Early Treatment Intensification Research Articles

HbA1c, Weight, and Blood Pressure Changes Associated with Early vs. Late Treatment Intensification with Dapagliflozin in U.K. Primary Care Patients with Type 2 Diabetes

Early treatment intensification in patients with type 2 diabetes (T2D) is often required to achieve glycaemic control. Patients with T2D from the UK Clinical Practice Research Datalink, aged ≥18 years, initiating dapagliflozin between Nov 2012 and Aug 2016 and with prior oral T2D therapy (N=3,774) were included in this study. The relationship between early (2nd line) vs. later (≥3rd line) use of dapagliflozin and changes from baseline in HbA1c (≥1.0% absolute reduction), weight (kg) (≥5.0% relative loss) and systolic BP (≥2 mmHg absolute reduction) after 6-12 months were assessed with logistic regression models. Early use of dapagliflozin occurred in 25.2% patients (951/3774) vs. later use in 74.8% (2823/3774). Patients with later use were older [mean: 60.1 (SD 10.3) vs. 55.7 (SD 10.5) years], more likely to be male (61.6% vs. 55.3%), had T2D for longer [median 8.1 vs. 4.0 years] and higher CVD prevalence (13.9% vs. 11.2%). Patients with early and later use of dapagliflozin had similar baseline mean HbA1c levels [9.3% (SD 1.5) vs. 9.2% (SD 1.7)] and BP [134.2 (SD 14.2) vs. 135.0 (SD 14.6) mmHg]. Late users had lower BMI [mean 33.6 (SD 6.3) vs. 36.5 (SD 6.8) kg/m2] than early users. Early dapagliflozin users experienced mean (S.E) reductions of 1.6 (0.07)%, 3.8 (0.25)% and 3.0 (0.82) mmHg in HbA1c, weight and BP, respectively, vs. 1.0 (0.04)%, 4.6 (0.21)% and 3.1 (0.43) mmHg in later users. Compared to later dapagliflozin use, early initiation was associated with a greater likelihood of adjusted HbA1c reduction ≥1% (OR: 1.68, 95% CI: 1.15-2.45). Weight and BP reductions were observed with similar likelihood among early and late users (weight OR: 0.79, 95% CI: 0.54-1.14; BP OR: 0.87, 95% CI: 0.58-1.30). In conclusion, glycaemic benefits of dapagliflozin were greater in patients receiving it earlier in their treatment pathway. Weight and BP reductions were achieved with similar likelihood among early and later users. Disclosure J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc. U. Rigney: Employee; Self; AstraZeneca. B.T. Blak: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S.T. Nolan: Employee; Self; AstraZeneca. P. Fenici: Employee; Self; AstraZeneca. J. Medina: Employee; Self; AstraZeneca.

Impact of Early Intensification with Sitagliptin on Glycemic Goal Attainment among Patients with Metformin Monotherapy Failure

Background: Delay in the intensification of type 2 diabetes (T2DM) treatment after metformin monotherapy failure, or clinical inertia, is often observed among patients with poor glycemic control. Sitagliptin is used frequently as an add-on to metformin monotherapy among patients with T2DM. The objective of the study is to evaluate the association between early treatment intensification with sitagliptin and glycemic goal attainment among patients failing metformin monotherapy. Methods: This retrospective database study of adult T2DM patients was conducted using the Quintiles Electronic Medical Record (EMR) database. The study population consisted of patients diagnosed with T2DM who failed to achieve A1c level of <7% on metformin monotherapy between January 20and June 2015. The study included two groups (1) those who did not receive treatment intensification within 3 months after metformin failure (non-early group), but were intensified with any oral anti-hyperglycemic agent between 4 and 12 months and (2) those who were intensified with sitagliptin within 3 months (early sitagliptin group). A Cox regression analysis was conducted to evaluate the association between sitagliptin use and A1c goal attainment within 12 months. Results: We identified 2,852 patients aged ≥18 years with T2DM who failed metformin monotherapy, of which 362 patients were intensified with sitagliptin within 3 months and 2,490 patients were included in the non-early group. A multivariate Cox regression model adjusted for age, gender, BMI, smoking status, baseline A1c, comorbidities, and other nondiabetic medications showed that early sitagliptin therapy resulted in doubling the likelihood of achieving A1c goal attainment (HR 2.12; 95% CI 1.80-2.50) within 12 months compared to non-early group. Conclusion: Early intensification with sitagliptin results in higher goal achievement levels among patients failing metformin monotherapy failure. Disclosure F. Ejzykowicz: Employee; Self; Merck Sharp & Dohme Corp. J. Liu: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; Anthem, Inc.. Employee; Self; Janssen Scientific Affairs, LLC. S.S. Engel: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. S. Rajpathak: Employee; Self; Merck & Co., Inc..

Can the Use of Bone Marrow Parameters Improve the Efficacy of Risk Prediction Scores in Chronic Myeloid Leukemia in Imatinib Era?

Many attempts have been made to develop risk prediction scores for chronic myeloid leukemia in chronic phase (CML-CP) to identify the subgroup with a poorer response to therapy to enable early intensification of treatment. Because the bone marrow (BM) provides a more sensitive reflection of the disease process, we hypothesized that using BM parameters in the Sokal and European Treatment and Outcome Study (EUTOS) risk scores could improve their efficacy in an imatinib-treated population. We analyzed cases of CML-CP for their response and survival outcomes with imatinib using risk groupings determined by the Sokal and EUTOS scores using peripheral blood (PB) or BM parameters (Sokal-PB, Sokal-BM, EUTOS-PB, and EUTOS-BM). A total of 371 cases were analyzed. The concordance for risk groups was greater for the EUTOS scores (81.9%) than for the Sokal scores (68.1%) using PB versus BM parameters. For all 4 risk scores, the predictive efficacy was statistically significant. EUTOS-PB and EUTOS-BM could better prognosticate for progression-free survival (PFS) and overall survival (OS) between the low- and high-risk groups (P< .0001). However, with the Sokal risk score, the use of BM parameters improved the prognostic capacity for PFS between the low- and intermediate-risk groups, with a statistically significant difference (P= .025), but not for OS (P= .88). The use of BM parameters, a simple method that is feasible in routine clinical practice could improve the prognostic efficacy of the Sokal score for PFS but not for OS in low- and intermediate-risk groups. Further research to improve the sensitivity of risk scores for CML-CP prognosis and attempts at risk-directed therapy is warranted.

Impact of health policy and practice on finding the best fit for patients with type 2 diabetes after metformin failure: Croatian pilot study

AimWe assessed the impact of clinical practice and health policy on the choice and efficacy of different second-line therapies for the treatment of type 2 diabetes (T2DM) after failure of metformin. MethodsThis retrospective database analysis included 200 patients with a follow-up period of 6 months. The primary end-point was achievement of HbA1c <7% and fasting (FBG) and postprandial glucose levels (PPG) <7.2mmol/L and <10mmol/L, respectively after three and six months of different add-on treatments. Secondary end-points were weight change during treatment and incidence of hypoglycemia. ResultsAll second-line therapeutic options, except human basal insulin (BHI) and thiazolidendions (TZD) significantly increased the proportion of patients reaching target HbA1c after 6 months (p<0.01). Only sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitors significantly reduced all monitored parameters of glucoregulation without changing body weight and BMI after 3 and 6 months as opposed to insulin agents. However, there were no statistically significant differences between the groups when adjusting for starting HbA1c, FBG and PPG (F=1.16, p=NS), although a statistically significant difference in HbA1c levels (F=3.35, p<0.01) persisted in DPP-4 inhibitor users. The incidence of hypoglycemia was significantly higher in patients treated with NPH insulin and premixed insulin than in patients treated with other agents. ConclusionA more aggressive approach is needed with early treatment intensification using available agents.

Change in HbA1c associated with treatment intensification among patients with type 2 diabetes and poor glycemic control

Objective: We conducted a retrospective cohort study to investigate the HbA1c change associated with treatment intensification in a real-world population of patients with type 2 diabetes (T2D).Methods: Using a large US insurance claims database, patients aged ≥18 years with a T2D diagnosis and HbA1c ≥8.0% (64 mmol/mol) after ≥3 months of oral pharmacotherapy with metformin (± other oral antidiabetes agents) were identified (index date). Continuous enrollment was required for ≥12 months before (baseline) and after the index date with no baseline use of injectable antidiabetes drugs. We defined treatment intensification as prescriptions for injectable or additional oral antidiabetes drugs. Time to intensification was classified as timely (within 6 months) or not (≥6 months or not intensified). Linear regression models with propensity score 1:1 matching were performed to assess the effect of timely intensification on HbA1c.Results: Of the 11,525 patients meeting the inclusion criteria, only 37% had treatment intensified within 6 months. Mean age at index date was 57 years, 40% of the sample was female. The mean baseline A1C was 9.4% and 9.0%, while post-index A1C was 7.9% and 8.2% for timely intensified patients versus not, respectively. Patients with timely intensification had significantly greater HbA1c reduction compared with others (−0.33%, 95% CI: −0.41% to −0.25%) within 1 year of follow up.Conclusions: In this analysis of patients with T2D and treatment failure in a real-world setting, earlier treatment intensification was associated with better glycemic control as indicated by lower HbA1c values.

Impact of insulin sensitivity, beta-cell function and glycaemic control on initiation of second-line glucose-lowering treatment in newly diagnosed type 2 diabetes.

The aim of this study was to investigate whether insulin sensitivity, beta-cell function or glycaemic control at diagnosis predict initiation of second-line treatment in newly diagnosed type 2 diabetes. Type 2 diabetes patients (n = 138) undergoing initial metformin monotherapy (age [mean ± SD], 52 ± 10 years; 67% males; BMI, 32 ± 6 kg/m2 ) from the prospective German Diabetes Study cohort (n = 398) were included. Patients remained under care of their general practitioners, yet underwent detailed metabolic characterization after diabetes diagnosis for study purposes (hyperinsulinemic-euglycemic clamp, M value; i.v. glucose tolerance test, incremental C-peptide area under the curve0-60 minutes, CP iAUC). The associations of baseline M value, CP iAUC, fasting glucose and HbA1c with time to second-line therapy were assessed using parametric survival analysis, accounting for interval-censoring. Second-line treatment was initiated in 26% of newly diagnosed type 2 diabetes patients within the first 3.3 years after diagnosis, using mostly DPP-4 inhibitors or GLP-1 receptor agonists (64%). In age-, sex- and BMI-adjusted survival models, higher baseline HbA1c and fasting glucose values were associated with earlier treatment intensification. Lower baseline M value and C-peptide secretion (CP iAUC) were also related to an earlier initiation of second-line treatment. In the best multivariable model, baseline HbA1c ≥ 7% (hazard ratio, HR; 95% CI: 3.18; 1.35-7.50) and fasting glucose ≥140 mg/dL (HR, 2.45; 95% CI, 1.04-5.78) were associated with shorter time to second-line therapy, adjusting for age, sex and BMI. Baseline hyperglycaemia is a strong predictor of requirement of early intensification of glucose-lowering therapy in newly diagnosed type 2 diabetes.

Role of peripheral blood minimum residual disease at day 8 of induction therapy in high-risk pediatric patients with acute lymphocytic leukemia.

Risk stratification and treatment intensification, based on minimal residual disease (MRD) mensurement, changed the prognosis of pediatric patients with acute lymphocytic leukemia (ALL). The main aim of this study was to investigate whether peripheral blood (PB) MRD measurement at day 8 (D8) could predict the risk stratification category determined by bone marrow (BM) MRD at day 15 (D15). The study was performed prospectively, in a cohort of 40 children with B-lineage ALL, adopting the protocol of the Brazilian Cooperative Group of the Treatment Childhood Leukemia (GBTLI-2009). MRD was detected by flow cytometry (FC) using a simplifed panel that can reliably identify MRD at early phases of induction therapy. Upon diagnosis, the proportion of low and high-risk patients, was 24:16 (60%:40%). The main result of our study demonstrated the potential of D8 MRD in anticipating of week the risk stratification of high-risk patients as determined by D15 BM MRD. In these patients D8 MRD level of 1% was able to segregate high risk fast responders from high risk slow responders (p = 0.0097). This result could represent an opportunity for early treatment intensification, as already performed in some protocols.

Early Treatment Intensification with R-ICE Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) Using Zevalin-BEAM for Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) As Identified By Interim PET/CT Scan Performed after Four Cycles of R-CHOP-14: A Multicenter Phase II Study of the Australasian Leukaemia Lymphoma Study Group (ALLG)

Early Treatment Intensification with R-ICE Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) Using Zevalin-BEAM for Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) As Identified By Interim PET/CT Scan Performed after Four Cycles of R-CHOP-14: A Multicenter Phase II Study of the Australasian Leukaemia Lymphoma Study Group (ALLG)

Integration of Minimal Residual Disease with Other Patient Risk Factors Identifies a Population with Very Poor Overall Survival in Pediatric ALL: Results from the UKALL 2003 Trial

Background:Overall survival (OS) for children with ALL treated on contemporary protocols is now > 90%. To further improve outcomes, stratification must direct intensive treatment to those patients with the highest risk of relapse. Whilst minimal residual disease (MRD) has emerged as the most powerful predictor of outcome, its use in isolation is insufficient to identify those patients with the greatest risk. To address this, we performed a detailed analysis of the entire patient cohort from the recently reported large multi-center randomized controlled trial, UKALL 2003. Integration of end of induction (EOI) MRD with other predictive factors - cytogenetics, age and white cell count (WCC) - allowed the identification of very high risk groups that are likely to benefit from early treatment intensification or novel therapies.Methods:The UKALL 2003 trial recruited 3126 patients aged 1-25 years with Philadelphia-negative ALL between Oct 1, 2003, and June 30, 2011. Treatment was initially stratified based on NCI risk and cytogenetic results. Subsequent treatment was directed by EOI MRD measured using EuroMRD approved real-time quantitative PCR for immunoglobulin and T-cell receptor gene rearrangements. Analysis was performed on 2666 patients with available MRD results and focused on the systematic integration of MRD results with other patient characteristics to identify subgroups with a very poor OS (<75% at 5 years). MRD was considered positive at a level ≥0.005% and low risk if <0.005% unless otherwise stated.Results:Both MRD and cytogenetic risk group were independently predictive of survival. In particular, patients with high risk (HR) genetic abnormalities - low hypodiploidy, near haploidy, KMT2A (MLL) rearranged, iAMP21 and t(17;19)(q23;p13) (n=100) had a poor outcome with 5 yr OS of 76.0%. Combining these factors showed that MRD could stratify the HR cytogenetic subgroup with a significant difference in survival between those with low risk MRD and positive MRD (5yr OS 93.0 vs. 63.1%, p=0.002, n=43 vs. 57). Crucially, this demonstrates that HR cytogenetics are only truly poor risk in the context of poor treatment response. Importantly, there were almost no survivors following relapse in the HR cytogenetic/MRD positive group, whilst 50% of those with low risk MRD could be salvaged after relapse. In addition, whilst t(1;19)(q23;p13)was not considered a HR cytogenetic factor in this trial, combination with positive EOI MRD identified an additional subgroup of 20 patients with a 5yr OS of only 74.7% (vs. 96.7% in MRD low risk patients, p=0.003).Whilst WCC at presentation was also predictive of outcome, this difference was significant only in those with B-ALL and not T-ALL. In B-ALL, WCC>100 x109/L was associated with significantly poorer survival (5yr OS 95.1 vs. 84.0%, p<0.0001) whilst high WCC in T-ALL had little effect on survival, even at WCC >200 x109/L (5yr OS 90.2 vs. 86.7%, p=0.283). Integration of MRD results allowed the identification of a very high risk group with B-ALL, WCC>100 and positive EOI MRD (n=80) which had a 5yr OS of only 71.3%. Further breakdown by cytogenetic risk group showed those patients with good risk cytogenetics (ETV6-RUNX1, high hyperdiploidy) (n=19) had a remarkably good survival despite WCC>100 (5yr OS 94%). In contrast, those with intermediate (n=34) or HR cytogenetics (n=15) had a very poor 5yr OS (65.7% and 60.0% respectively).Older age (≥10yr) was also associated with poorer outcomes compared to those <10yr (5yr OS 95.8 vs. 87.4%, p<0.0001). Integration with MRD results further separated these groups but did not identify a very high risk subgroup. However, combining older age with a higher EOI MRD cut-off of 1% successfully identified a subgroup (n=96) with a very poor 5yr OS of 51.3% (vs. 91.4% in those with MRD<1%, p<0.0001). Interestingly, this was independent of cytogenetic risk group.Conclusions:Through the integration of EOI MRD with other risk factors in a large pediatric ALL cohort we have identified a population of patients with a very poor OS. When combined, these criteria select only 6% of all patients, but capture 35% of all deaths suggesting current treatment is suboptimal in this group. This information is essential for the planning of future trials to ensure that treatment intensification and novel therapies are targeted at those patients at greatest risk, whilst avoiding unnecessary treatment in those patients that already experience good outcomes. DisclosuresNo relevant conflicts of interest to declare.

Health economic evaluation of type 2 diabetes mellitus: a clinical practice focused review.

Type 2 diabetes mellitus (T2D) is a growing healthcare burden primarily due to long-term complications. Strict glycemic control helps in preventing complications, and early introduction of insulin may be more cost-effective than maintaining patients on multiple oral agents. This is an expert opinion review based on English peer-reviewed articles (2000–2012) to discuss the health economic consequences of T2D treatment intensification. T2D costs are driven by inpatient care for treatment of diabetes complications (40%–60% of total cost), with drug therapy for glycemic control representing 18% of the total cost. Insulin therapy provides the most improved glycemic control and reduction of complications, although hypoglycemia and weight gain may occur. Early treatment intensification with insulin analogs in patients with poor glycemic control appears to be cost-effective and improves clinical outcomes.

Impact of time to treatment intensification on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy

BackgroundPatients with type 2 diabetes on metformin monotherapy frequently require treatment intensification with another anti-hyperglycemic medication over time. Previous studies have indicated that a high proportion of patients with diabetes have a significant delay in the initiation of oral add-on therapy after metformin alone fails to achieve targeted glycemic control. In this study, we evaluated the impact of the timing of treatment intensification with oral add-on drug on glycemic goal attainment among diabetic patients failing metformin monotherapy. Research design and methodsUsing the General Electric (GE) Centricity Electronic Medical Record database (January 2004 through December 2009), we identified 5,870 patients with type 2 diabetes with treatment failure on metformin monotherapy - defined by a glycosylated hemoglobin (HbA1c) of ≥7.5% (index date). This cut-off of ≥7.5% (trigger HbA1c) was chosen rather than that of >7.0% to ensure that selected patients were more likely to be indicated for treatment intensification with add-on drug. Continuous enrollment of one year prior and two years after index date was required to be included in the study. Add-on treatment was defined as prescription of second oral agent from any available therapeutic classes while continuing metformin. Early treatment intensification was defined as initiation of oral add-on therapy within 3months (n=1,012) of index date while late intensification was defined as add-on initiation between 10 and 15months after index date (n=461). The study outcome was defined as glycemic goal attainment (HbA1c<7%), which was evaluated between 18 and 24months after index date. ResultsOur results suggested that at the end of the follow-up period, 47.2% of patients in the early add-on group were at glycemic goal compared to 41.7% in the late add-on group (p=0.039). In a multivariable logistic regression model that accounted for age, gender, trigger HbA1c level, Charlson comorbidity index, anti-hypertensive and anti-hyperlipidemic drug use and history of cardiovascular disease, the adjusted odds ratio (OR) for glycemic goal attainment was 1.36 (95% confidence intervals [CI]: 1.09–1.72) comparing early add-on to late add-on treatment. This association was stronger among patients with higher trigger HbA1c at baseline; ORs of 1.53 (95% CI: 1.08–2.19) for HbA1c ≥8% and 2.63 (95% CI: 1.40–5.27) for HbA1c ≥9%. ConclusionThese results suggest that earlier use of oral add-on drug in treatment regimen helps better achieve glycemic goal attainment in patients with metformin failure. Future studies should evaluate whether earlier treatment intensification is also associated with longer term health outcomes such as risk of microvascular and macrovascular complications.

P0226 Patterns of recurrence in locally advanced squamous cell carcinomas of the head and neck after three-dimensional conformal radiotherapy: An institutional experience

Background Loco-regional recurrences continue to plague head and neck cancers, even with combined modality treatment. We report patterns of loco-regional recurrence after three-dimensional (3D) conformal radiotherapy among patients with locally advanced (non-nasopharyngeal) head and neck squamous cell cancers. Methods From 2009 to 2012, 263 patients with stage III–IV head and neck squamous cell carcinoma received treatment at our institute with radical external beam radiotherapy with or without chemotherapy. Patients who had surgical resection of primary tumour or nodal site were excluded. Sites of loco-regional relapses were compared and correlated with radiotherapy treatment plans by the radiation oncologist and medical physics team. Findings Median follow-up was 38 months (range 3–62). Median patient age was 52 years. After a mean follow-up of 21 months (range 0–44), there were 42 patients with loco-regional failure. The median time to failure among these patients was 12.5 months (range 3–17). Of the 42 cases, 20 failed locally, 17 had regional failure, and five had simultaneous loco-regional failure. 38 patients had in-field recurrence, three had simultaneous in-field and out-of-field recurrence, and one patient had marginal recurrence. Interpretation In this study, the predominant pattern of recurrence after 3D conformal radiotherapy was in-field. Sites of primary gross disease and nodal levels initially involved were the most common sites of recurrence. Further studies on radio-resistant tumour populations are needed, to enhance early identification and appropriate treatment intensification.

Options for Combination Therapy in Type 2 Diabetes: Comparison of the ADA/EASD Position Statement and AACE/ACE Algorithm

Treating patients with diabetes is one of the most challenging and important activities a physician (primary care physician or specialist) can undertake. A key to successful therapy for type 2 diabetes is the insight that this condition is progressive and that the need for additional agents over time is normative. The ability to individualize therapy by patient and medication characteristics comes from experience and knowledge of pertinent clinical studies. However, guidelines from expert bodies such as the American Diabetes Association/European Association for the Study of Diabetes and American Association of Clinical Endocrinologists/American College of Endocrinology can help clinicians of all levels of expertise to approach therapy choices more rationally. There is unity across these guidelines about the role and benefits of metformin as first-line pharmacological treatment, probability of good efficacy, low risk of hypoglycemia, modest weight loss, and overall long-term data. Unfortunately, this unity does not extend to recommendations for subsequent pharmacological agents and their use in combination to intensify treatment when insulin is not (yet) appropriate. Across both statements, some drug classes seem more prominent, and looking at their benefit–risk profile, it is clear why this is the case. The most profound recent change in diabetes therapy has been the introduction of incretin therapies. Incretin therapies minimize 2 important adverse effects seen with many other therapies: hypoglycemia and weight gain. These agents have increased the range of options available for early intensification of treatment of type 2 diabetes. In combination with more established therapies, there are more opportunities than ever to accommodate patient preferences while improving glycemic control and harnessing extraglycemic benefits of a second (or third) agent.

Early Treatment Intensification in Advanced-Stage High-Risk Hodgkin Lymphoma (HL) Patients, with a Positive FDG-PET Scan After Two ABVD Courses – First Interim Analysis of the GITIL/FIL HD0607 Clinical Trial

AbstractAbstract 550 Background:Interim FDG-PET performed after 2 chemotherapy courses (PET-2) is the most powerful predictor of treatment outcome in advanced-stage, ABVD-treated HL (AAHL) patients (pts). Whether early therapy intensification in PET-2 positive HL pts improves overall treatment efficacy for all AAHL pts compared to standard ABVD is still unproven. Patients and study design:In the HD 0607 clinical trial (ClinicalTRial.gov identifier 00795613), AHL (stage IIB-IVB) pts prospectively enrolled by 26 Italian and one Israelian institution are treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2+ pts are randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab (R). PET-2 negative pts are treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy (Rxt) on the sites of initial bulky disease or no further treatment. Primary endpoint is the efficacy and feasibility of the overall therapeutic strategy. All the non-negative PET-2 (nnPET-2), defined as scans without any residual FDG uptake in any site outside the physiological areas of the tracer concentration, are uploaded in a website for blinded independent central review (BICR) by 6 nuclear medicine experts. Scans are interpreted by visual assessment according to the Deauville 5-point scale (5PS). Results:Starting from 07/2008 till 07/2012, 497 AHL pts were consecutively enrolled and 446 scanned with PET-2. 189/446 (42%) PET-2scans, judged as nnPET-2 by the local PET center, underwent review: 92 were adjudged as positive (62 score 4, 30 score 5) and 97 as negative (score 1–3). Altogether, of 446 pts scanned with a PET-2, 92 (20%) resulted positive and 354 (80%) negative. Age, sex, stage III-IV, bulky, extranodal sites or IPS class where equally distributed among PET-2 positive and negative pts.(p>.05). The median time from PET uploading in the website to review was 45.38 hours, (1–119). The BICR yielded a binary concordance rate among pair of reviewers “very good”, ranging from 0.77 to 0.83 (Cohen’s k coefficient) and a overall concordance rate of 0.77 (Krippendorf’s alpha). In 92 PET-2+ pts, 60 showed a single site of residual uptake in mediastinal (48), laterocervical (4), supraclavear (2), abdominal (3), axillary (1) nodes and in lung (2).In 32 there were ≥ 2 sites of persistent FDG uptake. In 38/40 pts with a positive PET-2 and bulky disease at baseline the residual FDG uptake (singe or multifocal) was seen within the bulky lesion. Overall response to treatment could be assessed in a cohort of 263 pts who had been fully restaged after lymphoma treatment. Forty-one (15%) had a positive and 222 (84%) a negative PET-2 scan. The relative dose intensity (RDI) for Be+Bb ± R and ABVD ± RxT treated pts. was 94.7% and 97.8%, respectively. Among 41 PET-2+ pts CR was achieved in 30 (73%), PR in 1 (2%) Progression or Relapse (Pro/Rel) in 8 (19%) and not evaluable (NE) in 2(5%). Among 222 PET-2- pts. CR was achieved in 212 (95.5%), PR in 2 (1%), Pro/Rel in 6 (3%), NE in 1 (0,5%). Treatment efficacy could be assessed in a cohort of 187 pts. with a complete treatment and a minimum follow-up of 12 months from treatment completion: 27 (15%) with a positive PET-2, treated with Be+Bb ± R and 160 (85%) with a negative PET-2, treated with ABVD ± RxT. The median follow-up from diagnosis was 845 days (101–1345). Among 27 PET-2+ pts, CCR (Continuous CR) was recorded in 22 (81%) Pro/Rel in 5 (18%). Three patients died in CR: 2 for septic shock and one for pneumonia. Among 160 PET-2- pts. CCR was recorded in 146 (91%), Pro/Rel in 9 (5%), Lost of FU (in CR) in 5 (3%). The 1-y PFS was 80.5%, 97.3% and 94.7% for PET-2+, PET-2- p, and for the entire population, respectively. Overall, treatment was well tolerated: 512 Adverse effects were reported: WHO grade 0+1: 453, grade 2: 45. Grade 3 were observed in 12 pts: anemia (2), neutropenia (6), pancytopenia (1), sepsis (1), diverticulitis (1), Vomiting (1). Grade 4 in 2 pts: pneumonia and neutropenia. Conclusions:These preliminary findings suggest that 1) an early switch from ABVD to escalated BEACOPP can be done safely in PET-2 positive pts, with CR achievement in the majority of cases; 2) a centralized online PET scan review system is feasible and allows a real time decision making process, without significant reduction in the RDI administered; 3) 5PS is a reliable interpretation criteria for interim PET scan, with a very good concordance rate among reviewers. Disclosures:No relevant conflicts of interest to declare.

Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial

AbstractThe CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.

Acute Gastrointestinal Graft-versus-Host Disease in Pediatric Patients: Serum Albumin on Day 5 from Initiation of Therapy Correlates with Nonrelapse Mortality and Overall Survival

The aim of the present study was to identify factors associated with the risk of development of gastrointestinal acute graft-versus-host disease (GI-aGVHD), as well as to evaluate the impact of various baseline parameters on response to treatment, nonrelapse mortality (NRM), and overall survival (OS) in pediatric patients with GI-aGVHD after allogeneic hematopoietic stem cell transplantation (allo-SCT). We retrospectively analyzed 300 pediatric patients who underwent allo-SCT from HLA-matched related or volunteer unrelated donors in our institution. GI tract involvement was observed in 46 out of 133 patients with aGVHD grade II-IV. Severe aGVHD (grade III-IV) was more frequently observed among patients with GI-aGVHD in comparison with patients without GI involvement (P < .001). Treatment with steroids resulted in durable responses in 22/46 patients; 14 additional patients responded to salvage therapy, whereas 10 were refractory to all treatments administered. Using Cox regression analysis, we observed that serum albumin level ≥ 3 mg/dL on day 5 after the initiation of therapy with steroids was statistically significantly associated with decreased hazard of NRM and improved OS (P = .021 and P = .026, respectively). In our study, serum albumin level, early (+ day 5) after the onset of steroids in patients with GI-aGVHD, was a predictor of treatment outcome. Prospective randomized trials need to be performed to verify the predictive significance of serum albumin and the need for early intensification of immunosuppressive treatment.

Intensively timed combination chemotherapy for the induction of adult patients with acute myeloid leukemia

Despite advances in therapy, the majority of adult patients diagnosed with acute myeloid leukemia (AML) develop disease recurrence and die of their disease. Early intensification of treatment for AML using timed sequential therapy (TST) has been proposed as a means of improving the survival outcome in children. The Children's Cancer Group demonstrated that children with AML who were randomized to receive 2 courses of daunorubicin, cytarabine, thioguanine, etoposide, and dexamethasone (the DCTER regimen) given 10 days apart had an improved event-free survival (EFS) and disease-free survival (DFS) (42% ± 7% and 55% ± 9%, respectively, at 2 years). Reports have suggested an improved outcome in adult patients with AML using TST (at the cost of increased toxicity). The current study was conducted to evaluate the feasibility and effectiveness of the intensively timed DCTER regimen for non-core-binding factor AML in adult patients aged <50 years. Between February 2004 and August 2005, 61 patients received this timed sequential induction regimen. Their outcomes were compared with matched historical patients treated with the combination of idarubicin and cytarabine (IA). The median follow-up for surviving patients was 67 months (range, 35-85 months). The timed sequential DCTER regimen had a lower complete remission (CR) rate when compared with the IA combination,, (71% vs 80%, respectively), but this appeared to be counterbalanced by a higher long-term leukemia-free survival rate using the intensified regimen (48% vs 30%, respectively) in patients who achieved a CR (P = .06). The intensively timed regimen of DCTER was found to induce durable remissions in adult patients with AML, including those patients with high-risk disease. The identification of patients who would potentially benefit from such an intensive regimen may justify the higher early risk of early treatment failure that was found to accompany the intensified DCTER regimen in selected patients.

Early intensification of imatinib treatment based on precise definition of accelerated phase in patients with chronic myeloid leukemia: Population-based analysis.

6588 Background: The phase of chronic myeloid leukemia (CML) at diagnosis (dx) remains significant prognostic factor for the outcome of therapy with tyrosine kinase inhibitors (TKI) therefore patie...

Phase II Study of Risk-Adapted Therapy of Newly Diagnosed, Aggressive Non-Hodgkin Lymphoma Based on Midtreatment FDG-PET Scanning

In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%-93%). On intention-to-treat analysis, 2-year EFS was 67% (53%-86%) in all PET-positive patients and 89% (77%-100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning.

Early PET assessment and therapy de-escalation in patients with advanced Hodgkin’s lymphoma treated with escalated BEACOPP regimen

8541 Background: In Europe both ABVD and escalated BEACOPP regimens are considered as a “standard therapies”. In our previous analysis (ASCO 2007, Abstract No. 8063), patients with advanced disease treated outside clinical trials, chose the first line therapy, after being informed about possible advantages and side effects. De-escalation of therapy after the first 3 cycles in good responders (based on PET or CT scan) didn’t make OS and EFS inferior, while in poor responders to 3 initial ABVD cycles, even early treatment intensification, didn’t improve the outcome. Methods: 31 patients with advanced HD IIBX-IV (43,3% of pts in IV-th clinical stage, 66% with ≥ 3 EORTC risk factors, 33% ≥3 GHSG risk factors) where staged with PET scans at diagnosis (average SUV 13.2), after the second cycle for early response assessment and at the end of treatment. De-escalation of chemiotherapy (escalated BEACOPP ⋄ ABVD) was considered after the 3-rd cycle, if an early response assessment PET scan confirmed adequate regression. Results: Early response assessment PET scan allowed for treatment de-escalation in 20/31 patients (64%). Further 10/31 patients completed the full course of 6 escalated BEACOPP cycles. Additional radiotherapy was allowed for IIBX patients with a large residual masses. With the relatively short observation time of 19,7 months (range 12-32) overall survival (OS) and event free survival (EFS) were both 100%. There were no treatment related mortality, nor relapses within the first year after negative PET scan results. Conclusions: The early treatment assessment PET scans may allow for better identification of responders, leading to limitation of toxicity of upfront escalated BEACOPP regimen without limiting it’s efficiency. No significant financial relationships to disclose.