0.87 and 0.51 respectively). None of the regimens showed a significant survival benefit. Allogeneic stem cell transplantation (SCT) was performed in 27 (28%) patients at a median of 15 months after first salvage. Patients receiving SCT had a significantly superior OS than those who did not undergo SCT (not reached vs 30 months, p=0.03). Of the 14 patients surviving for more than four years, 11 (79%) had undergone a SCT. Patients who fail FCR therapy had high risk disease features including elevated β2m, unmutated IgVH and ZAP-70 positivity, and most had adverse cytogenetic findings at relapse. Results of salvage therapy in this group were poor with a median survival of less than three years. The majority of long-term survivors had received allogeneic stem cell transplantation.

Prognosis of AIDS-Related Systemic Non-Hodgkin Lymphoma Treated With Chemotherapy and Highly Active Antiretroviral Therapy Depends Exclusively on Tumor-Related Factors

To assess complete remission (CR) and survival in patients with systemic AIDS-related non-Hodgkin lymphoma (ARL) receiving highly active antiretroviral therapy (HAART). We analyzed the Grupo de Estudio del SIDA register of systemic ARL, which started in Jan 1994, to collect cases diagnosed at 15 institutions prospectively and with active follow-up every 6 months. The date of censorship for this study was March 2005. During the study period, 210 consecutive patients were diagnosed with ARL, with a median age 39 of years, 75.7% of whom were male, and with a median baseline CD4 count of 160 cells/microL. Histologic subtypes were diffuse large B-cell lymphoma (DLCL; n = 153 [72.9%]), Burkitt and atypical Burkitt/Burkitt-like lymphoma (BL; n = 40 [19.0%]), T-cell lymphoma (TC; n = 8 [3.8%]), and miscellaneous (n = 9 [4.3%]). Chemotherapy with or without other modalities was administered to 186 (88.6%) patients. In an intent-to-treat analysis of 184 patients who received at least 1 chemotherapy course with adequate follow-up to assess their response, 119 (64.7%) achieved CR, and the median length of survival (Kaplan-Meier analysis) was 52 months (95% confidence interval [CI]: 23 to 82 months). Factors independently associated with CR were histologic subtype and International Prognostic Index (IPI) score. Factors independently associated with improved overall length of survival (OS) were CR, low IPI score, and histologic subtype. The single factor independently associated with disease-free survival was Ann Arbor stage. In patients with ARL treated with HAART, CR was associated exclusively with tumor-related factors. The CR rate was poorer in patients with BL and TC subtypes and was inversely correlated with IPI score. OS was independently associated with CR, IPI score, and the histologic subtype.