Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary analysis of the Ro-CHOP phase III randomized controlled trial (ClinicalTrials.gov identifier: NCT01796002) established that romidepsin (Ro) plus cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) did not yield an increased efficacy compared with CHOP alone as first-line treatment of peripheral T-cell lymphoma. We report the planned final analysis 5 years after the last patient enrolled. With a median follow-up of 6 years, median progression-free survival (PFS) was 12.0 months compared with 10.2 months (hazard ratio [HR], 0.79 [95% CI, 0.62 to 1.005]; P = .054), while median overall survival was 62.2 months (35.7-86.6 months) and 43.8 months (30.1-70.2 months; HR, 0.88 [95% CI, 0.68 to 1.14]; P = .324) in the Ro-CHOP and CHOP arms, respectively. In an exploratory analysis, the median PFS in the centrally reviewed follicular helper T-cell lymphoma subgroup was significantly longer in the Ro-CHOP arm (19.5 v 10.6 months, HR, 0.703 [95% CI, 0.502 to 0.985]; P = .039). Second-line treatments were given to 251 patients with a median PFS2 and OS2 after relapse or progression of 3.3 months and 11.5 months, respectively. Within the limits of highly heterogeneous second-line treatments, no specific regimen seemed to provide superior disease control. However, a potential benefit was observed with brentuximab vedotin in association with chemotherapy even after excluding anaplastic large-cell lymphoma subtype or after adjusting for histology and international prognostic index in a multivariate model (HR for PFS, 0.431 [95% CI, 0.238 to 0.779]; P = .005).

Outcome prediction by interim positron emission tomography and IgM monoclonal gammopathy in diffuse large B-cell lymphoma.

In diffuse large B-cell lymphoma (DLBCL), a positive interim positron emission tomography (PET) scan predicts treatment failure, but the proportion of high-risk patients thus identified is small. To improve prediction, we combined the interim PET result with the presence or absence of an associated IgM gammopathy. Of 108 DLBCL patients participating in a prospective trial, nine (8%) were interim PET positive and 19 (18%) had an IgM gammopathy. The monoclonal protein was not associated with distinguishing genetic features, and its light chain restriction was not always concordant with the light chain restriction of the lymphoma. The information provided by interim PET and IgM gammopathy was combined to dichotomize the population into sizeable high-risk (1-2 adverse factors) and low-risk groups (no adverse factor) with widely different outcomes (population size, 25% vs. 75%; 3-year risk of progression, 51% vs. 10%; 3-year overall survival, 64% vs. 95%). Multivariable analyses including established risk factors revealed the interim PET result and the IgM gammopathy status to be the only factors significantly associated with outcome. Information about interim PET response and IgM gammopathy may be useful in studies testing risk-adapted treatment strategies.

An artificial intelligence method using FDG PET to predict treatment outcome in diffuse large B cell lymphoma patients.

Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum intensity projection (MIP) images from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL 18F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmaxbulk was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL.

Neutropenia-related aspergillosis in non-transplant haematological patients hospitalised under ambient air versus purified air conditions.

BACKGROUND: To reduce the risk of invasive aspergillosis (IA), air purification by high-efficiency particulate air filtration and laminar air flow (HEPA/LAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non-transplant haematological patients is inconsistent. OBJECTIVES: We sought to assess the incidence and outcome of pulmonary IA in non-transplant patients with life-threatening neutropenia by comparing an ambient air hospitalisation period (2008-2011) with a subsequent HEPA/LAF hospitalisation period (2012-2014). PATIENTS AND METHODS: We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia-related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia-related hospitalisations under HEPA/LAF conditions. IA was defined using the 2008 EORTC/MSG criteria. RESULTS: Within a 7-year study period, we observed one 'proven', three 'probable' and 73 'possible' IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life-threatening neutropenia (1-10 days, 1.8%; >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2%; >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPA/LAF conditions (odds ratio [OR], 0.368 [95% confidence interval, 0.207-0.654]; p < .001) and duration of neutropenia (OR, 1.043 [1.023-1.062] per day; p < .001) and anaemia (OR, 1.044 [1.008-1.081] per day; p = .016). IA-associated fatal outcomes were non-significantly reduced under HEPA/LAF (OR, 0.077 [0.005-1.151]; p = .063). The protective effect of HEPA/LAF was not seen under posaconazole prophylaxis (OR, 0.856 [0.376-1.950]; p = .711). CONCLUSIONS: Implementation of HEPA/LAF was associated with a significant reduction in neutropenia-related IA in non-transplant haematological patients.

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

Baseline radiomics features and MYC rearrangement status predict progression in aggressive B-cell lymphoma.

We investigated whether the outcome prediction of patients with aggressive B-cell lymphoma can be improved by combining clinical, molecular genotype, and radiomics features. MYC, BCL2, and BCL6 rearrangements were assessed using fluorescence in situ hybridization. Seventeen radiomics features were extracted from the baseline positron emission tomography-computed tomography of 323 patients, which included maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis, and 12 dissemination features pertaining to distance, differences in uptake and volume between lesions, respectively. Logistic regression with backward feature selection was used to predict progression after 2 years. The predictive value of (1) International Prognostic Index (IPI); (2) IPI plus MYC; (3) IPI, MYC, and MTV; (4) radiomics; and (5) MYC plus radiomics models were tested using the cross-validated area under the curve (CV-AUC) and positive predictive values (PPVs). IPI yielded a CV-AUC of 0.65 ± 0.07 with a PPV of 29.6%. The IPI plus MYC model yielded a CV-AUC of 0.68 ± 0.08. IPI, MYC, and MTV yielded a CV-AUC of 0.74 ± 0.08. The highest model performance of the radiomics model was observed for MTV combined with the maximum distance between the largest lesion and another lesion, the maximum difference in SUVpeak between 2 lesions, and the sum of distances between all lesions, yielding an improved CV-AUC of 0.77 ± 0.07. The same radiomics features were retained when adding MYC (CV-AUC, 0.77 ± 0.07). PPV was highest for the MYC plus radiomics model (50.0%) and increased by 20% compared with the IPI (29.6%). Adding radiomics features improved model performance and PPV and can, therefore, aid in identifying poor prognosis patients.

Interim FDG-PET analysis to identify patients with aggressive non-Hodgkin lymphoma who benefit from treatment intensification: a post-hoc analysis of the PETAL trial.

The randomized PETAL trial failed to demonstrate a benefit of interim FDG-PET (iPET)-based treatment intensification over continued standard therapy with CHOP (plus rituximab (R) in CD20-positive lymphomas). We hypothesized that PET analysis of all lymphoma manifestations may identify patients who benefitted from treatment intensification. A previously developed neural network was employed for iPET analysis to identify the highest pathological FDG uptake (max-SUVAI) and the mean FDG uptake of all lymphoma manifestations (mean-SUVAI). High mean-SUVAI uptake was determined separately for iPET-positive and iPET-negative patients. The endpoint was time-to-progression (TTP). There was a significant interaction of additional rituximab and mean-SUVAI in the iPET-negative group (HR = 0.6, p < 0.05). Patients with high mean-SUVAI had significantly prolonged TTP when treated with 6xR-CHOP + 2 R (not reached versus 52 months, p < 0.05), whereas max-SUVmanual failed to show an impact of additional rituximab. In the iPET-positive group, patients with high mean-SUVAI had a significantly longer TTP with (R-)CHOP than with the Burkitt protocol (14 versus 4 months, p < 0.01). Comprehensive iPET evaluation may provide new prognosticators in aggressive lymphoma. Additional application of rituximab was associated with prolonged TTP in iPET-negative patients with high mean-SUVAI. Comprehensive iPET interpretation could identify high-risk patients who benefit from study-specific interventions.

A tumor volume and performance status model to predict outcome before treatment in diffuse large B-cell lymphoma.

Aggressive large B-cell lymphoma (LBCL) has variable outcomes. Current prognostic tools use factors for risk stratification that inadequately identify patients at high risk of refractory disease or relapse before initial treatment. A model associating 2 risk factors, total metabolic tumor volume (TMTV) >220 cm3 (determined by fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography) and performance status (PS) ≥2, identified as prognostic in 301 older patients in the REMARC trial (#NCT01122472), was validated in 2174 patients of all ages treated in 2 clinical trials, PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas; N = 510) and GOYA (N = 1315), and in real-world clinics (N = 349) across Europe and the United States. Three risk categories, low (no factors), intermediate (1 risk factor), and high (2 risk factors), significantly discriminated outcome in most of the series. Patients with 2 risk factors had worse outcomes than patients with no risk factors in the PETAL, GOYA, and real-world series. Patients with intermediate risk also had significantly worse outcomes than patients with no risk factors. The TMTV/Eastern Cooperative Oncology Group-PS combination outperformed the International Prognostic Index with a positive C-index for progression-free survival and overall survival in most series. The combination of high TMTV > 220 cm3 and ECOG-PS ≥ 2 is a simple clinical model to identify aggressive LBCL risk categories before treatment. This combination addresses the unmet need to better predict before treatment initiation for aggressive LBCL the patients likely to benefit the most or not at all from therapy.

AFM13 in patients with relapsed or refractory classical Hodgkin lymphoma: final results of an open-label, randomized, multicenter phase II trial.

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

Mitochondrial Kv1.3 Channels as Target for Treatment of Multiple Myeloma.

Despite several new developments in the treatment of multiple myeloma, all available therapies are only palliative without curative potential and all patients ultimately relapse. Thus, novel therapeutic options are urgently required to prolong survival of or to even cure myeloma. Here, we show that multiple myeloma cells express the potassium channel Kv1.3 in their mitochondria. The mitochondrial Kv1.3 inhibitors PAPTP and PCARBTP are efficient against two tested human multiple myeloma cell lines (L-363 and RPMI-8226) and against ex vivo cultured, patient-derived myeloma cells, while healthy bone marrow cells are spared from toxicity. Cell death after treatment with PAPTP and PCARBTP occurs via the mitochondrial apoptotic pathway. In addition, we identify up-regulation of the multidrug resistance pump MDR-1 as the main potential resistance mechanism. Combination with ABT-199 (venetoclax), an inhibitor of Bcl2, has a synergistic effect, suggesting that mitochondrial Kv1.3 inhibitors could potentially be used as combination partner to venetoclax, even in the treatment of t(11;14) negative multiple myeloma, which represent the major part of cases and are rather resistant to venetoclax alone. We thus identify mitochondrial Kv1.3 channels as druggable targets against multiple myeloma.

A phase II trial to evaluate the combination of pixantrone and obinutuzumab for patients with relapsed aggressive lymphoma: Final results of the prospective, multicentre GOAL trial.

The prognosis of patients with relapsed diffuse large B-cell lymphoma (DLBCL) remains poor with current options. Here we prospectively evaluated the combination of pixantrone with obinutuzumab for up to six cycles for patients with relapsed or refractory DLBCL. Overall response rate (ORR) was the primary end-point. Sixty-eight patients were evaluated, median age was 75 years, median number of prior lines was three (range 1-10), 52 patients (76.5%) were diagnosed with DLBCL and 16 (23.5%) patients had transformed indolent lymphoma or follicular lymphoma (FL) IIIB. ORR was 35.3% for all and 40% for evaluable patients (16.6% complete response), median progression-free survival (PFS) and overall survival (OS) were 2.8 months and 8 months, respectively. Analysis of the cell of origin revealed a superior course for patients with non-GCB (germinal centre B-cell-like) phenotype [median OS not reached (n.r.) vs 5.2 months]. Patients with one prior line had an improved outcome over patients treated in later lines (PFS n.r. vs 2.5 months). Disease progression was the main reason for premature termination. Adverse events were mainly haematologic. The combination treatment revealed no unexpected adverse events. Most relevant non-haematologic toxicity was infection in 28% of patients. In summary, pixantrone-obinutuzumab showed clinical activity with sometimes long-term remission; however, the trial failed to meet its primary end-point.

Proposed New Dynamic Prognostic Index for Diffuse Large B-Cell Lymphoma: International Metabolic Prognostic Index.

PURPOSE: Baseline metabolic tumor volume (MTV) is a promising biomarker in diffuse large B-cell lymphoma (DLBCL). Our aims were to determine the best statistical relationship between MTV and survival and to compare MTV with the International Prognostic Index (IPI) and its individual components to derive the best prognostic model. METHODS: PET scans and clinical data were included from five published studies in newly diagnosed diffuse large B-cell lymphoma. Transformations of MTV were compared with the primary end points of 3-year progression-free survival (PFS) and overall survival (OS) to derive the best relationship for further analyses. MTV was compared with IPI categories and individual components to derive the best model. Patients were grouped into three groups for survival analysis using Kaplan-Meier analysis; 10% at highest risk, 30% intermediate risk, and 60% lowest risk, corresponding with expected clinical outcome. Validation of the best model was performed using four studies as a test set and the fifth study for validation and repeated five times. RESULTS: The best relationship for MTV and survival was a linear spline model with one knot located at the median MTV value of 307.9 cm3. MTV was a better predictor than IPI for PFS and OS. The best model combined MTV with age as continuous variables and individual stage as I-IV. The MTV-age-stage model performed better than IPI and was also better at defining a high-risk group (3-year PFS 46.3% v 58.0% and 3-year OS 51.5% v 66.4% for the new model and IPI, respectively). A regression formula was derived to estimate individual patient survival probabilities. CONCLUSION: A new prognostic index is proposed using MTV, age, and stage, which outperforms IPI and enables individualized estimates of patient outcome.

Follicular lymphoma grade 3B and diffuse large B-cell lymphoma present a histopathological and molecular continuum lacking features of progression/ transformation.

The sole distinguishing feature of follicular lymphoma grade 3B and diffuse large B-cell lymphoma is the growth pattern assessed by histopathology. Diffuse growth defines diffuse large B-cell lymphoma but the clinical relevance of this finding when occurring in follicular lymphoma grade 3B is uncertain. To address this issue, individual and coexisting follicular lymphoma grade 3B and diffuse large B-cell lymphoma were separated and analyzed for immunophenotype and molecular genetic features by fluorescence in situ hybridization, targeted sequencing and gene expression profiling. Clinical features of follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma were studied in homogeneously treated patients from a prospective randomized trial. Follicular lymphoma grade 3B and diffuse large B-cell lymphoma frequently show an intermediate growth pattern and/or occur simultaneously in the same tissue at the time of initial diagnosis. When occurring simultaneously follicular lymphoma grade 3B and diffuse large B-cell lymphoma do not differ significantly for genetic aberrations or phenotype but have distinct gene expression features reflecting a divergent microenvironment. Follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma do not differ for major clinical parameters such as International Prognostic Index, response to immuno-chemotherapy, progression or overall survival. Follicular lymphoma grade 3B and simultaneous diffuse large B-cell lymphoma are molecularly homogenous. Histological detection of diffuse large B-cell lymphoma is not associated with features of a more aggressive disease and does not reflect transformation or progression of follicular lymphoma grade 3B.

Ibrutinib- and bortezomib-extended R-CHOP induction in elderly higher-risk patients newly diagnosed with diffuse large B-cell lymphoma - first analysis of toxicity and efficacy signals.

Diffuse large-cell B-cell lymphoma (DLBCL) is the most common lymphoid malignancy. About 30-40% of the patients will not be cured by standard Rituximab (R)-CHOP-like immune-chemotherapy, and many of them experience relapse and eventually succumb to their disease. Enhancing first-line efficacy in patients at higher risk, among them many elderly, is key to improve long-term outcomes. Numerous attempts to combine R-CHOP with targeted agents failed in large randomized phase III trials. The addition of Ibrutinib enhanced survival in younger patients, but increased toxicity across all age groups, especially in the elderly. Older DLBCL patients impose particular challenges, since they often present with more advanced disease, and exhibit treatment-relevant comorbidities. ImbruVeRCHOP trial aims at identifying patients who need that benefit from rationally augmented first-line regimens without experiencing overt toxicity and detecting their molecular signatures of response. This first analysis presents encouraging feasibility, safety, and preliminary response data in elderly high-risk DLBCL patients.

Reinduction therapy with everolimus in combination with dexamethasone, high-dose cytarabin and cisplatinum in patients with relapsed or refractory classical Hodgkin lymphoma: an experimental phase I/II multicentre trial of the German Hodgkin Study Group (GHSG HD-R3i).

Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18-60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0-13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.

Romidepsin Plus CHOP Versus CHOP in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Results of the Ro-CHOP Phase III Study (Conducted by LYSA).

PURPOSE: Romidepsin, a histone deacetylase inhibitor, has demonstrated activity in relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used as first-line treatment of PTCL; however, it has limited efficacy. Results from a phase Ib and II study showed the feasibility of combining romidepsin with CHOP (Ro-CHOP). METHODS: This study is a randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m2, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria. RESULTS: Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 (P = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% (P > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% v 10% in the Ro-CHOP v CHOP arms, respectively), neutropenia (49% v 33%), anemia (47% v 17%), and leukopenia (32% v 20%). CONCLUSION: The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL.

Impact of germline polymorphisms in genes regulating glucose uptake on positron emission tomography findings and outcome in diffuse large B-cell lymphoma: results from the PETAL trial.

BACKGROUND: [18F]Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is the standard imaging procedure in diffuse large B-cell lymphoma (DLBCL). Disease presentation, FDG-PET/CT performance, and outcome may be influenced by germline single nucleotide polymorphisms (SNP) in genes regulating glucose uptake. METHODS: Clinical variables, FDG-PET findings, and outcome were analysed in relation to SNPs in 342 DLBCL patients participating in the 'Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas' (PETAL) trial. Genes analysed included SLC2A1 (SNPs rs1385129, referred to as HaeIII; rs710218, HpyCH4V; rs841853, XbaI), VEGFA (rs3025039), HIF1A (rs11549465, P582S; rs11549467, A588T), and APEX1 (rs1130409, D148E). Statistical significance was assumed at p ≤ 0.05. RESULTS: The SLC2A1 HaeIII and HpyCH4V SNPs were tightly linked and statistically significantly associated with baseline maximum standardized uptake value (SUVmax) and Ann Arbor stage, with slightly lower SUVmax (HaeIII, median 18.9, interquartile range [IQR] 11.5-26.6, versus 21.6, IQR 14.4-29.7; p = 0.019) and more frequent stage IV disease (HaeIII, 44.5% versus 30.8%; p = 0.011) in minor allele carriers. As previously reported for lung cancer, the association was dependent upon the coexistent APEX1 D148E genotype. The HIF1A A588T SNP was associated with total metabolic tumour volume (TMTV) and time-to-progression, with significantly lower TMTV (median 16 cm3, IQR 7-210, versus 146 cm3, IQR 34-510; p = 0.034) and longer time-to-progression in minor allele carriers (log-rank p = 0.094). Time-to-progression was also associated with the SLC2A1 XbaI and APEX1 D148E SNPs, with shorter time-to-progression in homozygous and heterozygous SLC2A1 XbaI (HR 1.456; CI 0.930-2.280; p = 0.099) and homozygous APEX1 D148E minor allele carriers (HR 1.6; CI 1.005-2.545; p = 0.046). In multivariable analyses including SNPs, International Prognostic Index factors, sex, and B symptoms, HIF1A A588T, SLC2A1 XbaI, and APEX1 D148E retained statistical significance for time-to-progression, and SLC2A1 XbaI was also significantly associated with overall survival. CONCLUSIONS: Common SNPs in genes regulating glucose uptake may impact SUVmax, tumour distribution, tumour volume, and outcome in DLBCL. The effects on SUVmax are of low magnitude and appear clinically negligible. The results are consistent with findings in other types of cancer. They need to be confirmed in an independent DLBCL population of sufficient size. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov NCT00554164; EudraCT 2006-001641-33. Registration date November 5, 2007, https://www. CLINICALTRIALS: gov/ct2/show/NCT00554164.

Quantitative evaluation of interim positron emission tomography in peripheral T-cell lymphoma.

BACKGROUND: Interim [18F]fluoro-deoxyglucose-positron emission tomography predicts outcome in peripheral T-cell lymphoma (PTCL). We compared two quantitative evaluation methods. METHODS: Interim scans from 43 patients with anaplastic lymphoma kinase-negative PTCL from the 'Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas' trial were re-analyzed by qPET (relating residual lymphoma-related uptake to liver uptake) and ∆SUVmax (relating interim scan to baseline scan). The endpoint was progression-free survival. RESULTS: qPET and ∆SUVmax were closely correlated (Pearson's r = 0.627). Up to the 60th percentile of values ranked by increasing residual activity, the positive predictive value for progression or death increased from 60 to 95%, with stable negative predictive values (NPV) of 60%. Beyond the 60th percentile, the NPV decreased to 40%. qPET ≥ 2 and ∆SUVmax < 50% identified high-risk populations comprising 41.9% and 39.5% of patients, with 3-year progression-free survival rates of 5.6% (95% confidence interval, 0.8-37.3) and 0%, respectively, as compared to 63.7% (47.4-85.8) and 61.3% (45.1-83.3) in low-risk patients. CONCLUSIONS: qPET and ∆SUVmax identify large fractions of PTCL patients destined to experience treatment failure. qPET may be preferred because it requires a single PET scan, halving the diagnostic effort.

Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.