Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue.

BACKGROUND: Minimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing-based assay of immunoglobulin gene rearrangements for MRD assessment. PATIENTS AND METHODS: In a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. RESULTS: Of the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. CONCLUSION: The next-generation sequencing-based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma.

BACKGROUND: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study. PATIENTS AND METHODS: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression. RESULTS: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia). CONCLUSIONS: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01393106.

Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma.

BACKGROUND: Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT. METHODS: In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II). RESULTS: In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [

A case report of concurrent embryonal rhabdomyosarcoma and diffuse large B-cell lymphoma in an adult without identifiable cancer predisposition.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. Rhabdomyosarcoma, the most common soft tissue sarcoma of childhood. makes up less than 1% of solid malignancies in adults with around 400 new cases each year in the United States. They have not previously been reported concurrently. CASE PRESENTATION: A 37 year old woman presented with painful enlarging leg mass. Biopsy of the mass was consistent with embryonal rhabdomyosarcoma. Staging imaging revealed a PET avid anterior mediastinal lymph node. Excisional biopsy of this mass was consistent with diffuse large B-cell lymphoma. Hybridization capture-based next-generation DNA sequencing did not reveal shared somatic tumor mutations. Germline analysis did not show identifiable aberrations of TP53 or other heritable cancer susceptibility genes. She was treated with a personalized chemotherapy regimen combining features of R-CHOP and Children's Oncology Group ARST 0331. CONCLUSIONS: This case illustrates a unique clinical entity successfully treated with a personalized chemotherapeutic regimen.

Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study.

In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.

Comparison of CT volumetric measurement with RECIST response in patients with lung cancer.

PURPOSE: To examine the correlations between uni-dimensional RECIST and volumetric measurements in patients with lung adenocarcinoma and to assess their association with overall survival (OS) and progression-free survival (PFS). MATERIALS AND METHODS: In this study of patients receiving chemotherapy for lung cancer in the setting of a clinical trial, response was prospectively evaluated using RECIST 1.0. Retrospectively, volumetric measurements were recorded and response was assessed by two different volumetric methods at each followup CT scan using a semi-automated segmentation algorithm. We subsequently evaluated the correlation between the uni-dimensional RECIST measurements and the volumetric measurements and performed landmark analyses for OS and PFS at the completion of the first and second follow-ups. Kaplan-Meier curves together with log-rank tests were used to evaluate the association between the different response criteria and patient outcome. RESULTS: Forty-two patients had CT scans at baseline, after the first follow up scan and second followup scan, and then every 8 weeks. The uni-dimensional RECIST measurements and volumetric measurements were strongly correlated, with a Spearman correlation coefficient (ρ) of 0.853 at baseline, ρ=0.861 at the first followup, ρ=0.843 at the 2nd followup, and ρ=0.887 overall between-subject. On first follow-up CT, partial responders and non responders as assessed by an "ellipsoid" volumetric criteria showed a significant difference in OS (p=0.008, 1-year OS of 70% for partial responders and 46% for non responders). There was no difference between the groups when assessed by RECIST criteria on first follow-up CT (p=0.841, 1-year OS rate of 64% for partial responders and 64% for non responders). CONCLUSION: Volumetric response on first follow-up CT may better predict OS than RECIST response. CLINICAL RELEVANCE STATEMENT: Assessment of tumor size and response is of utmost importance in clinical trials. Volumetric measurements may help to better predict OS than uni-dimensional RECIST criteria.

Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study.

Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line treatment for relapsed and refractory diffuse large B-cell lymphoma (DLBCL). However, the strategy is less clear in patients who require third-line treatment. Updated outcomes of 203 patients who could not proceed to scheduled ASCT in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) are herein reviewed. In the intent-to-treat analysis, overall response rate to third-line chemotherapy was 39%, with 27% CR or CR unconfirmed, and 12% PR. Among the 203 patients, 64 (31.5%) were eventually transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS) of the entire population was 4.4 months. OS was significantly improved in patients with lower tertiary International Prognostic Index (IPI), patients responding to third-line treatment and patients transplanted with a 1-year OS of 41.6% compared with 16.3% for the not transplanted (P<0.0001). In multivariate analysis, IPI at relapse (hazard ratio (HR) 2.409) and transplantation (HR 0.375) independently predicted OS. Third-line salvage chemotherapy can lead to response followed by transplantation and long-term survival in DLBCL patients. However, improvement of salvage efficacy is an urgent need with new drugs.

Updated prostate imaging reporting and data system (PIRADS v2) recommendations for the detection of clinically significant prostate cancer using multiparametric MRI: critical evaluation using whole-mount pathology as standard of reference.

OBJECTIVES: To evaluate the recommendations for multiparametric prostate MRI (mp-MRI) interpretation introduced in the recently updated Prostate Imaging Reporting and Data System version 2 (PI-RADSv2), and investigate the impact of pathologic tumour volume on prostate cancer (PCa) detectability on mpMRI. METHODS: This was an institutional review board (IRB)-approved, retrospective study of 150 PCa patients who underwent mp-MRI before prostatectomy; 169 tumours ≥0.5-mL (any Gleason Score [GS]) and 37 tumours <0.5-mL (GS ≥4+3) identified on whole-mount pathology maps were located on mp-MRI consisting of T2-weighted imaging (T2WI), diffusion-weighted (DW)-MRI, and dynamic contrast-enhanced (DCE)-MRI. Corresponding PI-RADSv2 scores were assigned on each sequence and combined as recommended by PI-RADSv2. We calculated the proportion of PCa foci on whole-mount pathology correctly identified with PI-RADSv2 (dichotomized scores 1-3 vs. 4-5), stratified by pathologic tumour volume. RESULTS: PI-RADSv2 allowed correct identification of 118/125 (94 %; 95 %CI: 90-99 %) peripheral zone (PZ) and 42/44 (95 %; 95 %CI: 89-100 %) transition zone (TZ) tumours ≥0.5 mL, but only 7/27 (26 %; 95 %CI: 10-42 %) PZ and 2/10 (20 %; 95 %CI: 0-52 %) TZ tumours with a GS ≥4+3, but <0.5 mL. DCE-MRI aided detection of 4/125 PZ tumours ≥0.5 mL and 0/27 PZ tumours <0.5 mL. CONCLUSIONS: PI-RADSv2 correctly identified 94-95 % of PCa foci ≥0.5 mL, but was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL. DCE-MRI offered limited added value to T2WI+DW-MRI. KEY POINTS: • PI-RADSv2 correctly identified 95 % of PCa foci ≥0.5 mL • PI-RADSv2 was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL • DCE-MRI offered limited added value to T2WI+DW-MRI.

The CT20 peptide causes detachment and death of metastatic breast cancer cells by promoting mitochondrial aggregation and cytoskeletal disruption.

Metastasis accounts for most deaths from breast cancer, driving the need for new therapeutics that can impede disease progression. Rationally designed peptides that take advantage of cancer-specific differences in cellular physiology are an emerging technology that offer promise as a treatment for metastatic breast cancer. We developed CT20p, a hydrophobic peptide based on the C terminus of Bax that exhibits similarities with antimicrobial peptides, and previously reported that CT20p has unique cytotoxic actions independent of full-length Bax. In this study, we identified the intracellular actions of CT20p which precede cancer cell-specific detachment and death. Previously, we found that CT20p migrated in the heavy membrane fractions of cancer cell lysates. Here, using MDA-MB-231 breast cancer cells, we demonstrated that CT20p localizes to the mitochondria, leading to fusion-like aggregation and mitochondrial membrane hyperpolarization. As a result, the distribution and movement of mitochondria in CT20p-treated MDA-MB-231 cells was markedly impaired, particularly in cell protrusions. In contrast, CT20p did not associate with the mitochondria of normal breast epithelial MCF-10A cells, causing little change in the mitochondrial membrane potential, morphology or localization. In MDA-MB-231 cells, CT20p triggered cell detachment that was preceded by decreased levels of α5ß1 integrins and reduced F-actin polymerization. Using folate-targeted nanoparticles to encapsulate and deliver CT20p to murine tumors, we achieved significant tumor regression within days of peptide treatment. These results suggest that CT20p has application in the treatment of metastatic disease as a cancer-specific therapeutic peptide that perturbs mitochondrial morphology and movement ultimately culminating in disruption of the actin cytoskeleton, cell detachment, and loss of cell viability.

Diagnostic accuracy of ¹8F-FDG PET/CT for detection of advanced colorectal adenoma.

AIM: To determine the accuracy of 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) in the detection of advanced colorectal adenomas. MATERIALS AND METHODS: In this retrospective study, patient consent was waived by the institutional review board. Combined FDG whole-body PET and computed tomography (CT) images (2000-2009) were re-read and compared with reports of complete colonoscopy performed up to 1 year after the PET examination. One or more areas of focal colonic uptake greater than the background indicated a positive PET result, irrespective of standardized uptake value (SUV). Lesion and patient-level measures of PET accuracy with their 95% confidence intervals (CI) were calculated. RESULTS: One hundred and eighty patients undergoing colonoscopy with or without biopsy underwent PET within 1 year prior to colonoscopy. There were 92 women and 88 men (mean age 63.3 years). Indications for PET were extent of disease and treatment response in all cases. Patients had non-colorectal cancer (n = 160) or colon cancer (n = 20). One hundred and fourteen FDG-avid lesions were present. In 33, there was no colonoscopic correlate. Two hundred and fifty-eight biopsies revealed tubular adenomas (n = 91, one with intra-mucosal cancer), tubulovillous adenomas (n = 28), adenocarcinoma (n = 37), inflammation (n = 22), hyperplastic polyps (n = 54), serrated adenoma (n = 5), metastatic disease (n = 5), normal/benign mucosa or submucosal benign tumors (n = 13) or miscellaneous (n = 3). Per-lesion performance of PET showed a sensitivity of 38% (95% CI: 31-46; 64/167) for all adenomas and carcinomas and 58% (95% CI: 49-67; 57/98) for lesions ≥ 10 mm. At the patient level, for all adenomas and carcinomas the sensitivity was 54% (95% CI: 44-63; 61/113), specificity 100% (pre-defined), positive predictive value (PPV) 100% (pre-defined), and negative predictive value (NPV) 56% (95% CI: 47-65; 67/119). For patients with advanced adenoma, PET sensitivity was 49% (95% CI: 35-63; 26/53) specificity, 100%, PPV 100% and NPV 82% (95% CI: 76-88; 127/154). Five of 37 adenocarcinomas were not detected, one of which was mucinous at histology. CONCLUSION: FDG PET detected most cancers, but only identified one-half of patients harbouring advanced adenomas. Based on the data, PET cannot be relied upon to accurately identify patients with advanced adenoma.

Reproducibility and clinical correlations of post-treatment changes on CT of prostate cancer bone metastases treated with chemotherapy.

OBJECTIVES: The objective of this study was to determine whether, in patients with prostate cancer (PCa) bone metastases receiving chemotherapy, early post-treatment changes on CT are reproducible and associated with clinical outcomes. METHODS: Blinded to outcomes, two radiologists with 1 year and 5 years of experience independently reviewed CTs obtained before and 3 months after chemotherapy initiation in 38 patients with bone metastases from castration-resistant PCa, recording the size, matrix and attenuation of ≤5 lesions; presence of new lesions, extraosseous components, periosteal reactions and cortical thickening; and overall CT assessment (improved, no change or worse). Kappa statistics were used to assess inter-reader agreement; the Kruskal-Wallis test and Cox regression model were used to evaluate associations. RESULTS: Inter-reader agreement was low/fair for size change (concordance correlation coefficient=0.013), overall assessment and extraosseous involvement (κ=0.3), moderate for periosteal reaction and cortical thickening (κ=0.4-0.5), and substantial for CT attenuation (κ=0.7). Most metastases were blastic (Reader 1, 58%; Reader 2, 67%) or mixed lytic-blastic (Reader 1, 42%; Reader 2, 34%). No individual CT features correlated with survival. Readers 1 and 2 called the disease improved in 26% and 5% of patients, unchanged in 11% and 21%, and worse in 63% and 74%, respectively, with 64% interreader agreement. Overall CT assessment did not correlate with percentage change in prostate-specific antigen level. For the more experienced reader (Reader 2), patients with improved or unchanged disease had significantly longer median survival (p=0.036). CONCLUSIONS: In PCa bone metastases, interreader agreement is low in overall CT post-treatment assessment and varies widely for individual CT features. Improved or stable disease identified by an experienced reader is statistically associated with longer survival.

Prognostic significance of adrenal gland morphology at CT in patients with three common malignancies.

OBJECTIVES: To determine whether minor alterations in adrenal gland morphology at baseline CT in three common cancers indicate early metastasis. METHODS: 689 patients (237 with lung cancer, 228 with breast cancer, 224 with melanoma) underwent baseline and follow-up CTs that included the adrenals. Two readers independently scored each adrenal at baseline CT as normal, smoothly enlarged, nodular or mass-containing. Adrenals containing a mass >10 mm were excluded. The appearance of each adrenal on the latest available CT was assessed for change since baseline. Cox models were used to assess the association between adrenal morphology at initial CT and subsequent development of adrenal metastasis (defined as new mass >10 mm, corroborated by follow-up imaging). κ statistics were calculated to assess inter-reader agreement. RESULTS: Initial and follow-up CT evaluations were recorded for 1317 adrenals (median follow-up, 18.6 months). At initial CT, Readers 1 and 2 interpreted 1242 and 1230 adrenals as normal, 40 and 57 as smoothly enlarged, 29 and 25 as nodular, and 6 and 5 as containing masses ≤ 10 mm, respectively. κ-values were 0.52 (moderate) at initial CT and 0.70 (substantial) at follow-up. The hazard ratio for developing a metastasis at follow-up CT given an abnormal adrenal assessment at baseline was 0.7 [95% confidence interval (CI) 0.2-2.1; p = 0.47] for Reader 1, and 2.0 (95% CI 0.8-4.7; p = 0.12) for Reader 2. CONCLUSION: Minor morphological abnormalities of adrenals at initial CT did not represent early adrenal metastasis in most patients in this population.

Clinical vignettes in Parkinson's disease: a collection of unusual medication-induced hallucinations, delusions, and compulsive behaviours.

Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD.

Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience.

BACKGROUND: The Stanford group has reported excellent results with the Stanford V regimen for patients with bulky and/or advanced Hodgkin lymphoma (HL). However, Gobbi reported markedly inferior failure-free survival (FFS) comparing Stanford V to other regimens but included major deviations from the original program. We retrospectively examined whether treatment at our institution carefully following Stanford V guidelines would confirm the original Stanford outcome data. PATIENTS AND METHODS: From June 1995 to May 2002, 126 patients with either locally extensive or advanced HL were treated with the 12-week Stanford V chemotherapy program followed by 36-Gy involved-field radiotherapy to sites initially > or =5 cm and/or to macroscopic splenic disease. Overall, 26% had stage IV disease and 20% had international prognostic score (IPS) > or =4. Overall survival (OS), disease-specific survival, progression-free survival (PFS), FFS, and freedom from second relapse (FF2R) were determined. RESULTS: The 5- and 7-year OS were 90% and 88%, respectively. The 5-year FFS was 78%. IPS > or =4 was a significant independent predictor of worse OS and PFS. The FF2R was 64% at 3 years. CONCLUSION: Stanford V with appropriate radiotherapy is a highly effective regimen for locally extensive and advanced HL.

Prognostic impact of proliferative index determined by quantitative image analysis and the International Prognostic Index in patients with mantle cell lymphoma.

BACKGROUND: The proliferative index (PI) is a powerful prognostic factor in mantle cell lymphoma (MCL); however, its utility is hampered by interobserver variability. The mantle cell international prognostic index (MIPI) has been reported to have prognostic importance. In this study, we determined the prognostic value of the PI as determined by quantitative image analysis in MCL. PATIENTS AND METHODS: Eighty-eight patients with adequate tissue were included in this analysis. Patients were treated with one of two treatment programs: sequential therapy with high-dose therapy consolidation or radioimmunotherapy followed by combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone. Patients were divided into four groups based on PI (<10%, 10%-29.9%, 30%-49.9%, and >50%), and outcomes were analyzed. RESULTS: Thirty percent was identified as the optimal cut-off for PI. By univariate analysis, intensive treatment and a low PI were associated with a superior progression-free survival (PFS); only PI was associated with overall survival. By multivariate analysis, both intensive treatment and PI correlated with PFS. The MIPI had no prognostic impact. CONCLUSIONS: PI is the most important prognostic factor in MCL. The cut-off of 30% is clinically meaningful and can be used to tailor the intensity of therapy in future clinical trials.

Barriers to mental health service use among hematopoietic SCT survivors.

This study examined barriers to mental health service use and the demographic, medical and psychosocial correlates of these barriers among hematopoietic SCT (HSCT) survivors. A sample of 253 HSCT survivors who were 1 to 3 years posttransplant completed measures of demographic, physical, psychological and social characteristics as well as a newly modified measure of barriers to mental health service use. Only 50% of distressed HSCT survivors had received mental health services. An exploratory factor analysis of the barriers to mental health service use scale yielded four factors: scheduling barriers, knowledge barriers, emotional barriers and illness-related barriers. Patients with higher social constraints (perceived problems discussing the illness experience with significant others) reported higher levels of all four types of barriers. General distress and transplant-related posttraumatic stress symptoms were positively associated with emotional, knowledge and illness-related barriers to mental health service use, whereas physical and functional well-being were inversely associated with these barriers. Having more knowledge barriers and more emotional barriers predicted a lower likelihood of receiving mental health services, as did lower levels of education and general distress. Results suggest that a significant number of HSCT survivors may benefit from education about mental health services that is tailored to individual barriers.

The role of FDG-PET imaging and involved field radiotherapy in relapsed or refractory diffuse large B-cell lymphoma.

We examined the role of fluorodeoxyglucose-positron emission tomography (FDG-PET) and the addition of involved field radiotherapy (IFRT) as potential modifiers of salvage therapy. From January 2000 to June 2007, 83 patients with chemosensitive relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) underwent FDG-PET scans following second-line chemotherapy before high-dose therapy with autologous stem cell rescue (HDT/ASCR). We evaluated the prognostic value of having a negative FDG-PET scan before HDT/ASCR and whether IFRT improved the outcomes. Median follow-up was 45 months, and the 3-year PFS, disease-specific survival (DSS) and OS were 72, 80 and 78%, respectively. Multivariate analysis revealed that a positive FDG-PET scan had worse PFS (hazard ratio=(HR) 3.4; P=0.014), DSS (HR=7.7; P=0.001) and OS (HR=5.4; P=0.001), and that patients not receiving IFRT had worse PFS (HR=2.7; P=0.03) and DSS (HR=2.8, P=0.059). Patients who received IFRT had better local control with fewer relapses within prior involved sites compared with those that did not receive IFRT (P=0.006). These outcomes confirm the important prognostic value of FDG-PET scans before undergoing HDT/ASCR. It also suggests that the role of IFRT should be evaluated further.

Maintaining the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin lymphoma.

INTRODUCTION: HDT/ASCT is standard for relapsed and refractory DLCL patients responding to second-line chemotherapy. We incorporated a thrombopoietic agent into the ICE chemotherapy program to potentially: decrease platelet associated toxicities, augment stem cell collection and maintain dose intensity. METHODS: This randomized, double-blind, placebo-controlled phase I/II trial examines PEG-rHuMGDF versus placebo with ICE chemotherapy. Phase I compared three cohorts and defined a clinically effective dose (CED). Phase II evaluated the CED versus placebo. Outcome measures included safety, hematological end-points, stem cell collection and the impact of dose-intensity on outcome. RESULTS: Forty-one patients with primary refractory (16) or relapsed DLCL (25) were treated; Response rates for evaluable patients are: 75% (12/16) for placebo and 82% (18/22) for PEG-rHuMGDF. PEG-rHuMGDF treated patients had significantly less grade IV thrombocytopenia, higher median platelet nadirs, and less platelet transfusion per cycle. ICE dose intensity was improved with PEG-rHuMGDF versus placebo: 75 versus 42% (P = 0.008). At 8.5 years median follow-up, overall and event-free survival are 47 and 31%, respectively. Patients treated on PEG-rHuMGDF versus placebo had improved survival (59 versus 31%, P = 0.06). CONCLUSION: PEG-rHuMGDF ameliorated thrombocytopenia, improved platelet recovery, and maintained ICE dose intensity. Potential survival advantages conferred by maintaining dose intensity require validation with newer thrombopoietic agents.

Pretreatment prognostic factors and outcome in patients with relapsed or primary-refractory diffuse large B-cell lymphoma treated with second-line chemotherapy and autologous stem cell transplantation.

The age-adjusted International Prognostic Index assessed before salvage therapy with ICE (ifosfamide, carboplatin, etoposide) predicts outcome in patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL). Patients can be stratified according to this index into favorable and unfavorable cohorts. Subsequently we attempted to determine if the cell of origin as determined by immunohistochemistry would predict outcome, as it had in the first-line setting. However, none of the molecular markers, which are prognostic in first-line therapy, nor immunohistochemical classification by cell of origin, relate to survival outcome of DLBCL patients in the second-line setting, implying that dose intensification of therapy can overcome the prognostic import of these unfavourable risk factors.

Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population.

BACKGROUND: Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment. PATIENTS AND METHODS: One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms. RESULTS: Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13). CONCLUSION: These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.