Risk-adapted Treatment Strategies Research Articles

Best treatment option for clinical stage I seminoma patients.

In the present cross sectional study comprising 106 patients, the authors compared a risk adapted therapeutic strategy in patients with CSI seminoma [1]. The patients were distributed to active surveillance (AS) (n = 84) and adjuvant chemotherapy (ACT) (n = 22) with single dose carboplatin groups. The relapse rates between the 2 groups were similar. The authors advocated AS for patients with low risk of relapse and, on the other hand, ACT for those with high risk of relapse. The current management options for CSI seminomas include adjuvant radiotherapy (ART), AS, and ACT. ART has been the preferred treatment modality for a long time, but concerns regarding its side effects, such as risks of cardiovascular disease and secondary malignancies, resulted in a significant change in the concept of ART. Thus, the option of ART has been removed from the current guidelines [2, 3]. Surveillance avoids overtreatment in approximately 85% of patients when appropriate follow-up protocols are used [4]. However, identifying the 15% who may harbor micrometastatic disease should be of utmost importance in patients under AS. Surveillance requires highly compliant patients willing to have multiple abdominal CT scans. The radiation from abdominal CT is not benign, with a lifetime attributable risk of secondary malignancy from 4 scans for an 18 year old patient calculated at 0.64% [5]. ACT has been shown to be non-inferior to ART [6]. In the largest series of ACT, a 4.1% relapse rate was demonstrated with a median time to relapse of 22.7 months among 517 patients [7]. A recent study which investigated the practice patterns for adjuvant therapies for CSI seminoma in the US population has demonstrated that ART has been largely replaced by ACT, rather than AS [8]. However, the authors concluded that the lack of an increase in AS in their cohort might represent overtreatment of the population. Proponents of AS consider ACT a potentially harmful and unnecessary intervention. However, in recent studies, especially low risk patients were selected for AS, whereas high risk patients were given ACT [9]. Due to this reason, such series may possibly be flawed by selection bias in favor of AS, whereas predominantly low risk patients were included rather than high risk ones [10]. The long term side effects of single dose ACT remain unclear; moreover, the use of ACT does not obviate the need for abdominal CT scans, which has been proposed as a concern against AS. A risk adapted treatment strategy seems to be logical for CSI seminoma patients. Although rete testis invasion and primary tumor >4 cm were reported to be independent prognostic factors for relapse, these data have not been validated in prospective studies [11]. Currently, AS has been recognized as the treatment of choice of CSI seminomas in the EAU and American Society of Clinical Oncology guidelines [2, 3].

Higher Incidence of Treatment-Related Toxicities in Non-Hispanic Patients Undergoing Therapy for Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001

Background: Risk-adapted treatment strategies have contributed to excellent outcomes in pediatric acute lymphoblastic leukemia (ALL); however, treatment-associated acute and long-term toxicities persist. Therapy-associated toxicities of note in pediatric ALL are related to a treatment backbone that relies heavily on corticosteroids (prednisone and dexamethasone) and asparaginase (ASP). The most frequently observed toxicities include, but are not limited to, serious infection, pancreatitis, thrombosis and bony morbidities including osteonecrosis (ON) and fracture. Previous studies suggest that children of racial and ethnic minorities are at higher risk for treatment-associated toxicities. We assessed the incidence of treatment-related toxicities in Hispanic and non-Hispanic patients undergoing treatment for pediatric ALL.Patients and Methods: Retrospective cohort study investigating the incidence of treatment-related toxicities including infection, allergy to ASP, pancreatitis, thrombosis and bony morbidities in Hispanic and non-Hispanic children and adolescents with newly diagnosed ALL undergoing therapy on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. The ethnicity of each patient was designated at the time of study enrollment by research coordinators. Descriptive statistics were calculated, mean +/- SD for continuous variables and frequency and percentages for categorical variables. Toxicity rates were based on number of patients. Comparison between groups was done by Chi-square test or FisherÕs exact test and p -value < 0.05 was considered significant.Results: Between 2005 and 2011, 794 children and adolescents (ages 1 - 18 years) were enrolled on Protocol 05-001, 730 of whom were evaluable for this investigation: 150 Hispanic (18%), 580 non-Hispanic (73%). Sixty-four patients did not have ethnicity documented. There was no significant difference in disease-risk group, age or gender between the two groups. Weight was significantly higher in Hispanic patients (31.9 ± 24.4 kg in Hispanic and 26.9 ± 18.7 kg in non-Hispanic, p = 0.021). There was no significant difference in the incidence of ASP-related toxicities (allergy, pancreatitis, thrombosis) between Hispanic and non-Hispanic patients. There was no significant difference in the overall incidence of infection between the two groups (42% in Hispanic and 50% in non-Hispanic, p = 0.081). Non-Hispanic patients had significantly higher rates of opportunistic infection (Pneumocystis pneumonia) than Hispanic patients (0.7% in Hispanic and 4% in non-Hispanic, p = 0.041). A similar difference in the incidence of bacteremia between the two groups approached, but did not reach statistical significance (p = 0.052). The overall incidence of fracture in all patients was 14.5% and was significantly higher in non-Hispanic patients (6% in Hispanic and 16.7% in non-Hispanic, p < 0.001). The overall incidence of ON was 8.9% and was significantly higher in non-Hispanic patients (3.3% in Hispanic and 10.3% in non-Hispanic, p = 0.007). (Table 1)Conclusion: The incidence of opportunistic infections and bony morbidities was significantly higher in non-Hispanic patients undergoing treatment for pediatric ALL on the DFCI ALL Consortium Protocol 05-001. The risk for, and impact of therapy-related toxicities varies by a patientÕs treatment tolerance, perhaps as a function of age and gender or as a result of disease biology or genetic polymorphisms affecting drug metabolism. Additionally, non-biologic factors such as medication adherence and nutritional status may also contribute to toxicity incidence in patients undergoing treatment for pediatric ALL. Prospective studies to further investigate our findings are warranted.TableAll Patients, (N = 730)Non-Hispanic, (N = 580)Hispanic, (N = 150)p -valueOverall Infection353/730 (48.4%)290/580 (50%)63/150 (42%)0.081Bacteremia289/730 (39.6%)240/580 (41.4%)49/150 (9.3%)0.052Opportunistic Infection24/730 (3.3%)23/580 (4%)1/150 (0.7%)0.041Fracture106/730 (14.5%)97/580 (16.7%)9/150 (6%)<0.001Osteonecrosis65/730 (8.9%)60/580 (10.3%)5/150 (3.3%)0.007Thrombosis*36/730 (4.9%)26/580 (4.5%)10/150 (6.7%)0.271Pancreatitis*78/730 (10.7%)60/580 (10.3%)18/150 (12%)0.559ASP Allergy*76/730 (10.4%)57/580 (9.8%)19/150 (12.7%)0.310*ASP-related toxicity DisclosuresNo relevant conflicts of interest to declare.

Cost Description on a Cohort of 659 Patients with Adult MDS Included into the Italian Lazio Region Registry (the GROM-L)

Intro:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematology neoplasms ranging from indolent to very aggressive conditions. The reported incidence is of 5/100,000/year in the whole population changing up to 50/100,000/year after the age of 60 and up to 165 after 65. Due to the heterogeneity of MDS, patients are stratified into subgroups according to prognostic score systems (IPSS) to identify the best risk-adapted treatment strategy. These therapeutic strategies are not univocally agreed, creating differences among groups. Moreover data on economic aspects are partial and sometimes controversial, owing to different healthcare resources considered (transfusions, medications, procedures, hospitalization, treatment of comorbidities, first of all infectious complications). The adoption of Regional Hemato-Oncology Registries of Diagnostic Service Registries can allow for better quality in diagnostic procedures and treatment as well as improving the evaluation of healthcare costs in these patients.Methods: In the Italian Lazio Region the Rome and Lazio Group of Myelodysplasias (GROM-L) is presently active as a registry of MDS in adults, exploiting the collaboration of all Hematology Centers in the Region: diagnostic procedures and therapeutic protocols of patients included into this registry are harmonized. In the present study we report the results of the evaluation of costs of the healthcare resources supplied to 659 patients with MDS in the Lazio Region during the period 2002-2009, adopting the ‎ third party payer viewpoint (.e. the Healthy Service of the Lazio Region -SSR Lazio). In Table 1 is reported the distribution of the MDS diagnostic categories in our cohort of patients. The following healthcare resources are included: Red Blood Cell (RBC) and Platelet (Plt) transfusions, Erythropoietic Stimulating Agents, antineoplastic and immunomodulatory drugs, hospitalization and treatment of infectious (bacterial, viral and fungal) complications (Table 2). Healthcare resources are valued according to published ‎sources. Costs are expressed in Euros (€) 2013. Costs occurred after 2002 are discounted at 3% real social rate.Results:The overall cost for the 659 patients of the GROM-L Registry is €22.05 millions (US$24.21 millions), with an average cost per patient of €33.455,65 (US$ 36.727) (Table 3). The estimated annual cost for the SSR Lazio for the management of all the resident patients with adult MDS (around 183 per year) reaches €1.23millions (US$ 1.35millions). Data on costs related with MDS diagnostic subgroups are available too. In particular our data confirm that the transfusion dependency do represent one of the more valid predictor index of the healthcare costs in patients with MDS (Frytak et al., 2009, Drummond et al. 2005, Goldberg et al. 2012). The reduction of transfusion dependency in these patients do represent a new challenge for improving not simply the healthcare costs but the Health-Related Quality of Life- HRQoL) in these patients (Drummond et al. 2005; Brazier et al. 2007, Szende et al. 2009).AcknowledgmentsThe study was supported by a grant from Regione Lazio: " Sindromi mielodisplastiche dell'adulto nell'area di Roma e del Lazio: Grant 2011-Progetti di farmacovigilanza -Area tematica 5". The authors would like to thank all the patients and investigators who took part in the study.Table 1Distribution of the 659 patients among the WHO diagnostic categories of MDS.WHO MDS categoriesRARSRARCMDRAEB-1RAEB-25q-MDS-UPatients3324614896812728Table 2Health care resources supplied to 659 patients with adult MDS in the period 2002-2009 included in the Italian Lazio Region.659 Patients in TotalTreatmentQuantityTransfusionsRBC7875 UnitsPlt74 UnitsHigh cost therapiesAzacytidine126 cyclesLenalidomide34 cyclesErythropoietin554 cyclesHospitalizations due to infectious complicationsAntibacterial345 cyclesAntiviral25 cyclesAntifungal42 cyclesTable 3Cost details of 659 patients with adult MDS included into the GROM-L Registry in the period 2002-2009 in the Italian Lazio Region.Healthcare resourcesOverall CostsAverage cost per patient% of the overall costsRBC transfusions€3.04 millions€4.606,3213,77%Plt transfusions€28.619,07€43.430,13%High cost therapies€18.55 millions€28.146,4184,13%Treatment for infectious complications€0.43 millions€659.501,97%Grand total€22.05 millions€33,455.65100,00% DisclosuresVoso:Celgene: Honoraria, Research Funding.

Occurrence and Prognostic Significance of Cytogenetic Evolution in Patients with Multiple Myeloma

Abstract Background: Cytogenetic evaluation, especially using fluorescence in situ hybridization (FISH), at the time of diagnosis is essential for initial risk stratification and the employment of risk-adapted treatment strategies in multiple myeloma. Little is known about the occurrence and prognostic significance of cytogenetic evolution during follow up. Methods: We studied 433 patients who were diagnosed with multiple myeloma between January 2000 and December 2011 and had at least two FISH evaluations at Mayo Clinic Rochester, including the diagnostic specimen. Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Cytogenetic evolution was defined as a new deletion, monosomy, trisomy, tetrasomy, or translocation during follow up. Multivariable-adjusted logistic regression models were used to assess the associations between the parameters of interest and the presence of cytogenetic evolution in follow-up specimens. Multivariable-adjusted Cox proportional hazards models were used to assess the effect of cytogenetic evolution on overall survival. All models were adjusted for sex, age, the presence of high-risk FISH abnormalities, and the number of abnormalities at the time of diagnosis. Likelihood ratio tests were used to assess the goodness of fit of nested models. The χ2 or Fisher's exact test was used to assess the distribution of cytogenetic abnormalities in subgroups. Results: The median age at diagnosis was 60 years (32 - 82), 264 (61%) of the patients were male. The median overall survival for the entire cohort was 7.0 years (6.2 - 7.8). At the time of diagnosis, 150 (35%) and 57 (13%) of the 433 patients presented with a hyperdiploid karyotype and cytogenetic high-risk abnormalities, respectively. Independent of each other, the presence of a translocation at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow up (OR 0.39, 95% CI 0.24 - 0.63, p &lt; 0.001) while the presence of at least one trisomy or tetrasomy at the time of diagnosis was associated with increased odds (OR 2.53, 95% CI 1.37 - 4.70, p = 0.003). A greater proportion of patients presenting with a hyperdiploid karyotype experienced cytogenetic evolution during follow up. Those patients more frequently evolved additional trisomies and tetrasomies, while translocations were more common in those presenting with a non-hyperdiploid karyotype (Table 1). The development of additional abnormalities during the three years following diagnosis (compared to no new abnormalities) was associated with increased subsequent mortality in those who survived at least three years (HR 3.22, 95% CI 1.82 - 5.68, p &lt; 0.001). Including the time between first and last cytogenetic evaluation as a covariate did not significantly change the parameter estimates or improve model fit (p = 0.727). Conclusions: Demographics, risk profile, and overall survival of this cohort reflect the fact that patients had to survive long enough to undergo repeated cytogenetic evaluation. Hyperdiploid and non-hyperdiploid genotypes were associated with distinct behavior regarding cytogenetic evolution during follow up. The identification of cytogenetic evolution was an adverse prognostic factor in those who survived at least three years after diagnosis. These findings emphasize the importance of the dynamics of the underlying clonal disease process for accurate risk assessment and suggest that selected subgroups of patients may benefit from risk stratification during follow up. Table 1. Cytogenetic evolution during follow up in 433 patients with multiple myeloma stratified by karyotype at the time of diagnosis Hyperdiploid (n = 150) Non-hyperdiploid (n = 283) p New abnormality 76 (51%) 108 (38%) 0.012 New monosomy 8 (5%) 24 (8%) 0.243 New trisomy 48 (32%) 55 (19%) 0.004 New tetrasomy 37 (25%) 27 (10%) &lt; 0.001 New deletion 17 (11%) 27 (10%) 0.557 New translocation 1 (1%) 11 (4%) 0.065 Most common new abnormality [type (percent of type in each group)] Monosomy mono(13) (75%) mono(13) (62%) Trisomy tri(11) (22%) tri(3) (22%) Tetrasomy tetra(15) (48%) tetra(15) (30%) Deletion del(17p) (79%) del(17p) (63%) Translocation t(11;14) (100%) t(11;14) (36%) Data are given as count (percent) unless denoted otherwise. Disclosures Binder: American Society of Hematology: Research Funding. Kumar:AbbVie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Risk-Adapted Induction and Maintenance with Ofatumumab in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)

Introduction: Pre-treatment cytogenetics and post-treatment minimal residual disease (MRD) status are predictive biomarkers in CLL. We hypothesized the two markers can guide a risk-adapted treatment strategy to achieve deep and durable responses in previously untreated CLL/SLL.Methods and Patients: 31 subjects were enrolled. Risk assessment was performed before treatment and after induction. Based on pre-treatment FISH, patients were categorized into either high-risk (with deletion 17p or 11q) or standard-risk (no deletion 17p or 11q) and treated with up to 6 cycles of OFC (Ofatumumab 300mg i.v. on cycle 1 day 1, 1000mg i.v. on cycle 1 day 8 and on day 1 of subsequent cycles; Fludarabine 25mg/m2 i.v. on day 1-3; Cyclophosphamide 250mg/m2 i.v. on day 1-3;) or OF (Ofatumumab given as described for the high-risk group; Fludarabine 25mg/m2 /d i.v. on day 1-5), respectively. Three months after completion of chemoimmunotherapy, a second risk stratification was performed based on presence or absence of MRD. MRD negative (MRDneg) state was defined as <1 monoclonal B cell among 104 leukocytes based on 8-color peripheral blood flow cytometry (PBFC). MRDneg patients were observed and MRD positive (MRDpos) patients received ofatumumab maintenance (1000mg i.v. every two months for 4 cycles). Serial PBFCs were performed pre- and post-induction, pre- and post-maintenance, and at 24 months. The primary endpoint was progression free survival at 24 months.Results: 25 patients who completed ≥3 cycles of chemoimmunotherapy were considered evaluable; median age 60 years (range 26-79), 56% male, 48% in high Rai stage, 68.6% having unmutated IGHV. Nine (36%) patients received OFC, 16 (64%) received OF. 72% of all patients required dose reductions and 64% completed 6 cycles. After induction, 15 (60%) patients were MRDpos and received maintenance, while 10 MRDneg patients were observed. More patients on the OFC arm were MRDneg than on the OF arm (66.7 vs. 25%, P =0.087). At a median follow-up of 32 months, 7 patients had progressed. The projected PFS was 95% at 24 months (85-100%), 82.5% at 32 months (66-100%), and 75% at 36 months (56-100%), with no significant difference between subgroups divided by treatment regimen or MRD status after induction. The estimated median PFS was 36 months for MRDpos vs. 49 months for MRDneg patients (P =0.13). At 24 months, 3 out of 7 MRDneg patients maintained MRD negativity without further treatment. For MRDpos patients, the number of residual CLL cells appeared to decrease during maintenance ofatumumab and two patients became transiently MRDneg. However, the change in MRD burden was not statistically significant (median CLL cell count per 104 leukocytes: 50 vs. 36 at pre- vs. post-maintenance, P =0.13) and none of the patients receiving maintenance was MRDneg at 24 months. The median CLL count per 104 leukocytes increased from 36 at post-maintenance to 260 at 24 months (P =0.047). Taken together, MRD after chemoimmunotherapy was not eradicated with additional doses of ofatumumab. We hypothesized that loss of CD20 expression through trogocytosis (Fc-receptor mediated "stripping" of CD20 from CLL cells) or internalization may limit the efficacy of ofatumumab. In fact, among MRDpos patients, CD20 expression was negative by PBFC in 90% of patients at post-induction and in all patients at post-maintenance. On bone marrow biopsies, immunohistochemical staining for CD20 using an antibody against an intracellular epitope confirmed CD20 loss or demonstrated substantially decreased CD20 expression compared to matching baseline samples.Conclusion: Pre-treatment risk stratification with FISH cytogenetics can guide the choice of induction therapy. Maintenance therapy with four additional doses of ofatumumab in MRDpos patients did not improve the depth of response but appeared to reduce the risk of disease progression. Loss of CD20 expression on residual tumor cells may limit the efficacy of prolonged therapy with an anti-CD20 monoclonal antibody. DisclosuresWiestner:Pharmacyclics: Research Funding.

The Role of Interim F-18 FDG PET/CT in Patients of T Lymphoblastic Leukemia/Lymphoma Treated with ALL-Type Regimens

Background:T lymphoblastic leukemia/lymphoma (T-LBL) is highly aggressive. Although intensive chemotherapies such as acute lymphoblastic leukemia (ALL)-type regimens are commonly used, about half adult patients eventually relapse and die of T-LBL. Overwhelming evidences have confirmed the role of interim F-18 FDG PET/CT in Hodgkin lymphoma and many ongoing studies have implemented risk-adapted strategy determined by interim FDG-PET/CT. However, the role of interim FDG-PET/CT in T-LBL remains unclear.Materials and methods:47 adult patients of T-LBL treated with ALL-like regimens were retrospectively reviewed. They were treated with modified Berlin-Frankfurt-Münster (BFM)-90 regimen (n=27), Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 regimen (n=5), hyperCVAD/MA regimen (n=12), or other unspecified regimens (n=3). Interim (defined as the period between induction therapy and re-induction therapy) FDG-PET/CT was done in all 47 patients and evaluated according to the International Harmonization Project (IHP) criteria.Results:The male to female ratio was 3:1, and 29.8% of patients were older than 30 years old. About 90% of patients had mediastinal mass at presentation and 53.2% had bone marrow infiltration. 85.1% of patients had advanced disease. After induction therapy, interim FDG-PET/CT was positive in 19 patients (40.4%), most of whom had residual disease in the mediastinal lesion. Subsequent treatments were not changed according to this interim PET/CT results. After a median follow up time of 28 months, the 2-year and 3-year progression free survival (PFS) rate were 39% and 30%, respectively, and the 2-year and 3-year overall survival (OS) rate were 54% and 45%, respectively. Using Kaplan-Meier survival analysis and log-rank test, it was found that interim FDG-PET/CT positivity correlated with significantly inferior PFS and OS (p=0.002 and 0.010, respectively). Furthermore, patients with higher age (>30) had inferior PFS and OS than younger patients (p=0.037 and 0.036, respectively). However, there were no significant relationship between PFS, OS and bone marrow infiltration, LDH level, and stages (p>0.05).Conclusions:Interim FDG-PET/CT may predict PFS and OS in adult patients of T-LBL treated with ALL-type regimens, which needs to be validated in prospective clinical trials. The optimal criteria for interim FDG-PET/CT evaluation and risk-adapted treatment strategy determined by interim FDG-PET/CT should be investigated in future clinical practice. DisclosuresNo relevant conflicts of interest to declare.

Next-generation prognostic assessment for diffuse large B-cell lymphoma.

Current standard of care therapy for diffuse large B-cell lymphoma (DLBCL) cures a majority of patients with additional benefit in salvage therapy and autologous stem cell transplant for patients who relapse. The next generation of prognostic models for DLBCL aims to more accurately stratify patients for novel therapies and risk-adapted treatment strategies. This review discusses the significance of host genetic and tumor genomic alterations seen in DLBCL, clinical and epidemiologic factors, and how each can be integrated into risk stratification algorithms. In the future, treatment prediction and prognostic model development and subsequent validation will require data from a large number of DLBCL patients to establish sufficient statistical power to correctly predict outcome. Novel modeling approaches can augment these efforts.

Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy.

Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination. MRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors. Medulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve [AUC] = 0.88). The data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups.

HCT-CI Has Prognostic Value in Acute, but Not Chronic Gvhd Specific Survival

Introduction: Graft-versus-host disease (GVHD) is a major cause of treatment failure in allogeneic hematopoietic cell transplantation (HCT). The hematopoietic cell transplant-specific comorbidity index (HCT-CI) predicts transplant-related mortality (Sorror, et al: Blood, 2005; Raimondi, et al: Blood, 2012), but its prognostic value has not been well explored in the setting of GVHD. It is hypothesized that patients with a high HCT-CI score would have worse outcomes after developing GVHD compared to those with a low HCT-CI score. In this retrospective study we calculated the pre-transplant HCT-CI and analysed its relationship with GVHD specific survival (GSS).Methods: A total of 541 patients who received allogeneic HCT at Princess Margaret Cancer Centre between 2000 and 2012 were included in this retrospective cohort study. The GSS was defined as the time from diagnosis of GVHD (for acute and chronic GVHD separately) until death from a GVHD-related cause, including organ dysfunction directly related to GVHD and infection in the setting of GVHD and immunosuppressive treatment. The GSS in relation to the HCT-CI was analysed using the Cox proportional hazard regression model. The GSS was plotted using the Kaplan-Meier method and the Log-rank test was used for comparison.Results: The incidence of all grades of acute GVHD and grade 2-4 acute GVHD was 68.7±2.1% and 54.9±2.3%, respectively. The incidence of chronic GVHD by the NIH consensus criteria was 72.9±2.8%. With a median follow-up duration of 24 months among survivors after a diagnosis of GVHD, the 2-year rates of acute GSS (aGSS) and chronic GSS (cGSS) were 60.7±2.9 and 74.6±2.7%, respectively.Univariate analysis demonstrated that the HCT-CI score as a continuous variable was prognostic for aGSS (p=0.001, HR 1.198, 95% CI [1.082-1.325]), showing that an increase in the HCT-CI score by 1 resulted in an increase in mortality by 20%. However, for cGSS, there was only borderline statistical significance with a p-value of 0.068 (HR 1.130 95% CI [0.991-1.289]).Patients were divided into 3 groups according to their HCT-CI score: 0-1(n=232, 42.9%), 2-4 (n=267, 49.4%) and ≥5 (n=42, 7.8%). The HCT-CI was able to stratify patients in relation to aGSS (p=0.001): The 2 year aGSS rate was 72.0±3.9% in those with an HCT-CI of 0-1 (n=148), 53.6±4.4% with an HCT-CI of 2-4 (n=173), and 35.6±11.5% with an HCT-CI of ≥5 (n=25). In contrast, no correlation was found with cGSS among the 3 groups (p=0.355). The 2 year cGSS rate was 79.5±3.6% in patients with an HCT-CI of 0-1 (n=141), 70.5±4.3% with an HCT-CI of 2-4 (n=149), and 63.2±14.0% with an HCT-CI of ≥5 (n=24).A multivariable analysis was performed to confirm the HCT-CI score as an independent prognostic factor for GSS, accounting for the following covariates: age, donor type, source of stem cells, and severity of acute GVHD (grade 3-4 vs others) and chronic GVHD (NIH global score mild, moderate and severe). The HCT-CI was found to be an independent risk factor for aGSS (p=0.016, HR 1.15, 95% CI [1.03-1.3]), but not for cGSS (p=0.80, HR 1.02, 95% CI [0.84-1.2]).Conclusion: Patients undergoing allogeneic HCT with significant comorbidities prior to transplant demonstrated by a higher HCT-CI have a shorter GSS. This finding is only significant for survival following acute GVHD (i.e. acute GSS), but not for chronic GVHD. This study suggests that the HCT-CI score may provide additional prognostic information in the assessment of the risk of acute GVHD related outcomes but not chronic GVHD outcomes, and that the assessment of HCT-CI score prior to HCT may be useful in risk adaptive preventive and treatment strategies for GVHD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post-remission therapy for acute myeloid leukemia.

Induction followed by post-remission therapy including intensive chemotherapy with high-dose cytarabine, autologous and allogeneic hematopoietic stem cell transplantation is recognized as the main road towards cure in acute myeloid leukemia. In recent years, also a renaissance of maintenance therapy after completion of intensive consolidation has been observed with the introduction of kinase inhibitors and demethylating agents in clinical trials. Greater insight into the genetic background of the disease fostered the extension of disease classification and pretreatment risk-categorization by gene mutations. In addition, the pre-treatment risk-defining parameters have been supplemented by markers evaluated at distinct time points during treatment and follow up. In this context, minimal residual disease assessment is increasingly used to dynamically fine tune treatment recommendations. Currently, the gold standard to counterbalance a higher risk of relapse by treatment strategies based on hematopoietic stem cell transplantation with grafts from matched related or unrelated donors is still valuable, whereas autologous hematopoietic stem cell transplantation showed promising results especially in patients categorized as low-risk. Nonetheless, more targeted approaches including kinase inhibitors and demethylating agents in combination with or sequentially before or after intensive chemotherapy are currently in clinical evaluation and may lead to more genotype- instead of purely risk-adapted treatment strategies.

Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

P. Fenaux1, D. Haase2, G. F. Sanz3, V. Santini4 & C. Buske5 on behalf of the ESMO Guidelines Working Group* Service d’Hematologie Clinique, Groupe Francophone des Myelodysplasies (GFM), Hopital St Louis (Assistance Publique, Hopitaux de Paris) and Paris 7 University, Paris, France; Clinics of Hematology and Medical Oncology, University Medicine, Goettingen, Germany; Department of Haematology, Hospital Universitario y Politecnico La Fe, Valencia, Spain; Functional Unit of Haematology, AOU Careggi, University of Florence, Firenze, Italy; Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital, Ulm, Germany

Primary mediastinal large B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBCL) is a relatively rare lymphoma subtype affecting mainly young adults. Its molecular signature and clinical features resemble classical Hodgkin lymphoma. The optimal chemotherapy for this lymphoma subtype has not been established. The addition of rituximab to anthracycline based chemotherapy improved response rates and survival. Many centers use R-CHOP as standard treatment, but the role of the intensified regimens and consolidation radiotherapy has to be clarified. Recent data coming from retrospective analyses and an ongoing prospective study addressing the problem of consolidation radiotherapy will help to better identify risk groups and apply risk-adapted and effective treatment strategies. The latest research has helped to understand molecular mechanisms of PMBCL pathogenesis and indicated targets of directed therapy for the future.

Ectonucleoside triphosphate diphosphohydrolase-1 (E-NTPDase1/CD39) as a new prognostic marker in chronic lymphocytic leukemia

Numerous prognostic markers were introduced to screen for patients with B-cell chronic lymphocytic leukemia (B-CLL) likely to have a progressive course, bearing the potential to facilitate risk-adapted treatment strategies. Extracellular adenosine triphosphate (ATP) functions as a “natural adjuvant” that boosts immune response in the tumor microenvironment. Ectonucleoside triphosphate diphosphohydrolase-1 (CD39/ENTPD1) is the ectonucleotidase that catalyzes the hydrolysis of ATP. The present study was conducted to analyze CD39 expression in T cells and B-CLL cells to evaluate its impact on the clinical course of patients with B-CLL and correlate its levels with well-established risk factors. T-cell CD39 expression was significantly increased in patients’ peripheral blood compared to healthy controls. The higher levels were associated with advanced stages of disease and negatively interacted with time to first treatment. Overall, our data indicate that T-cell CD39 expression may identify subsets of patients with B-CLL with an unfavorable clinical outcome. Moreover, it can be incorporated into prognostic schema to improve the prediction of CLL disease progression.

Predictors of pathological complete response to neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma.

BackgroundsIn this study, we evaluated the factors associated with a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC).MethodsPre-nCRT parameters in ESCC patients treated between 1999 and 2006 were analyzed to identify predictors of pCR. All patients received 5-fluorouracil/cisplatin-based chemotherapy and external beam radiation followed by scheduled esophagectomy. Variables were analyzed using univariate and multivariate analyses with pCR as the dependent variable. Estimated pCR rate was calculated with a regression model.ResultsFifty-nine (20.9%) of 282 patients achieved pCR. Univariate analysis identified four patient factors (age, smoking status, drinking history and hypertension), one pre-nCRT parameter (tumor length) as significant predictors of pCR (all P <0.05). On multivariate analysis, tumor length ≤3 cm (favorable, odds ratio (OR): 4.85, P = 0.001), patient age >55 years (favorable, OR: 1.95, P = 0.035), and being a non-smoker (favorable, OR: 3.6, P = 0.003) were independent predictors of pCR. The estimated pCR rates based on a logistic regression including those three predictors were 71%, 35 to approximately 58%, 19 to approximately 38%, and 12% for patients with 3, 2, 1 and 0 predictors, respectively.ConclusionAge, smoking habit and tumor length were important pCR predictors. These factors may be used to predict outcomes for ESCC patients receiving nCRT, to develop risk-adapted treatment strategies, and to select patients who could participate in trials on new therapies.

Confirmation of the Mantle-Cell Lymphoma International Prognostic Index in Randomized Trials of the European Mantle-Cell Lymphoma Network

Mantle-cell lymphoma (MCL) is a distinct B-cell lymphoma associated with poor outcome. In 2008, the MCL International Prognostic Index (MIPI) was developed as the first prognostic stratification tool specifically directed to patients with MCL. External validation was planned to be performed on the cohort of the two recently completed randomized trials of the European MCL Network. Data of 958 patients with MCL (median age, 65 years; range, 32 to 87 years) treated upfront in the trials MCL Younger or MCL Elderly were pooled to assess the prognostic value of MIPI with respect to overall survival (OS) and time to treatment failure (TTF). Five-year OS rates in MIPI low, intermediate, and high-risk groups were 83%, 63%, and 34%, respectively. The hazard ratios for OS of intermediate versus low and high versus intermediate risk patients were 2.1 (95% CI, 1.5 to 2.9) and 2.6 (2.0 to 3.3), respectively. MIPI was similarly prognostic for TTF. All four clinical baseline characteristics constituting the MIPI, age, performance status, lactate dehydrogenase level, and WBC count, were confirmed as independent prognostic factors for OS and TTF. The validity of MIPI was independent of trial cohort and treatment strategy. MIPI was prospectively validated in a large MCL patient cohort homogenously treated according to recognized standards. As reflected in current guidelines, MIPI represents a generally applicable prognostic tool to be used in research as well as in clinical routine, and it can help to develop risk-adapted treatment strategies to further improve clinical outcome in MCL.

Management of myelodysplastic syndromes: Expert consensus opinion from the Saudi MDS Working Group

Myelodysplastic syndromes (MDSs) constitute a heterogeneous group of clonal hematopoietic disorders. A panel of Saudi hematologists representing the Saudi MDS Working Group convened with two international experts to develop the guidelines for MDS diagnosis and treatment. The recommendations were formulated on the basis of a list of real cases and therapy-related questions. The diagnostic procedures should help distinguish MDS from other causes of cytopenia and dysplasia and other clonal stem cell disorders. Blood smear, bone marrow aspirate and biopsy, and cytogenetic testing are among the mandatory diagnostic tests in MDS. Higher resolution genetic testing like mutational analysis and single nucleotide polymorphisms can be suggested for the workup depending on the clinical condition and availability of these technologies. The Working Group stressed that the heterogeneity of MDS strongly withstands a risk-adapted treatment strategy based on the international prognostic scoring system risk group of patients.

Impact of risk factors on outcomes in early-stage Hodgkin's lymphoma: an analysis of international staging definitions

BackgroundIn early-stage Hodgkin's lymphoma (HL), treatment according to the early favorable or unfavorable subgroup is guided by staging definitions, which differ between various study groups worldwide. We analyzed risk factors used in different international staging systems and their impact on the outcome of early-stage HL patients. Patients and methodsIn 1173 early-stage HL patients treated homogenously within the German Hodgkin Study Group (GHSG) trials HD10 and HD11, the impact of three staging systems developed and used by the GHSG, the European Organization for Research and Treatment of Cancer (EORTC), and the National Comprehensive Cancer Network (NCCN) in discriminating risk groups for progression-free survival (PFS) and overall survival (OS) was assessed and the relevance of their single risk factors was investigated. ResultsAll the three staging systems defined an unfavorable risk group out of early-stage patients of comparable size (56%, 55%, and 57%), having a significantly poorer PFS and OS as compared with the corresponding favorable group; 5-year differences between early favorable and early unfavorable in terms of PFS were 9.4% (HR 2.61, 95% CI 1.74–3.91), 6.7% (HR 2.10, 95% CI 1.41–3.13), and 8.6% (HR 2.14, 95% CI 1.45–3.16) with the GHSG, EORTC, and NCCN definition, respectively. Sensitivity was high for all systems (84%, 79%, and 83%); however, there was a low specificity with high rates of false-positive results (1-specificity 54%, 53%, and 55%, respectively). Models of high sensitivity included risk factors associated with large tumor burden and high tumor activity. Most risk factors for tumor-specific end points were also predictive of OS. ConclusionsDifferentiating between a favorable and an unfavorable risk group has significant impact on PFS and OS in early-stage HL patients in the modern treatment era. Risk-adapted treatment strategies using new risk factors with higher specificity are needed.

Treatment Results In Acute Myeloid Leukemia Over a Time Period Of 20 Years: Analysis Of The German-Austrian Acute Myeloid Leukemia Study Group (AMLSG)

▪ BackgroundOverall survival (OS) in acute myeloid leukemia (AML) treated with intensive chemotherapy has improved over the last 20 year especially in younger adults (18-60 years) but still remains poor in older patients (>60 years) (Döhner et al. Blood 2010). The German-Austrian AMLSG performed controlled prospective treatment trials since 1993 starting with a risk-adapted approach (phase I, 1993-1997), followed by randomized and risk-adapted treatment strategies based on cytogenetic risk groups (phase II, 1997-2002); since 2003 addition of differentiating agents and HiDAC inhibitors to intensive induction therapy was evaluated (phase III, 2003-2007). Of note, until 2007 younger and older patients (> 60 years) were treated in separate protocols with significantly lower dosages of chemotherapy in older patients. Starting from 2008, risk-adapted therapies were replaced successively by a genotype-adapted approach and the artificial age cut-off at 60 years was abandoned (phase IV, 2008-2012). AimsTo evaluate the outcome of adult AML patients within the different time periods. MethodsThe study included 4705 intensively treated adults (younger, n=3546; older, n=1159) with newly diagnosed AML enrolled on 11 AMLSG treatment trials between 1993 and 2012. Patients with acute promyelocytic leukemia were excluded. All patients received intensive induction and consolidation therapy. Analyzed outcome variables were first complete remission rates (CR1), relapse-free survival (RFS), survival after relapse (SAR) and OS. Analyses were performed according to age groups (18-60 vs. >60 yrs). In younger patients comparisons were performed for the 4 treatment phases (I-IV), whereas for older patients analyses were restricted to phase II-IV. ResultsIn younger patients CR rates did not improve over time (1993-2013) and varied between 72% and 77% (p=0.12), whereas early and hypoplastic (ED/HD) death rates significantly declined from 10% to 5% (p=0.0001). In older patients CR rates significantly improved over time from 44% to 50% between 1998 and 2007 to 67% after 2008 (p<0.0001); ED/HD rates gradually declined from 12% to 8%, but the difference was not statistically significant (p=0.17).The proportion of younger patients receiving an allogeneic hematopoietic stem cell transplantation (alloHSCT) increased from 30% (15% in CR1) in phase I to 58% (29% in CR1) in phase III and remained there in phase IV with 53% (26% CR1), whereas the proportion of patients receiving an autologous HSCT constantly decreased from maximally 16% (15% in CR1) in phase II to 0.4% (0.2% in CR1) in phase IV; the proportion of older patients receiving an alloHSCT steadily increased from 4% (2% CR1) in phase II to 21% (12% CR1) in phase IV; autoHSCT was rarely performed. OS at 4 years in both age groups significantly improved (p<0.0001, each) from 41% to 56% and from 10% to 23% in younger and older patients, respectively. This beneficial effect on OS over time in younger patients was due to a better RFS (p=0.01) and SAR (p<0.0001), whereas in older patients no improvement in RFS (p=0.20) and only in trend for SAR (p=0.07) was noted. In cytogenetically high-risk patients, OS in younger (p=0.001) and in older (p=0.007) patients got better; in older patients mainly driven by increase in CR rates (p=0.001) and in younger patients by an improvement in RFS (p=0.02) and SAR (p=0.05). Nearly the same pattern was identified for cytogenetically intermediate risk patients with a better OS in younger (p<0.0001) and older patients (p=0.01) due to higher CR rates in older patients (p<0.0001), no improvement in RFS in both age groups and a significantly better SAR in younger patients (p=0.0002). In contrast, in low risk patients improvement in OS was only present in older patients (p=0.02), due to a better RFS in older patients (p=0.02) but without any progress in younger patients. Furthermore we performed two subgroup analyses in intermediate risk patients. In the subgroup of patients characterized by the genotype NPM1-mut/FLT3-ITDneg a significant better OS was present only in younger patients (p=0.03); in FLT3-ITD positive AML a better OS was seen in younger patients (p<0.0001) due to a better RFS (p=0.05) and SAR (p=0.01). ConclusionsBased on the German-Austrian AMLSG experience the prognosis in younger and older AML patients has improved over time. In older patients this is mainly a result of higher CR rates and in younger patients of better RFS and SAR. Disclosures:Schlenk:Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Greil:Novartis: Honoraria, Research Funding.

The Role Of PET Imaging For Predicting Treatment Failure In Primary Mediastinal B-Cell Lymphoma

IntroductionPrimary mediastinal B-cell lymphoma (PMBL) is a distinct clinicopathologic subtype of diffuse large B-cell lymphoma (DLBCL). The optimal management of PMBL remains controversial. While R-CHOP with or without radiation therapy (RT) is established as a potentially curative regimen in this setting, there have been concerns about a subgroup of PMBL patients (pts) who are refractory to R-CHOP (Soumerai et al, Leuk Lymphoma, 2013). Efforts to improve outcomes led to the use of aggressive chemotherapy regimens such as dose-adjusted R-EPOCH despite the lack of a randomized trial demonstrating benefit (Dunleavy et al, N Engl J Med., 2013). Identifying early predictors of R-CHOP treatment failure may inform risk-adapted treatment strategies in PMBL. 18F-fluorodeoxyglucose-positron-emission tomography fused with CT (PET-CT) has been used as a predictor of treatment failure in Hodgkin lymphoma and DLBCL, but the role in PMBL has not been well described. MethodsWe conducted a retrospective analysis using our institutional database of PMBL pts treated with R-CHOP with or without RT. Overall survival (OS) and progression-free survival (PFS) for the entire cohort and for those with positive versus negative interim and post-treatment PET-CT were calculated by Kaplan Meier method (STATA version 12). PET-CT scans were graded as positive or negative based on the consensus criteria from the International Harmonization Project (IHP) (Juweid et al, J Clin Oncol, 2007). We also determined positive predictive value (PPV) and negative predictive value (NPV) for interim and post-treatment PET-CTs. ResultsWe identified 26 pts with PMBL treated with R-CHOP at our institution between 11/2001 and 5/2013. The median age at diagnosis was 36 years (range 18-57 years). Eight pts had stage I, 15 had stage II, 0 had stage III and 3 had stage IV PMBL. At diagnosis, IPI was low-risk in 21, low-intermediate in 2 and high-intermediate in 3 pts. LDH level was elevated in 18 pts (69%). Thirteen pts (50%) had bulky disease (> 10 cm). After R-CHOP, 19 pts (73%) underwent consolidative RT. At a median follow-up of 35.7 months, median OS was 94.7% (95%CI: 68.1-99.2%) and PFS was 75.3% (95%CI: 52.9-88.1%) for the entire cohort. The PFS and OS at 1 year was 75.3% and 100%, respectively. Six pts (23%) had progressive disease (PD): 5 progressed during or immediately following treatment with R-CHOP (prior to RT). Four pts with PD underwent high dose chemotherapy and autologous stem cell transplantation (ASCT) and all achieved complete response (CR). Only 1 of 26 pts died of progressive PMBL. Two patients required steroids for radiation pneumonitis which resolved.Twenty-two pts (85%) underwent an interim PET-CT following 2 cycles of R-CHOP (N=12), 4 cycles of R-CHOP (N=20) or at both time points (N=10). The PFS at 1 year for pts who had a positive interim PET-CT after either cycle 2 or cycle 4 (N=17) versus pts who had negative interim PET-CT (N=5) was 68.9% vs. 100%, respectively. The NPV of interim PET-CT was 100%, but the PPV was low at 43%. Fifteen pts (58%) underwent a PET-CT at the completion of therapy. Nine (60%) had a negative scan and did not relapse. Six (40%) had a positive scan at the completion of therapy: 3 pts with PD were treated with salvage therapy, one underwent a biopsy that was negative and has not relapsed, and 2 underwent sequential PET-CT scans until resolution of the abnormality. The PFS at 1 year for pts who had a positive post-treatment PET-CT (N=6) versus pts who had a negative post-treatment PET-CT (N=9) was 50% vs. 100% respectively. The NPV for a post-treatment PET-CT was 100% and the PPV was 50%. ConclusionIn our cohort, pts with PMBL had excellent outcomes using R-CHOP with or without RT. Those who failed primary therapy were salvaged with ASCT. There were no relapses after 6 months of completing primary therapy. Negative interim or negative post-treatment PET-CT identified patients who achieve long term remission. However, positive PET-CT in this setting is of limited clinical value in predicting treatment failure. Distinctive characteristics of this DLBCL subtype, including bulky presentation, localization to mediastinum, and necrosis, probably contribute to the high false positive rate, limiting the utility of IHP criteria. We are actively studying other factors (pathological, clinical, and radiographic) which would allow early prediction of therapeutic outcome and the ability to tailor first line therapy for PMBL. Disclosures:No relevant conflicts of interest to declare.

Gene expression profiles for the prediction of progression-free survival in diffuse large B cell lymphoma: results of a DASL assay

We performed the whole genome cDNA-mediated annealing, selection and ligation assay with 164 formalin-fixed paraffin-embedded (FFPE) tumor samples to develop robust prognostic gene expression profiles in patients with diffuse large B cell lymphoma. The prognostic gene expression profiles were developed and validated by a gradient lasso and leave-one-out cross-validation process. We identified a set of genes whose expression provided prognostic indicators from whole data set (PRKCDBP, CASP10, FAM3C, KCNK12, MAN1A2, PRND, RAB1A, TMEM39B, SLC6A6, MMP12, FEM1B, C3orh37, RBP1, HK1, LOC400464, KIAA0746, and SLC25A23). This gene expression profile-based risk model could classify patients into two cross-validated risk groups with a significant difference in 5-year progression-free survival rates (71.1 vs. 45.5 %) and with a hazard ratio for recurrence of 2.45 (95 % CI, 1.44-4.16, P = 0.001). This model provided prognostic information independent of the International Prognostic Index (IPI), and discriminated high-risk group from patients belong to high/high-intermediate risk of IPI and activated B cell-like type. Thus, gene expression profiling from FFPE could provide additional prognostic information for diffuse large B cell lymphoma and our data underscore the need for development of risk-adapted treatment strategies based on gene expression profiles.