A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of TP53 mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group.

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients aged over 65. We have now re-examined the classic prognostic factors, adding an assessment of the mutation status of TP53. Patients (n=74; median age 73 years) were treated with the RiBVD combination. Median Progression Free Survival (mPFS) was 79 months, and median Overall Survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level below 3.6 g/dL (Alb<3.6 g/dL) were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, p=0.014) was obtained for TP53mt versus TP53wt, and 3.6 (1.39-9.5, p=0.009) for Alb<3.6 g/dL vs Alb≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PFs: TP53mt (HR: 5.9 (1.77-19.5, p=0.004)), Alb<3.6 g/dL (HR: 5.2 (1.46-18.5, p=0.011)), and ECOG=2 (HR: 3.7 (1.31-10.6, p=0.014)). Finally, a score combining TP53 status and albumin level distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.

A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma.

We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [18F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (P<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. ClinicalTrials.gov: NCT 01457144.

Bendamustine-based conditioning prior to autologous stem cell transplantation (ASCT): Results of a French multicenter study of 474 patients from LYmphoma Study Association (LYSA) centers.

Carmustine shortage has led to an increase use of alternative conditioning regimens prior to autologous stem cell transplantation for the treatment of lymphoma, including Bendamustine-based (BeEAM). The aim of this study was to evaluate the safety of the BeEAM regimen in a large cohort of patients. A total of 474 patients with a median age of 56 years were analyzed. The majority of patients had diffuse large B-cell lymphoma (43.5%). Bendamustine was administered at a median dose of 197 mg/m2 /day (50-250) on days-7 and -6. The observed grade 1-4 toxicities included mucositis (83.5%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%), and cardiac rhythm disorders (4%). Nonrelapse mortality (NRM) was reported in 3.3% of patients. Acute renal failure (ARF) was reported in 132 cases (27.9%) (G ≥2; 12.3%). Organ toxicities and death were more frequent in patients with post conditioning renal failure. In a multivariate analysis, pretransplant chronic renal failure, bendamustine dose >160 mg/m2 and age were independent prognostic factors for ARF. Pretransplant chronic renal failure, hyperhydration volume, duration of hyperhydration, and etoposide dose were predictive factors of NRM. A simple, four-point scoring system can stratify patients by levels of risk for ARF and may allow for a reduction in the bendamustine dose to avoid toxicity. Drugs shortage may have dangerous consequences. Prospective, comparative studies are needed to confirm the toxicity/efficacy extents from this conditioning regimen compared to other types of high dose therapy.

The prognostic value of hematogones in patients with acute myeloid leukemia.

In acute myeloid leukemia (AML), new prognostic tools are needed to assess the risk of relapse. Hematogones (HGs) are normal B-lymphocyte precursors that increase in hematological diseases and may influence remission duration in AML. HG detection was prospectively investigated in 262 AML patients to determine its prognostic value. Flow cytometric HG detection was performed in bone marrow aspiration after intensive chemotherapy at the time of hematological recovery. Patients with HGs in bone marrow samples had a significantly better relapse-free survival (RFS) and overall survival (OS) than patients without HGs (P = 0.0021, and P = 0.0016). Detectable HGs independently predicted RFS (HR = 0.61, 95%CI: 0.42 - 0.89, P = 0.012) and OS (HR = 0.59, 95%CI: 0.38 - 0.92, 0.019) controlling for age, ELN classification, the number of chemotherapy cycles to achieve CR, performance status, secondary AML and flow cytometric minimal residual disease (MRD). In intensively treated AML, individual determination of HGs could be useful to stratify the optimal risk-adapted therapeutic strategy after induction chemotherapy. Am. J. Hematol. 91:566-570, 2016. © 2016 Wiley Periodicals, Inc.

Hematogones: a new prognostic factor for acute myeloblastic leukemia.

Acute myeloid leukemia (AML) patient outcomes remain heterogeneous, and new prognostic tools are needed to assess the risk of relapse. Hematogones (HGs) are normal B-lymphocyte precursors, which increase in number in hematologic diseases. The prognostic impact of the presence of detectable HGs on the leukemia-free survival (LFS) and overall survival of 120 consecutive patients with AML in first complete remission was investigated by flow cytometry. Patients who had HG levels more than 0.01% had a significantly better median LFS (29.2 vs 11.7 months; P = .001) and overall survival (not reached vs 23.5 months; P = .011). According to Cox analysis, an HG level more than 0.01% was an independent predictor of LFS (hazard ratio = 0.5; 95% confidence interval, 0.28-0.90, P < .03) when age, leukocytosis, the number of chemotherapy cycles, and the standardized cytogenetic and molecular risk subgroups were controlled for. These results indicate that HG analysis may help to define the risk of relapse in AML patients.

A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial.

In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after obinutuzumab-ibrutinib induction for 9 months, patients (n = 10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n = 115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the end of treatment using a highly sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in the PB MRD status were apparent per to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes. METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants. FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group. INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics. FUNDING: Janssen Pharmaceuticals.

High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years.

Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.

Diagnostic value of baseline 18FDG PET/CT skeletal textural features in follicular lymphoma.

At present, 18F-fluorodesoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) cannot be used to omit a bone marrow biopsy (BMB) among initial staging procedures in follicular lymphoma (FL). The additional diagnostic value of skeletal textural features on baseline 18FDG-PET/CT in diffuse large B-cell lymphoma (DLBCL) patients has given promising results. The aim of this study is to evaluate the value of 18FDG-PET/CT radiomics for the diagnosis of bone marrow involvement (BMI) in FL patients. This retrospective bicentric study enrolled newly diagnosed FL patients addressed for baseline 18FDG PET/CT. For visual assessment, examinations were considered positive in cases of obvious bone focal uptakes. For textural analysis, the skeleton volumes of interest (VOIs) were automatically extracted from segmented CT images and analysed using LifeX software. BMB and visual assessment were taken as the gold standard: BMB -/PET - patients were considered as bone-NEGATIVE patients, whereas BMB +/PET -, BMB -/PET + and BMB +/PET + patients were considered bone-POSITIVE patients. A LASSO regression algorithm was used to select features of interest and to build a prediction model. Sixty-six consecutive patients were included: 36 bone-NEGATIVE (54.5%) and 30 bone-POSITIVE (45.5%). The LASSO regression found variance_GLCM, correlation_GLCM, joint entropy_GLCM and busyness_NGLDM to have nonzero regression coefficients. Based on ROC analysis, a cut-off equal to - 0.190 was found to be optimal for the diagnosis of BMI using PET pred.score. The corresponding sensitivity, specificity, PPV and NPV values were equal to 70.0%, 83.3%, 77.8% and 76.9%, respectively. When comparing the ROC AUCs with using BMB alone, visual PET assessment or PET pred.score, a significant difference was found between BMB versus visual PET assessments (p = 0.010) but not between BMB and PET pred.score assessments (p = 0.097). Skeleton texture analysis is worth exploring to improve the performance of 18FDG-PET/CT for the diagnosis of BMI at baseline in FL patients.

End-of-treatment 18F-FDG PET/CT in diffuse large B cell lymphoma patients: ΔSUV outperforms Deauville score.

In DLBCL, the Deauville scoring system (DS) is the standard for PET/CT response assessment. An alternative system, based on the semi-quantitative change in standardized uptake values, namely ΔSUVmax, has been reported to be more objective than the DS. We aimed to compare ΔSUVmax and DS for risk stratification of DLBCL patients on end-of-treatment (EoT) PET. 108 consecutive patients were included. 2-year EFS Kaplan-Meier survival analyses and Cox regression models were performed. 2-year EFS was significantly different between favorable ΔSUVmax (favΔ < -86.5%) and unfavorable ΔSUVmax (unfavΔ ≥ -86.5%) patients: 100.0% ± 0.0 versus 58.3% ± 14.2 (p = 0.001). On Cox multivariable regression, ΔSUVmax status was the only independent predictor of 2-year EFS, outperforming DS. Therefore, ΔSUVmax should be computed for non-responder patients, especially DS4, as the 2-year EFS is not different between responders and non-responders in the case of favΔ. Further studies are needed in order to confirm this hypothesis.

Identification of anticancer drugs associated with atrial fibrillation: analysis of the WHO pharmacovigilance database.

AIMS: The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF. METHODS AND RESULTS: A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-CD20 monoclonal antibody. CONCLUSION: Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of haematologic malignancies.

Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95.

Peripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front-line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) and compared it to CHOP/21 as front-line treatment in non-cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2-year event-free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty-eight patients were identified between 1996 and 2002. Both arms were well balanced for patients' characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2-year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I-II were identified as two independent favourable prognostic factors influencing survival. VIP-rABVD was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.

Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma. Combined results of two prospective phase II trials from the French GOELAMS group.

UNLABELLED: Background There is currently no international consensus for first-line treatment (prior to autologous stem cell transplantation) in mantle cell lymphoma patients. Here, we investigated the efficacy and tolerance of VAD associated with chlorambucil (VAD+C) and rituximab or not before autologous stem cell transplantation. DESIGN AND METHODS: Between 1996 and 2005, 113 previously untreated mantle cell lymphoma patients were enrolled in two consecutive prospective phase II studies. Responses and response factors to the (R)VAD+C regimen were evaluated. The survival prognostic value of the MIPI score and Ki67 were also analyzed. RESULTS: The induction phase of 4 courses of (R)VAD+C showed very low hematologic and extra-hematologic toxicity (grade 3-4 thrombopenia and neutropenia, 9% and 2.7%, respectively and grade 3-4 extra-hematologic toxicities, 1.6%). Overall and complete response rates were 73% and 46%, respectively, and rose to 83% and 51% for the 70% of patients with less than two independent response factors (LDH, B symptoms and lymphocytosis). At the end of treatment, 65% of patients were in complete remission. Progression free and overall survival were significantly better in the transplanted population. The MIPI score was confirmed as a predictor of survival. Ki67, serum LDH, Performance Status (PS) and B symptoms were identified as independent prognostic factors of survival. A prognostic scoring system could stratify patients into three risk groups with markedly different median overall survival of 112, 44 and 11 months, respectively. Conclusions The (R)VAD+C is an effective regimen with very low toxicity. In addition to the MIPI score, Ki67 expression provides additional independent prognostic information for the prediction of overall survival (ClinicalTrials.gov Identifier: NCT00285389).

18F-Fludarabine PET for Lymphoma Imaging: First-in-Humans Study on DLBCL and CLL Patients.

This was the first-in-humans clinical study of 18F-fludarabine, which is a radiopharmaceutical for PET imaging in lymphoma, for which many issues remain controversial with the standard radiotracer 18F-FDG. Methods:18F-fludarabine PET or PET/CT was performed on 10 patients: 5 with diffuse large B-cell lymphoma (DLBCL) and 5 with chronic lymphocytic leukemia. The tumor uptake, biodistribution, and radiation dosimetry of 18F-fludarabine were evaluated. Six successive partial-body PET scans were acquired for 250 min after an intravenous 4 MBq/kg bolus of 18F-fludarabine. SUVs were recorded for each involved lymph node territory and for several extranodal sites, with particular reference to the liver. To assess the time-related uptake profile of 18F-fludarabine, PET images were analyzed by delineating volumes of interest over the uptake sites on the optimal scan for visual observation and were projected onto all coregistered scans of the same subject. Physical examination, laboratory studies, and contrast-enhanced CT were performed on all patients. For the DLBCL group, 18F-FDG PET was also considered. Results: In DLBCL patients, increased 18F-fludarabine uptake was observed in sites considered abnormal by CT or 18F-FDG, with SUVs significantly higher in involved lesions than in physiologic nontarget sites. Nonetheless, the comparison of 18F-fludarabine and 18F-FDG PET showed discrepancies in 2 patients. In chronic lymphocytic leukemia patients, the uptake of 18F-fludarabine coincided with sites expected to be involved (including splenic invasion) according to conventional clinical and CT staging and was significant in hematopoietic bone marrow. No uptake was observed, whatever the disease group, in cardiac muscle or brain. The mean effective dose from a mean injected 18F-fludarabine activity of 305 ± 76 MBq was 3.07 ± 0.81 mSv. Conclusion:18F-fludarabine PET might well be a promising tool for lymphoproliferative diseases. The radiation dose of this radiopharmaceutical is below that of 18F-FDG. The specificity of this PET probe for lymphoid cells, its absence of accumulation in reactive tissues, and its feasibility for detection of bone marrow infiltration might play an innovative role in lymphoma imaging.

Increased frequencies of circulating and tumor-resident Vδ1+ T cells in patients with diffuse large B-cell lymphoma.

Gamma-delta (γδ) T cells contribute to the innate immune response against cancer. In samples of 20 patients upon DLBCL diagnosis, we found that Vδ1+ T cells were the major γδ T cell subset in tumors and PBMCs of patients, while Vδ2 T cells were preponderant in PBMCs of healthy subjects. Interestingly, the germinal center (GC) subtype was associated with an increase in Vδ1+ T cells in tumors, whereas the non-GC subtype was associated with a lower frequency of γδ T cells. While circulating Vδ1+ T cells of patients or HSs mostly exhibited a naïve phenotype, the majority of tumor Vδ1+ T cells showed a central memory phenotype. Resident or circulating γδ T cells from patients were not functionally impaired since they produced high levels of IFN-γ. Collectively, our findings are in favor of γδ T cell activation in tumors and open new perspectives for their modulation in DLBCL immunotherapy.

Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study.

BACKGROUND: Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR). METHODS: This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m2 per day] and oral cyclophosphamide [250 mg/m2 per day] for the first 3 days of each cycle, rituximab at 375 mg/m2 intravenously on day 0 of cycle 1 and subsequently at 500 mg/m2 on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m2) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606. FINDINGS: Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47·7 months (IQR 30·4-65·8), median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6-not estimable) was improved compared with the observation group (49·0 months, 39·9-60·5; hazard ratio 0·55, 95% CI 0·40-0·75; p=0·0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group. INTERPRETATION: 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy. FUNDING: French National Cancer Institute (INCa), Roche, Chugai.