ALK-negative anaplastic large cell lymphoma: features and outcomes of 235 patients from the International T-Cell Project.

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK- ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P = .05) but not PFS (P = .18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK- ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.

FDG-PET/CT after two cycles of R-CHOP in DLBCL predicts complete remission but has limited value in identifying patients with poor outcome - final result of a UK National Cancer Research Institute prospective study.

The UK National Cancer Research Institute initiated a prospective study (UKCRN-ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in diffuse large B-cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post-cycle-2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end-of-treatment CT, progression-free (PFS) and overall survival (OS) was explored. The end-of-treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUVmax ) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow-up, the 5-year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1-5 (P = 0·01); and 72·6% and 57·1% by ∆SUVmax of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1-3) at interim PET/CT after two cycles of R-CHOP in DLBCL was associated with a higher end-of-treatment complete and overall response rate; however, only DS-5 patients had inferior PFS and OS.

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma.

PURPOSE: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. PATIENTS AND METHODS: Patients received continuous, once-daily oral TAK-659, 60-120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. RESULTS: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (T max ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). CONCLUSIONS: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study.

UNLABELLED: We report a phase II study to evaluate the efficacy and toxicity of abbreviated immunochemotherapy followed by (90) Y Ibritumomab tiuxetan ((90) Y-IT) in patients with recurrent follicular lymphoma. Of the 52 patients enrolled, 50 were treated with three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone), followed by (90) Y-IT regimen (15 MBq/kg, maximum 1200 MBq) preceded by two infusions of 250 mg/m(2) rituximab. The overall response rate was 98% with complete response (CR) 30% and partial response (PR) 68%. 18 patients with a PR following chemotherapy improved to a CR following (90) Y-IT: a conversion rate of 40%. Seven patients with PR following (90) Y-IT subsequently improved to a CR 12-18 months later, leading to an overall CR rate of 44%. With a median follow-up of 5 years, median progression-free survival was 23·1 months and overall survival was 77·5% at 5 years. High trough serum rituximab levels (median 112 µg/ml; range 52-241) were attained after four doses of rituximab, prior to (90) Y-IT; this was not found to influence response rates. The treatment was well tolerated with few (13·5%) grade 3 or 4 infective episodes and manageable haematological toxicity. Abbreviated immunochemotherapy followed by (90) Y-IT is an effective and well-tolerated treatment in recurrent follicular lymphoma patients previously exposed to rituximab. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00637832.

QuantiGene Plex Represents a Promising Diagnostic Tool for Cell-of-Origin Subtyping of Diffuse Large B-Cell Lymphoma.

Emerging therapies targeting the molecularly distinct GCB and non-GCB/ABC subtypes of diffuse large B-cell lymphoma (DLBCL) have created the need to develop an accurate subtyping assay for routine use. We investigated the potential of QuantiGene Plex (QGP)-branched DNA signal amplification assay-for DLBCL subtyping. We performed in silico analysis of public DLBCL datasets to develop and validate a naïve Bayes classifier, and migrated the resulting 21-gene classifier to QGP and real-time quantitative PCR (qPCR) assays. Forty DLBCL formalin-fixed, paraffin-embedded tumors of known subtype (20 per subtype by gene expression profiling of paired fresh-frozen tissues) were reclassified, and results for QGP (on 38/40 for 21/21 targets) and qPCR (on 40/40 samples for 19/21 targets) compared for recapitulation of microarray data and classification accuracy. The 21-gene bayesian classifier achieved mean area under the curve values >0.9 on independent validation. QGP showed a higher correlation with microarray data (mean R(2) = 0.66 ± 0.05 versus 0.34 ± 0.07; P < 0.0001) and classification accuracy (92.1% versus 78.9%). The proportion of validated targets was also higher for QGP (85.7% versus 47.4%). The QGP protocol was rapid and simple to perform, at a cost similar to qPCR. These promising preliminary results strongly support ongoing work to develop a QGP companion diagnostic assay for DLBCL subtyping.

Fractionated 9°Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria.

PURPOSE: We report an international, multicenter phase II trial to evaluate the efficacy and toxicity of fractionated (90)Y-ibritumomab tiuxetan ((90)Y-IT) as initial therapy of follicular lymphoma (FL). PATIENTS AND METHODS: A total of 74 patients, with a median age of 61 years (range, 28 to 80 years), were recruited requiring initial therapy by Groupe d'Etude des Lymphomes Folliculaires (GELF)/British National Lymphoma Investigation (BNLI) criteria. Among them, 78% had stage III-IV disease, 32% intermediate, and 44% high-risk (according to FL International Prognostic Index). Treatment consisted of two doses of (90)Y-IT (11.1 MBq/kg) administered 8 to 12 weeks apart. Patients with more than 20% lymphoma infiltration of bone marrow (BM) received one infusion per week for 4 consecutive weeks of rituximab (375 mg/m(2)) and proceeded to fractionated radioimmunotherapy (RIT) only if a repeat BM biopsy demonstrated clearing of lymphoma to less than 20% involvement. The primary end point was end of treatment response of the intention-to-treat population. Secondary objectives were safety and progression-free survival (PFS). RESULTS: Initial overall response rate (ORR) was 94.4% (68 of 72 patients) with combined complete response (CR/CRu) of 58.3% (42 of 72 patients). Nine patients subsequently improved response making an ORR of 95.8% (69 of 72 patients) and CR/CRu of 69.4% (50 of 72 patients). At a median follow-up of 3.1 years (range, 0.2 to 5.2 years) estimated 3-year PFS is 58%, treatment-free survival 66%, and overall survival 95%. Median PFS is 40.2 months. Thirty patients have experienced disease progression and 24 have required further treatment. The treatment was well tolerated with few (2.8%) grade 3 or 4 infectious episodes or adverse events and manageable hematologic toxicity. CONCLUSION: Fractionated RIT using (90)Y-IT is an effective initial treatment for advanced-stage FL in patients with higher tumor burden requiring treatment.

PLK1 and YY1 interaction in follicular lymphoma is associated with unfavourable outcome.

AIMS: Ying Yang 1 (YY1) is a transcription factor involved in both proliferation and apoptosis. It is prognostic in follicular lymphoma (FL), increased protein levels being associated with favourable outcome. PLK1 is a critical regulator of mitosis, playing a role in spindle formation and in regulation of the G2/M cell cycle checkpoint. PLK1 phosphorylates YY1 at the G2/M checkpoint with activation of YY1 and resultant progression from G2 into mitosis. METHODS: This study aims to investigate possible molecular coexpression and interaction of YY1 with PLK1 in FL using Duolink II in situ proximity ligation assay (PLA) in 51 FL samples in a tissue microarray. RESULTS: Positive PLA signals were present at variable frequency and Kaplan-Meier analysis showed association of signal frequency above the median with unfavourable outcome (p=0.0270). PLA signals were localised to the nuclear edge, with only one signal per cell, suggesting PLK1 and YY1 coexpression at the centrosome. In a minority of cells, two very close PLA signals were present in a single cell, and occasionally, there was a strong ring of semi-confluent fluorescent PLA signals round the nucleus of non-dividing cells, while rarely events were observed in the cytoplasm surrounding dividing cells. CONCLUSIONS: The results confirm association of YY1 and PLK1 with outcome in FL and suggest coexpression at the centrosome. Given the reported interaction of YY1 with PLK1 at the centriole and promotion of cell division at the G2/M checkpoint, the results would concord with the known association of higher proliferation with poor outcome in FL.

A statistical framework for analyzing hypothesized interactions between cells imaged using multispectral microscopy and multiple immunohistochemical markers.

BACKGROUND: Multispectral microscopy and multiple staining can be used to identify cells with distinct immunohistochemical (IHC) characteristics. We present here a method called hypothesized interaction distribution (HID) analysis for characterizing the statistical distribution of pair-wise spatial relationships between cells with particular IHC characteristics and apply it to clinical data. MATERIALS AND METHODS: We retrospectively analyzed data from a study of 26 follicular lymphoma patients in which sections were stained for CD20 and YY1. HID analysis, using leave-one-out validation, was used to assign patients to one of two groups. We tested the null hypothesis of no difference in Kaplan-Meier survival curves between the groups. RESULTS: Shannon entropy of HIDs assigned patients to groups that had significantly different survival curves (median survival was 7.70 versus 110 months, P = 0.00750). Hypothesized interactions between pairs of cells positive for both CD20 and YY1 were associated with poor survival. CONCLUSIONS: HID analysis provides quantitative inferences about possible interactions between spatially proximal cells with particular IHC characteristics. In follicular lymphoma, HID analysis was able to distinguish between patients with poor versus good survival, and it may have diagnostic and prognostic utility in this and other diseases.

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.

BACKGROUND: Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. METHODS: Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1·4 mg/m(2) (maximum dose 2 mg), and rituximab 375 mg/m(2) on day 1, and oral prednisolone 40 mg/m(2) on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 2 mg, rituximab 375 mg/m(2) on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m(2) on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISRCTN 16017947. FINDINGS: 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. INTERPRETATION: R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study. FUNDING: Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.

Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences.

We present data from a phase II study investigating a novel treatment strategy for relapsed/refractory mantle cell lymphoma (MCL). Twenty-six patients received lenalidomide 25 mg/d (days 1-21 of a 28-d cycle) for up to 6 cycles followed by low-dose maintenance lenalidomide (15 mg) in responding patients. Eight patients achieved complete or partial response to give an overall response rate of 31% with median response duration of 22·2 months [95% confidence interval (CI) 0·0-53·6] and median progression-free survival (PFS) of 3·9 months (95% CI 0·0-11·1). An additional six patients (23%) achieved stable disease. Eleven patients received maintenance with median PFS of 14·6 months (95% CI 7·3-21·9). Correlative studies showed that peripheral T and Natural Killer (NK) cells increased in responding patients by 40-60% over the first 6 cycles with an initial dip in NK cells suggestive of tumour infiltration. Peripheral regulatory T cells were increased in MCL patients (P = 0·001) and expanded further following lenalidomide. Sequential plasma analysis showed increased IL12 p40 and IL7 alongside decreased MMP9, IL10, and adiponectin. Finally, a significant correlation (P = 0·02) between gender and response suggested that female MCL patients were more sensitive to lenalidomide than males. In summary, we confirm the activity, safety and immunomodulatory properties of lenalidomide in MCL and highlight its potential as a low-dose maintenance agent.

Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study.

PURPOSE: To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. PATIENTS AND METHODS: Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. RESULTS: Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age ≥ 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving ≥ 40 Gy mantle radiotherapy at young ages was 48%. CONCLUSION: This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages.

Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial.

PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. PATIENTS AND METHODS: Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. CONCLUSION: Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.

Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study.

PURPOSE: We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge. PATIENTS AND METHODS: We followed 5,798 patients with HL treated with chemotherapy in Britain from 1963 to 2001--of whom 3,432 also received radiotherapy--to assess second primary malignancy risks compared with general population-based expectations. RESULTS: Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% CI, 1.7 to 2.4) but was much lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia, each contributing approximately equal absolute excess risk. After combined modalities, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. Risk was raised after each common chemotherapy regimen except, based on limited numbers and follow-up, adriamycin, bleomycin, vinblastine, and dacarbazine. The age and time-course relations of lung cancer differed between chemotherapy alone and combined modalities. CONCLUSION: Although chemotherapy alone leads to raised risk of second malignancy, this risk is lower and affects fewer anatomic sites than that after combined modalities, and it is slight if at all after 15 years follow-up. The mechanism of lung cancer etiology may differ between chemotherapy and radiotherapy.

YY1 expression predicts favourable outcome in follicular lymphoma.

AIMS: Follicular lymphoma is the second most common type of non-Hodgkin's lymphoma worldwide. The majority of patients diagnosed as having follicular lymphoma have an indolent form of the disease, but a subset of patients have aggressive disease with a shorter survival interval. Optimal treatment stratification requires a distinction between these two groups, though there are presently few prognostic biomarkers available. The transcription factor YY1 has been shown to play an important role in cancer biology. The authors have previously reported a correlation of Yin Yang 1 (YY1) mRNA levels with survival in FL. This study aimed to validate these findings at the protein level. METHODS: Quantification of YY1 protein was carried out on 26 FL biopsy samples using quantum dot labelled immunohistochemistry. Ki-67 percentage, grade, YY1 protein levels and T cell and macrophage markers were used in a multivariable analysis for survival in 26 cases of FL. RESULTS: Expression levels of YY1 protein were significantly increased in patients alive in comparison with those dead after follow-up (p ≤ 0.025). Kaplan-Meier analysis showed association of higher expression levels of YY1 with longer survival (p ≤ 0.01) (hazard ratio 3.33, 95% CI 1.26 to 8.85). The multivariable analysis identified YY1 protein level as the strongest predictor of outcome (p ≤ 0.018), with none of the other markers being significantly associated with outcome. CONCLUSION: These results support the prognostic utility of YY1 in FL, indicating potential as a clinical biomarker.

Consolidation radiotherapy in patients with advanced Hodgkin's lymphoma: survival data from the UKLG LY09 randomized controlled trial (ISRCTN97144519).

PURPOSE: This study analyzed the outcomes of nonrandomized consolidation radiotherapy (RT) given after chemotherapy in the initial treatment of advanced Hodgkin's lymphoma (HL). The results were collected prospectively within a randomized controlled trial of induction chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned between doxorubicin, bleomycin, vinblastine, and dacarbazine and one of two prespecified multidrug regimens. At least six cycles of chemotherapy were planned, with up to eight for patients showing slower response. Involved-field RT was recommended for incomplete response to chemotherapy or bulk disease at presentation. The primary outcome measure was progression-free survival (PFS), landmarked from the end of chemotherapy. RESULTS: Among 807 patients randomly assigned, 702 achieved objective response. Postchemotherapy RT for consolidation was reported in 300 (43%). With median follow-up of 6.9 years, 161 PFS events and 83 deaths were reported. Baseline characteristics showed more patients with bulk disease having RT (190 [63%] v 111 [28%]) and only partial response after chemotherapy (150 [50%] v 36 [9%]). Other baseline characteristics were similar. PFS was superior for patients having RT (hazard ratio [HR], 0.43; 95% CI, 0.30 to 0.60) with 5-year PFS 71% without RT, 86% with RT. A similar advantage was seen for overall survival (HR, 0.47; 95% CI, 0.29 to 0.77). There was no evidence of heterogeneity of treatment effect across subgroups. CONCLUSION: Patients who received consolidation RT apparently had better outcomes, consistently across all prognostic groups which persisted in multivariate analysis. This suggests that RT contributes significantly to the cure rate for advanced HL, although patient selection for combined modality treatment requires better definition in prospective trials.

A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial).

This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma (BL), applicable to routine practice, and to evaluate the efficacy of dose-modified (dm) CODOX-M/IVAC in patients diagnosed using these criteria. The study was open to patients with an aggressive B-cell lymphoma with an MKI67 fraction approaching 100%. Immunophenotype and fluorescent in situ hybridization (FISH) were used to separate BL from other aggressive B-cell lymphomas. BL was characterized by the presence of a cMYC rearrangement as a sole cytogenetic abnormality occurring in patients with a germinal center phenotype with absence of BCL-2 expression and abnormal TP53 expression. A total of 128 patients were eligible for the study, of whom 58 were considered to have BL and 70 to have diffuse large B-cell lymphoma (DLBCL). There were 110 clinically fit patients who received dmCODOX-M (methotrexate, dose 3 g/m(2)) with or without IVAC according to risk group. The 2-year progression-free survival was 64% (95% confidence interval [CI] 51%-77%) for BL, 55% (95% CI 42%-66%) for DLBCL, 85% (95% CI 73%-97%) for low risk, and 49% (95% CI 38%-60%) for high-risk patients. The observed differences in outcome and other clinical features validate the proposed diagnostic criteria. Compared with the previous trial LY06 with full-dose methotrexate (6.7 g/m(2)), there was a reduction in toxicity with comparable outcomes. This study was registered at www.clinicaltrials.gov as NCT00040690.

Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling.

Microarray gene expression profiling studies have demonstrated immune response gene signatures that appear predictive of outcome in follicular lymphoma (FL). However, measurement of these marker genes in routine practice remains difficult. We have therefore investigated the immune response in FL using real-time polymerase chain reaction (PCR) to measure expression levels of 35 candidate Indicator genes, selected from microarray studies, to polyA cDNAs prepared from 60 archived human frozen lymph nodes, in parallel with immunohistochemical analysis for CD3, CD4, CD7, CD8, CD10, CD20, CD21, and CD68. High levels of CCR1, a marker of monocyte activation, were associated with a shorter survival interval, and high levels of CD3 with better survival, while immunohistochemistry demonstrated association of high numbers of CD68(+) macrophages with a shorter survival interval and of high numbers of CD7(+) T cells with a longer survival interval. The results confirm the role of the host immune response in outcome in FL and identify CCR1 as a prognostic indicator and marker of an immune switch between macrophages and a T cell-dominant response. They demonstrate the utility of polyA DNA and real-time PCR for measurement of gene signatures and the applicability of using this type of "molecular block" in clinical practice.

Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study.

PURPOSE: Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. PATIENTS AND METHODS: This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. RESULTS: The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). CONCLUSION: Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.