Search

Key Points Diagnosis of TCL often relies on PCR-based TCR clonality testing, which displays low specificity and requires high-quality DNA.Targeted NGS and T-cell clonality assessment are complementary techniques that should be applied in hard front-line diagnosis., Immunomorphological diagnosis of T-cell lymphoma (TCL) may be challenging, especially on needle biopsies. Multiplex polymerase chain reaction (PCR) assays to assess T-cell receptor (TCR) gene rearrangements are now widely used to detect T-cell clones and provide diagnostic support. However, PCR assays detect only 80% of TCL, and clonal lymphocyte populations may also appear in nonneoplastic conditions. More recently, targeted next-generation sequencing (t-NGS) technologies have been deployed to improve lymphoma classification. To the best of our knowledge, the comparison of these techniques’ performance in TCL diagnosis has not been reported yet. In this study, 82 TCL samples and 25 nonneoplastic T-cell infiltrates were divided into 2 cohorts (test and validation) and analyzed with both multiplex PCR and t-NGS to investigate TCR gene rearrangements and somatic mutations, respectively. The detection of mutations appeared to be more specific (100.0%) than T-cell clonality assessment (41.7%-45.5%), whereas no differences were observed in terms of sensitivity (95.1%-97.4%). Furthermore, t-NGS provided a reliable basis for TCL diagnosis in samples with partially degraded DNA that was impossible to assess with PCR. Finally, although multiplex PCR assays appeared to be less specific than t-NGS, both techniques remain complementary, as PCR recovered some t-NGS negative cases.

BACKGROUND No study has focused on the economic burden in non-Hodgkin lymphoma (NHL) survivors, even though this knowledge is essential. This study reports on health care resource use and associated health care costs as well as related factors in a series of 1671 French long-term NHL survivors. METHODS Health care costs were measured from the payer perspective. Only direct medical costs (medical consultations, outpatient treatments, hospitalizations, and medical transport) in the past 12 months were included (reference year 2015). Multiple linear regression was used to search for explanatory factors of health care costs. RESULTS In total, 1100 survivors (66%) reported having used at least 1 health care resource, and 867 (52%) reported having used at least 1 outpatient treatment. After the authors accounted for missing data, the mean health care cost was estimated at €702 ± €2221. Hospitalizations and outpatient treatments were the main cost drivers. Sensitivity analyses confirmed the robustness of the results. For the 1100 survivors who reported using at least 1 health care resource, the mean health care cost was €1067 ± €2268. Several factors demonstrated statistically significant relationships with health care costs. For instance, cardiovascular disorders increased costs by 66% ± 16%. In contrast, rituximab or autologous stem cell transplantation as initial therapy had no effect on health care costs. CONCLUSIONS The consideration of economic constraints in health care is now a reality. This retrospective study reports on a better understanding of health care resource use and associated health care costs as well as related factors. It may help health care professionals in their ongoing efforts to design person-centered health care pathways.

Over the past decades, there has been a significant expansion of the treatment options for patients with chronic lymphocytic leukemia (CLL) due to Brutons tyrosine kinase (BTK) inhibitors, which changed approaches in CLL therapy. Ibrutinib was the first BTK inhibitor approved for CLL treatment, but adverse events such as atrial fibrillation and hypertension may limit the use of ibrutinib. In the first head-to-head trial of acalabrutinib and ibrutinib ELEVATE-RR, acalabrutinib was statistically superior to ibrutinib in all-grade atrial fibrillation/flutter (9.4% vs 16.0%; р=0.023). In all-grade arterial hypertension (9.4% vs 23.2%) and grade 3 (4.1% vs 9.1%) acalabrutinib was statistically superior to ibrutinib. Acalabrutinib demonstrated fewer discontinuations due to adverse events (14.7%) vs ibrutinib (21.3%). Based on ELEVATE-RR results acalabrutinib should be considered as a drug of choice among BTK inhibitors for CLL patients, including patients with cardiovascular diseases and risks of cardiovascular diseases.

Objective Hematological treatment decisions in older adults with hematological malignancies are complex. Our objective is to study the impact of a comprehensive geriatric assessment on hematological treatment decision in older patients and the factors associated with change in treatment plan. Methods We conducted a cross-sectional analysis of patients aged 65 years and above with hematological malignancies, hospitalized between 2008 and 2019 at the University Cancer Institute of Toulouse. They were assessed by a geriatrician/nurse team using a comprehensive geriatric assessment (CGA). A penalized logistic regression model with elastic net regularization was used to identify factors associated with change in hematological treatment plan. Results A total of 424 patients were included. Main hematological malignancies were lymphoma (36.1 %), acute myeloid leukemia (26.9 %) and myelodysplastic syndrome (19.8%). Change in hematological treatment plan was suggested after CGA for 92 patients (21.7%). Factors associated with change in treatment plan were functional impairment according to ADL and IADL scale, mobility impairment, the presence of comorbidity defined by the Charlson score > 1 and increasing age. Conclusion A CGA has a significant impact on hematological treatment decision in older patients. Functional and mobility impairment, comorbidities and age are predictive factors of change in treatment plan.

Hodgkin’s lymphoma (HL) is a hematological neoplasm generally related to a favorable prognosis, since approximately 80% of patients will be cured with actual regimen treatment. However, 10 to 30% o...

Follicular lymphoma (FL) is the most common indolent lymphoma. Despite the clear benefit of CD20-based therapy, a subset of FL patients still progress to aggressive lymphoma. Thus, identifying early biomarkers that incorporate positron emission tomography metrics could be helpful to identify patients with a high risk of treatment failure with rituximab. We retrospectively included a total of 132 untreated FL patients separated into training and validation cohorts. Optimal threshold of baseline whole-body maximum standardized uptake (SUVmax) was first determined in the training cohort (n=48) to predict progression-free survival (PFS). The PET results were investigated along with the tumor and immune microenvironment, which were determined by immunochemistry and transcriptome studies involving gene set enrichment analyses and immune cell deconvolution, together with the tumor mutation profile. We report that baseline SUVmax>14.5 was associated with poorer PFS than baseline SUVmax≤14.5 (hazard ratio =0.28; P=0.00046). Neither immune T-cell infiltration nor immune checkpoint expression were associated with baseline PET metrics. By contrast, FL samples with Ki-67 staining ≥10% showed enrichment of cell cycle/DNA genes (P=0.013) and significantly higher SUVmax values (P=0.007). Despite similar oncogenic pathway alterations in both SUVmax groups of FL samples, four out of five cases harboring the infrequent FOXO1 transcription factor mutation were seen in FL patients with SUVmax>14.5. Thus, high baseline SUVmax reflects FL tumor proliferation and, together with Ki-67 proliferative index, can be used to identify patients at risk of early relapse with rituximab chemotherapy.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).

The aims of this study were to characterize the incidence and outcomes of severe toxicities following the administration of high-dose methotrexate (HD-MTX; ≥1 g/m2). Among the 468 patients included...

ALK-positive histiocytosis is a recently described entity with few reported cases in literature. Herein, we report an unusual case of ALK-positive histiocytosis showing an Erdheim-Chester disease (ECD)-like presentation, occurring in a 37-year-old woman with a 2-year history of chronic lymphocytic leukaemia (CLL). Our CLL patient relapsed 6 months after the end of fludarabine, cyclophosphamide and rituximab frontline therapy and complained of lower limb pains. A bone marrow biopsy was performed and showed concomitant CLL/small lymphocytic lymphoma and ALK-positive histiocytosis with an identical immunoglobulin heavy-chain gene rearrangement in both neoplasms, suggesting clonal relationship. After 4 years under ibrutinib therapy, our patient remains free of both diseases. This report extends the spectrum of composite hematolymphoid neoplasms and shows that ALK rearrangement should be considered in all histiocytosis subtypes. Moreover, both tumours eradication under ibrutinib suggests that BTK inhibitors may also be effective in histiocytic neoplasms.

New treatment strategies in follicular lymphoma (FL) are driven by a deeper understanding of microenvironmental cues supporting lymphomagenesis, chemoresistance, and immuno-escape. These immune-mediated signaling pathways contribute to initial learnings and clinical successes with lenalidomide, the first, oral, non-chemotherapeutic immunomodulatory drug, combined with anti-CD20 antibodies. This combination of lenalidomide with rituximab showed similar efficacy to chemoimmunotherapy (CIT) in first-line patients requiring therapy, and is approved in relapsed/refractory FL. We review the biology supporting the rationale for adequate inhibitory receptor/ligand pathways targeting the tissue immune microenvironment of FL cells, and potential immunomodulating combinations to replace CIT in the near future.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, for which conventional chemotherapy has poor outcomes. CD123, the α-subunit of interleukin (IL)-3 receptor, is constantly overexpressed at the surface of tumoral cells. Tagraxofusp (or SL-401) is a recombinant cytotoxin which consists of human interleukin-3 fused to a truncated diphtheria toxin. It is currently the only novel therapy with a prospective evaluation of efficacy and safety in the treatment of BPDCN and is also the only one to achieve FDA approval. In this short review, the results of tagraxofusp are summarized and perspectives of its use in BPDCN and in other malignancies are discussed. The safety profile is also summarized, since capillary leak syndrome is the main toxic effect of the drug, along with more common toxicities including an increase in transaminases and thrombocytopenia.

Venetoclax with high‐dose methotrexate and rituximab seem effective and safe to treat central nervous system involvement of chronic lymphocytic leukemia.

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.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy [1,2,3,4,5]. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitors may address some limitations.

Background Previous studies have suggested that lymphoma survivors commonly display altered Health-Related Quality of Life (HRQoL). Because these were predominantly cross-sectional studies, the dynamic of events as well as the factors which influence HRQoL remain to be determined. Methods We conducted a prospective study on a cohort of 204 Hodgkin and non-Hodgkin lymphoma survivors who remained disease-free 2 years after undergoing chemotherapy (referred to the M0-M12-M24 periods). Results We found that although Physical and Mental Component Scores (PCS and MCS) of HRQoL significantly improved from M0 to M24 in the vast majority of patients (favorable group), approximately 20% of patients displayed severe alterations in HRQoL (global SF-36 scores Conclusions Although the HRQoL of lymphoma survivors generally improved over time, persistent and severe HRQoL alterations still affected approximately one fifth of patients, resulting in important social consequences. This specific group, which presents with identifiable risk factors, may benefit from early, targeted psycho-social support.

PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

A staging system was developed a decade ago for patients with Waldenstrom’s macroglobulinemia (WM), however, since then WM treatments have changed. A revised staging system could better capture prognosis of WM patients in the chemoimmunotherapy era. We developed a revised system based on data from 492 symptomatic patients with at least 3 years and a median of 7 years of follow up while an independent validation cohort included 229 symptomatic patients. We identified age (≤65 vs 66–75 vs ≥76 years), b2-microglobulin ≥ 4 mg/L, serum albumin 65 years and

Delivering of 80% planned relative dose intensity (RDI) of fludarabine-cyclophosphamide-rituximab (FCR) is key to benefit from longer progression free survival (PFS) and survivals in CLL. In this randomized trial, we sought to investigate whether a telephone intervention strategy (called AMA) delivered by an oncology nurse could reduce the risk of RDI 80% by alleviating adverse events and supporting patients' adherence. Sixty FCR patients were randomized 1:1 for AMA (stratified on Binet stage C). As per guidelines, patients received pegfilgrastim as primary prophylaxis of febrile neutropenia. At the end of therapy, RDI 80% was reported in 31% of patients, shortening PFS (median 26 months versus not reached, P = 0.021) and OS at 3 years (100 vs 70%, P = 0.0089). Oncology nurse interventions tended to significantly reduce this event (RDI 80%: 41.4% in non-AMA versus 20.7% in AMA patients (p = 0.09)). By adjusting our logistic regression model on published parameters exposing to RDI 80%, we found that AMA protected significantly against the risk of reduced RDI (OR = 0.22, IC95% 0.05-0.84, p = 0.04), independently of grade 3/4 neutropenia ( 15% per cycle) and febrile neutropenia ( 5% per cycle) events. As a conclusion, we confirmed that 20% reduction of FCR dose-intensity was detrimental for PFS/OS, but that oncology nurse interventions reduced the risk of dose concessions.

Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine–based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.

The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.

International audience; High-definition transcriptomic studies through single-cell RNA sequencing (scRNA-Seq) have revealed the heterogeneity and functionality of the various microenvironments across numerous solid tumors. Those pioneer studies have highlighted different cellular signatures correlated with clinical response to immune checkpoint inhibitors. scRNA-Seq offers also a unique opportunity to unravel the intimate heterogeneity of the ecosystems across different lymphoma entities. In this review, we will first cover the basics and future developments of the technology, and we will discuss its input in the field of translational lymphoma research, from determination of cell-of-origin and functional diversity, to monitoring of anti-cancer targeted drugs response and toxicities, and how new improvements in both data collection and interpretation will further foster precision medicine in the upcoming years.

TO THE EDITOR : Patients with chronic lymphocytic leukemia (CLL) exhibit a variety of skin lesions including mostly non-specific cutaneous manifestations (such as cutaneous infections or exaggerated reactions to insect bite) and secondary cutaneous malignancies, as patients are at high risk of developing basal cell carcinoma, squamous cell carcinoma, melanoma, and Merkel cell carcinoma. Specific cutaneous infiltration by neoplastic B lymphocytes with clinically identifiable skin lesions, also called leukemia cutis (LC), is more uncommon and has seldom been reported in chronic lymphocytic leukemia. [...]

Introduction Brentuximab vedotin (Bv) has been approved for the treatment of Refractory/Relapsed (R/R) Anaplastic Large Cell Lymphomas (ALCL) and cutaneous T-Cell Lymphomas, but is also effective in other CD30+ malignancies. We report here the outcomes of patients with various R/R Peripheral T Cell Lymphoma (PTCL) treated with Bv in real life practice. Method This was a retrospective, single-center study based on medical records of patients with R/R PTCL treated either with Bv alone or in combination with chemotherapy. Results Among 27 patients treated with Bv, neutropenia was the main serious adverse event observed in particular when Bv was used as combination treatment. The complete Response Rates (CRR) was 40.7%; it was significantly improved when Bv was used as combination treatment. The majority of eligible patients (7/10) underwent Stem Cell Transplantation. Median Progression Free Survival (PFS) and Overall Survival (OS) were 5.2 months and 12.5 months respectively. Conclusion Our current study shows that Bv used in combination with chemotherapy provides a high CRR and thereby allows SCT in R/R PTCL. The use of Bv treatments in this setting warrants further investigation.

Complete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2–detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10−4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.

The development of Bruton’s tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood) family that plays a critical role in the B-cell receptor signaling pathway. It also induces an ‘off-target’ inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other ‘off-target’ kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.

As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.

Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p, This study was partly funded by an unrestricted contribution from Janssen Pharmaceuticals and from GILEAD Sciences SA. A.C.L. is supported by the Peters van der Laan foundation. J.C.S. was funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (C34999/A18087, ECMC C24563/A15581), Wessex Medical Research and the Bournemouth Leukaemia Fund. K.P., M.J., and S.P. are supported by the project MHCR DRO no. 65269705, the research infrastructures NCMG LM2015091, and EATRIS-CZ LM2015064, and the project CEITEC2020 LQ1601, funded by MEYS CR. R.R. is supported by Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Karolinska University Hospital, and Radiumhemmets Forskningsfonder, Stockholm.

Few reports assess prognosis during follow-up of patients with symptomatic Waldenström macroglobulinemia (WM). In 121 WM patients treated between 1993 and 2016, we analyzed the prognostic role during the clinical course of the initial International Prognostic Scoring System for WM (IPSSWM). Then, we assessed onset of response, progression, and second treatment initiation coded as time-dependent covariates. High-risk IPSSWM was an adverse prognostic factor for survival after first treatment initiation (SAFTI). Nevertheless, the corresponding Dxy concordance index obtained in multiple landmark analyses decreased from 0.24 to 0.08 during the first 6 years, in accordance with a departure from the proportional hazard assumption. By contrast with onset of response (whatever its level), onset of progression and initiation of second-line treatment retained prognostic value for SAFTI (P = .02 and P = .006, respectively). These findings were confirmed in cause-specific Cox models for deaths related to WM, but not for unrelated deaths. Time to progression after first-line treatment and time to initiation of second-line treatment had no prognostic value for survival after these 2 events. These results were confirmed in an independent series of 119 patients homogeneously treated with chemoimmunotherapy. Finally, after second-line and third-line treatment, onset of progression had significant prognostic value for subsequent risk of related death only. Thus, taking initial IPSSWM and delayed response to treatment into account, only onset of progression and second treatment initiation provided additional prognostic information for SAFTI. Therefore, progression-free survival or time to next treatment may be satisfactory surrogate end points of SAFTI in WM.

Resume La maladie residuelle minime (MRD) est de plus en plus utilisee dans le domaine de l’onco-hematologie. Sa mesure par cytometrie en flux ou biologie moleculaire a notamment une place grandissante dans la leucemie lymphoide chronique (LLC) avec l’amelioration importante des resultats des traitements ces dernieres annees. Du fait du benefice en survies sans progression et globale apporte par l’obtention d’une maladie residuelle minime indetectable, sa mesure en post-therapeutique est recommandee comme marqueur de substitution pour l’enregistrement des medicaments cytotoxiques. Cet effet est independant du traitement prealablement recu et pose la question de mesures sequentielles de la maladie residuelle minime en cours de traitement pour envisager un arret precoce en cas de reponse profonde, mais aussi de la poursuite des traitements jusqu’a obtention d’une maladie residuelle minime indetectable (en passant par des schemas associant traitements d’induction puis de maintenance). De plus, un suivi de maladie residuelle minime en post-therapeutique pourrait aider a proposer des traitements preemptifs de la rechute. Des facteurs tels que la cinetique de croissance de la maladie residuelle minime ou la lymphopenie CD4 post-therapeutique permettent d’ameliorer la prediction de la survie sans progression des patients ayant une leucemie lymphoide chronique. Les inhibiteurs de la voie du BCR n’induisent quant a eux pas de maladie residuelle minime indetectable, mais leur association a des traitements cytotoxiques type immunochimiotherapie permet d’augmenter la proportion de patients obtenant une reponse profonde. Les inhibiteurs de BCL2 permettent l’obtention de maladie residuelle minime indetectable chez beaucoup de patients y compris en rechute, ce qui donne a la maladie residuelle minime une place centrale dans l’evaluation des traitements actuellement a l’etude.

Background: Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain an unmet need population. Monotherapy with mosunetuzumab (M), a CD20xCD3 bispecific antibody, has demonstrated high and consistent response rates in high-risk R/R FL subsets, with early evidence of response durability and a favorable benefit/risk profile (Assouline et al. ASH 2020). Lenalidomide (Len) is clinically active in pts with FL, and its potent immunomodulatory activity offers the potential for additive/synergistic efficacy when combined with M. Here, we present initial data from an ongoing Phase Ib study (NCT04246086) evaluating the safety and activity of M+Len in R/R FL pts who have received at least one prior line of therapy. Methods: Pts with R/R FL (Grade [Gr] 1-3a) and at least one prior systemic anti-cancer therapy were enrolled to receive 12 cycles of M+Len (cycle duration: Cycle [C] 1, 21 days; C2-12, 28 days). In C1, step-up doses of M (IV infusion) are given on C1 Day (D)1 (1mg) and C1D8 (2mg), with the target dose given on C1D15 (30mg) and on D1 of C2-12. Len (20mg orally) is administered on D1-21 of C2-12. No hospitalization is mandated by the protocol. The primary objective is to evaluate the safety of M+Len; secondary objectives include assessment of response and long-term efficacy outcomes. Cytokine release syndrome (CRS) is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Results: At data cut-off (May 31, 2021), 27 pts had been enrolled. Median age was 59 years (range: 31-79 years); 12 pts (44%) were male. All pts had an ECOG performance status of 0 (18 pts, 67%) or 1 (9 pts, 33%). Median number of prior lines of therapy was 1 (range: 1-4), and 3 pts (11%) had disease progression (PD) 9 months. All 27 pts were safety evaluable at data cut-off. Twenty pts (74%) experienced ≥1 adverse event (AE) of any Gr; the most common AE was CRS (8 pts, 30%). Gr 3-4 AEs occurred in 8 pts (30%) and serious AEs in 8 pts (30%). No Gr 5 (fatal) AEs were observed. AEs relating to M occurred in 20 pts (74%) and AEs relating to Len occurred in 10 pts (37%). There were no AEs leading to withdrawal of M or Len; 2 pts had M-related AEs leading to M dose delays, 6 pts (22%) had Len-related AEs leading to Len dose interruption and/or reduction. In all pts, CRS events were Gr 1 (7/8 pts) or Gr 2 (1/8 pts). For most pts (6/8), CRS events occurred C1D1-C1D7; 2 pts experienced Gr 1 CRS events in C2. Median time to CRS onset was 1 day after first study drug administration (range: 1-28 days), median CRS duration was 3 days (range: 2-5 days). All CRS events resolved without sequelae. No pt required tocilizumab, ICU admission, high flow oxygen, or vasopressor support. Five pts (19%) reported 14 events of Gr 3-4 neutropenia; all neutropenia events occurred between D41 and D218, with a duration of 6-16 days. All neutropenia events resolved, with 1 patient receiving primary G-CSF prophylaxis and 2 pts receiving G-CSF treatment. No febrile neutropenia events occurred. The efficacy-evaluable population included all pts who had been assessed for response at any time on study, who had withdrawn from treatment or study prior to reaching their first response assessment, or who had been on study long enough to have reached their first scheduled response assessment, planned per protocol for D15-21 of C3. Objective response rate in the 13 pts who were efficacy evaluable at data cut-off was 92%, with complete metabolic response observed in 10 pts (77%), partial metabolic response (PMR) in 2 pts (15%), and stable disease in 1 patient (8%). One pt who initially achieved PMR experienced PD after 8 cycles of treatment. Conclusions: M+Len appears to have an acceptable safety profile in pts with R/R FL who have received at least one prior line of therapy, with encouraging preliminary anti-lymphoma activity observed. These data support initiation of a randomized Phase III study of M+Len versus rituximab+Len. Updated safety, efficacy, and pharmacokinetic data will be presented at the meeting. Disclosures Morschhauser: AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Servier: Consultancy. Bishton: Nottingham University Hospitals NHS Trust: Current Employment; Celltrion: Honoraria; Tevapharma: Honoraria; Bristol-Myers Squibb: Honoraria; Gilead: Honoraria; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Eyre: Oxford University Hospitals NHS Foundation Trust: Current Employment; LOXO Oncology: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; KITE/Gilead: Consultancy, Honoraria, Speakers Bureau; Secura Bio: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Knapp: F. Hoffmann-La Roche Ltd: Current Employment. Yaqub: Genentech, Inc./F. Hoffmann-La Roche Ltd: Current Employment. Wei: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. O'Hear: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Li: F. Hoffmann-La Roche Ltd: Current Employment. Townsend: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Celgene (Bristol-Myers Squibb): Consultancy, Honoraria. OffLabel Disclosure: Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Background: Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are 2 drug candidates recently identified as promising candidate for the treatment of T-Cell prolymphocytic leukemia (T-PLL). We recently reported that JAK/STAT pathway inhibition with RUX enhances BCL-2 dependence, thereby sensitizing T-PLL cells to VEN (Herbaux et al., Blood, 2021). We also showed that JAK/STAT pathway mutational status could impact RUX activity. Here, we report results on the 15 first patients who were treated with RUX and VEN oral combination for T-PLL. All patients were refractory to, or ineligible for alemtuzumab, the principal therapeutic option to date. Methods: In this multicenter retrospective study from the French Innovative Leukemia Organization, 15 patients with T-PLL (according to consensus criteria) were included. All patients were informed about the off-label use of this combination and provided informed consent. Patients received a maximum dose of RUX 15 mg twice daily, and VEN 800 mg daily. VEN was started with daily ramp-up from 20 mg to 800 mg over 6 days, with TLS prophylaxis (rasburicase and IV hydration). Responses were assessed by consensus criteria. Next generation sequencing (NGS) was performed using a custom-designed panel of 33 genes, including among others: ATM, TP53, IL2R, JAK1, JAK3, and STAT5B. CytoScan HD microarray (Affymetrix) were used to study copy number variation and or uniparental disomy. In vivo dynamic BH3 profiling (DBP) was performed on samples obtained from two patients on treatment. Results: All 15 patients were refractory or relapsing after chemotherapy (mostly bendamustine and pentostatin), except one. They were either refractory to (n=10) or ineligible (n=5) for alemtuzumab (ineligibility was decided by the treating physician based on age and comorbidities). The median age was 70 years (48-88). Within a week of starting RUX, a transient increase of the absolute lymphocyte count was observed in 66.6% of the patients. Based on the molecular status of the JAK/STAT pathway, we established 2 groups of patients. One with samples where no mutations were found (WT, n=3), and one with at least one mutation in the JAK/STAT pathway (MUT, n=12). The overall response rate (ORR) was 73.3%, with only partial responses. Five patients nearly fulfilled CR criteria except that they had persistent lymphocytosis (over 4 x 10 9/L), all of them were in the MUT group. ORR was 83.3% in the MUT group, and only one patient of the WT group obtained a PR. With a median follow-up of 73 days (22 to 368), the median progression free survival was significantly shorter in the WT group in comparison to the MUT group (1.8 months versus 5.6 months, p=0.04, Figure). Of note, four patients were treated with VEN monotherapy before the start of the combination with RUX. With that treatment, 3 of these patients achieved stable disease followed by progression within 2 to 3 months, while 1 was primary refractory to VEN monotherapy. The most frequent reported adverse events (AEs) of the RUX plus VEN combination were cytopenias, with 46.6% grade 3 or 4 thrombocytopenia and 40% grade 3 or 4 neutropenia. DBP showed that overall priming and BCL2 dependence increased in vivo (n=2) during the treatment with RUX and VEN. Finally, SNP arrays identified clonal evolution in the 3 patients evaluated sequentially (before treatment versus at progression). In one case, emergence of EZH2 and JAK1 mutation was also observed at progression using NGS. Conclusions: These preliminary results suggest promising activity of RUX plus VEN in T-PLL, and justify the development of a prospective clinical trial of this combination. Our data seem to show that this combination may be especially active for patients with JAK/STAT pathway activating mutations and that disease progression is associated with clonal evolution. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Herbaux: Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Lemonnier: Gilead: Other: travel grant; Institut Roche: Research Funding. Laribi: Jansen: Research Funding; AstraZeneca: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; BeiGene: Other: Personal Fees. Moreaux: Diag2Tec: Consultancy. Morschhauser: Janssen: Honoraria; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Davids: Ascentage Pharma: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Eli Lilly and Company: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Research to Practice: Consultancy; BeiGene: Consultancy; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Takeda: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. OffLabel Disclosure: Ruxolitinib and venetoclax are used offlabel for patients refractory to current therapeutic options, based on preclinical data.

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality. Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9; if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped; if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned. One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR ; 8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV. At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 - 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4) ; for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them. The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm; 2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively. In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy. Disclosures Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding; Novartis: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees, Research Funding; BeiGene: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Jansen: Research Funding. Cymbalista: Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.

Background Richter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS patients is usually very poor with both low response rates to chemoimmunotherapy and short survival. While BCR and BCL2 inhibitors have transformed the management of CLL patients, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of patients with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. Recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in patients with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS patients failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for patients with untreated RS of DLBCL histology (NCT03931642). The patients with persisting (PR, SD) or progressive disease (PD) after 2 cycles of R-CHOP were eligible to receive an 8-week course of blinatumomab induction. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. An additional 4-week consolidation cycle was optional. Allo-HSCT was further allowed for eligible patients. Results A total of 34 patients out of 41 has already been enrolled in the trial to date. Median age was 66 years (range, 38-82) and sex ratio M/F was 23/12. CLL features at baseline were as follows: 57% had 17p deletion and 67% TP53 mutations. Sixty-five percent had complex karyotype and 79% unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-7): 19 (54%) patients previously received chemo-immunotherapy, 23 (66%) patients were exposed to ibrutinib and 11 (31%) to venetoclax. As of the data cut-off of June 1st, 2021, the blinatumomab induction course has been completed for 18 patients. Ten patients did not receive blinatumomab for the following reasons: 7 patients achieved CR after R-CHOP, 2 patients died because of febrile neutropenia after R-CHOP and 1 patient presented severe pneumonia after R-CHOP. Three patients are still on R-CHOP and 3 others on blinatumomab to date. Regarding toxicity during blinatumomab, data are available for the 18 patients having completed the blinatumomab induction to date. All patients had at least one grade 1 adverse event (AE), 10 had grade ≥3 AE. The most common AE (> 1 case), regardless of relationship to blinatumomab, were fever (4 patients), CRS (2 patients), sepsis (2 patients), vein thrombosis (2 patients), anemia (4 patients), neutropenia (3 patients), lymphopenia (5 patients), thrombocytopenia (3 patients) and hyperglycemia (5 patients). In terms of neurologic events, 5 (28%) experienced neurotoxicity (all recovered) including grade 3 encephalopathy, grade 4 confusion, grade 3 anxiety, grade 1 myoclonus, grade 2 ataxia, grade 1 sleep disorder and grade 1 ICANS (each in 1 pt). Blinatumomab was temporarly stopped in 3 patients and permanently in 2. In terms of efficacy, after R-CHOP debulking therapy (n=31 evaluable patients), 7 patients achieved CR, 6 patients were in PR, 7 patients were stable and 11 patients were progressive. At evaluation after the blinatumomab induction (n=18 evaluable patients), 4 (22.2%) patients achieved CR, 4 (22.2%) patients PR, 2 (11.1%) patients were stable and the remaining 8 (44.5%) were progressive. Considering the whole strategy (including R-CHOP debulking) (n=28), 15 (54%) patients achieved overall response including 11 (39%) CR. Conclusions Our preliminary data suggest that blinatumomab suggests encouraging anti-tumor activity and acceptable toxicity in patients with RS. Disclosures Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Ferrant: AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Laribi: Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; Jansen: Research Funding; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding. Feugier: Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. OffLabel Disclosure: blinatumomab is approved for acute lymphoblastic leukemia. The aim of this phase 2 study is to evaluated it in patients with Richter's syndrome.

Introduction The French health agency granted access to KTE-X19 in its early access program (French ATUs) for patients with relapsed or refractory (R/R) mantle-cell lymphoma (MCL) who failed after at least one line of chemoimmunotherapy and Bruton's tyrosine kinase (BTK) inhibitor. DESCAR-T is the French national registry for all patients treated with CAR-T cells (commercial or early access program). DESCAR-T designed and sponsored by LYSA/LYSARC aims to collect "real-life" data about CAR-T cell eligible patients in all hematological malignancies. We report the first results of "real-life" use of KTE-X19 in R/R MCL. Methods. All patients with MCL and registered in DESCAR-T were eligible for the present study. The data collection started at time of the medical decision to treat with KTE-X19. All patients gave informed consent before DESCAR-T registration. Response was determined by investigators per the Lugano criteria. CAR-T cells were monitored in peripheral blood samples of 14 patients by multiparametric flow cytometry routine procedures, using the biotinylated CD19 CAR detection reagent (Miltenyi Biotec©). Results Our study started at the beginning of the French early access program on January 7 th 2020 until data extraction on June 18 th 2021. A total of 57 patients were registered, including 6 commercial use registrations of KTE-X19 (after the end of early access program). KTE-X19 product has been ordered for 55 patients of whom 47 have been infused with CAR-T cells. KTE-X19 was not ordered in 2 cases because of patient decision. It was not infused in 8 patients because of disease progression (n=3), manufacturing failure (n=3), cardiac disease (n=1) and uncontrolled infection (n=1). At the time of registration in DESCAR-T, median age of infused patients was 67 years (range 45-79), 93.6% of patients were male. Median number of prior lines of treatment was 3 (range 2-8) with 34% of autologous stem cell transplant. Initial Ki67 was high (>30%) in 78.6% of patients, 52.4% of patients had elevated LDH and 21.1% had a poor performance status (PS≥2) at inclusion.Median time between CAR-T order and infusion was 56 days (range 35-134) and 87.2% of patients had a bridging therapy. Median follow-up since CAR-T administration was 3.3 months (range 0-12.6). The best overall response rate for the 42 patients with at least one efficacy evaluation was 88%, including CR in 61.9%. PFS calculated from KTE-X19 infusion at 6 months was 57.9% (Figure A) and median duration of 5.3 months. Cytokine release syndrome (CRS) was observed in 78.7% of patients and a neurotoxicity in 48.9%. Transfer in ICU was needed in 27.7% of patients, with a median duration of hospitalization of 5 days. CRS or neurotoxicity of ≥ grade 3 were seen in 4 patients (8.5%), one patient presented both AEs. Among the 47 infused patients, 5 died, 4 of progressive disease and 1 of grade 5 CRS. Cellular kinetics parameters including area under the curve (AUC) representing the exposure from day 0 to day 28 (Figure B), maximal expansion post infusion (C MAX, Figure C) and time to maximal expansion (T MAX, Figure D) are shown. We observed a statistical trend to a shorter T MAX in responders. Conclusion This first analysis of "real-life" use of KTE-X19 supports results of clinical trials using CAR-T cells in R/R MCL. The safety profile and the overall response rate are also in line with previously published data. Taken together, the present "real-life" study experience supports the use of KTE-X19 in R/R MCL who failed after BTKi. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Herbaux: Abbvie: Honoraria, Research Funding; Roche: Honoraria; Janssen: Honoraria; Takeda: Honoraria, Research Funding. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Bouabdallah: Abbvie: Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Sandoz: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings . Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Janssen: Honoraria; Genentech, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Houot: MSD: Honoraria; Gilead: Honoraria; Roche: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria; Jsnssen: Honoraria; CHU Rennes: Current Employment; Celgene: Honoraria.

Background: MRD status is an established predictive marker for progression-free survival (PFS) in CLL following chemoimmunotherapy as well as for fixed-duration treatment with venetoclax and an anti-CD20 antibody. To date, this relationship has not been explored for the combination of Ibr+Ven, an all-oral, once-daily, fixed-duration treatment with complementary mechanisms of action that work synergistically to eliminate CLL subpopulations in distinct tumor compartments. In the primary analysis of the phase 3 international GLOW trial, independent review committee (IRC)-assessed PFS for Ibr+Ven was superior to Clb+O (hazard ratio, 0.216; p < 0.0001). Herein we further investigate MRD outcomes at the time of the GLOW primary analysis. Methods: GLOW (NCT03462719) enrolled patients (pts) aged ≥65 years or 18-64 years with cumulative illness rating scale score >6 or creatinine clearance Results: 106 pts were randomized to Ibr+Ven and 105 to Clb+O. Median age was 71.0 years, 51.7% had confirmed unmutated (u)IGHV, 18.0% had del(11q), and 4.3% had a TP53 mutation. Median follow-up was 27.7 (range, 1.7-33.8) months. MRD results are all via NGS and reported for EOT+3 unless otherwise noted. MRD Results at 10 -4: Rate of uMRD was significantly higher for Ibr+Ven vs Clb+O in BM (51.9% vs 17.1%; p < 0.0001) (Fig A) and in PB (54.7% vs 39.0%; p = 0.0259). PB/BM uMRD concordance with Ibr+Ven was 92.9%. In the Ibr+Ven arm, 65.9% (27/41) of pts with a complete response (CR) or CR with incomplete marrow recovery (CRi) and 54.9% (28/51) with a partial response achieved uMRD in BM; rates for Clb+O were 33.3% (4/12) and 16.9% (13/77), respectively. BM uMRD rates were higher for Ibr+Ven vs Clb+O across prespecified subgroups, including bulky disease (≥5 cm), del(11q), and uIGHV . In the Ibr+Ven arm, BM uMRD was higher for uIGHV (58.2%) vs mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of pts maintained PB uMRD from EOT+3 to EOT+12 vs 29.3% (12/41) with Clb+O. For pts with detectable MRD after Ibr+Ven (n = 30), MRD levels remained stable for most patients from EOT+3 to EOT+12 (Fig B). MRD Results at 10 -5: Rate of uMRD PFS by MRD Status at 10 -4 : In the Ibr+Ven arm, PFS rate during the first 12 months after EOT was >90% for pts with uMRD as well as pts with detectable MRD. In contrast, pts in the Clb+O arm with detectable MRD in PB relapsed more quickly than those with uMRD (Fig C). PFS trends were similar according to MRD status in BM (Fig D). Note that not all pts in the Ibr+Ven arm had 12 months' follow-up post-EOT. Conclusion: All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post-treatment vs Clb+O in elderly or unfit pts with previously untreated CLL. Most pts with uMRD in the Ibr+Ven arm, including those with uIGHV, achieved clearance below 10 -5, and deeper clearance in PB was mirrored in BM. In the Ibr+Ven arm, clinical relapse was infrequent during the first year off treatment for pts with known MRD status at EOT+3 (whether uMRD or detectable MRD), supported by largely sustained uMRD/MRD levels over the same period. Additional follow-up will be important to confirm these early results. Figure 1 Figure 1. Disclosures Munir: Janssen, Abbvie, AstraZeneca, Morphosys, Alexion, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen, Abbvie, AstraZeneca, Alexion, Apellis, Gilead, Novartis: Honoraria. Moreno: Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Janssen, Abbvie: Research Funding. Owen: Abbvie, AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen, Roche, Merck, Gilead, Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Follows: Roche, Abbvie, Janssen, Takeda, Janpix: Consultancy. Benjamini: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Janssens: Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene, AstraZeneca: Consultancy, Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Robak: AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; Medical University of Lodz: Current Employment. Simkovic: Janssen-Claig, Gilead, Roche, AstraZeneca, Abbvie: Consultancy, Honoraria, Other: Travel Grants, advisiory boards. Voloshin: Janssen, Abbvie, Sanofi, AstraZeneca, Takeda: Other: Clinical Trials, Non-finanfial support, Speakers Bureau; Novartis, Pfizer, MSD, La ROche: Other: Clinical Trials, Non-finanfial support. Vorobyev: Janssen, Roche, Sanofi, Takeda, Biocad, Abbvie: Other: Advisory Boards, Speakers Bureau; Astellas, Novartis, AstraZeneca: Speakers Bureau. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Qi: Janssen: Current Employment. Steele: Janssen: Current Employment. Schuier: Janssen: Current Employment. Baeten: Janssen: Current Employment. Bennett Caces: Janssen: Current Employment. Niemann: Novo Nordisk Foundation: Research Funding; CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding. Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding.

Background: Immunochemotherapy induction followed by rituximab maintenance is the standard of care in previously untreated symptomatic follicular lymphoma (FL). The phase 3 RELEVANCE study of chemotherapy-free combination immunotherapy with lenalidomide and rituximab (R 2) showed promising activity comparable to standard rituximab + chemotherapy (R-chemo) options (Morschhauser, F and Fowler, NH, et al. N Engl J Med. 2018). Reported here are the results of the second interim analysis. Methods: RELEVANCE is a global, randomized, phase 3 trial (NCT01650701) of R 2 vs R-chemo followed by rituximab in patients with previously untreated grade 1-3a FL requiring therapy according to GELF criteria. Lenalidomide dose was 20 mg/d, d2-22/28 for 6-12 cycles (c), continued in responders at 10 mg/d for a total of 18 c. Rituximab dose was 375 mg/m 2 weekly c1 and d1 c2-6 and continued in responders for 12 additional c (q8wk). R-chemo was given per investigator's choice of standard R + cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), R + bendamustine (R-B), or R-CVP, followed by 12 c of rituximab (q8wk). Co-primary endpoints were complete response (CR)/CR unconfirmed (CRu) at 120 wk and progression-free survival (PFS) by independent review committee (IRC) based on 1999 IWG criteria. The prespecified second interim analysis was done after 75% of total PFS events were reached. Results: 1030 patients with high tumor burden were randomized to R 2 (n = 513) and R-chemo (n = 517; 72% R-CHOP, 23% R-B, 5% R-CVP); baseline characteristics were similar in both groups. As of October 30, 2020, at median follow-up of 72 mo, 6-year PFS, according to IRC assessment using FDA censoring rules, was 60% for R 2 and 59% for R-chemo with a hazard ratio (HR) of 1.03 (95% CI, 0.84-1.27). Data according to investigator assessment and EMA censoring rules are shown in the table. Median PFS was not reached for both groups. CR/CRu rates at 120 wk by IRC was 48% for R 2 and 53% for R-chemo (P = 0.10). Secondary endpoints, including overall survival, event free survival, and time to next antilymphoma treatment, were also similar in both groups. 162 (32%) R 2 and 166 (32%) R-chemo patients experienced progression/relapse according to investigator assessment of which 107 and 99 patients received additional treatment(s), respectively. Histological transformation was documented in 13/513 patients the R 2 group and 11/517 patients in the R-chemo group over the 72 mo follow-up period. ORR and overall survival after subsequent treatment(s) for relapse/progression were similar in both groups. The overall safety profile in both groups was consistent with the 1st interim analysis. The number of patients with second primary malignancies (SPMs) were similar between both groups, occurring in 57 (11%) R 2-treated and 67 (13%) R-chemo-treated safety population patients. The total number of SPMs was 64 in the R 2 group and 87 in the R-chemo group, with invasive SPM accounting for 43 (67%) and 52 (60%), respectively. Grade 5 adverse events were reported in 9 (2%) R 2 and 6 (1%) R-chemo treated patients. Conclusions: R 2 continues to demonstrate comparable efficacy vs R-chemo in patients with previously untreated grade 1-3a FL requiring therapy with similar 6-year PFS (60% and 59%) and 6-year OS (89% in both groups). Also, response and overall survival after subsequent treatment were similar in both groups. The overall safety profile of both groups was consistent with the previous analysis, with no new safety signals detected. R 2 provides a chemo-free alternative to R-chemo based on immunotherapy/immunomodulation. Figure 1 Figure 1. Disclosures Morschhauser: Chugai: Honoraria; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genentech, Inc.: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nastoupil: Bayer: Honoraria; Denovo Pharma: Other: DSMC; Gilead/Kite: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; MorphoSys: Honoraria; Caribou Biosciences: Research Funding; Genentech: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Feugier: Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Palomba: Wolters Kluwer: Patents & Royalties; Lygenesis: Honoraria; Pluto: Honoraria; Ceramedix: Honoraria; Priothera: Honoraria; Nektar: Honoraria; Novartis: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Rheos: Honoraria; Magenta: Honoraria; Juno: Patents & Royalties; BeiGene: Consultancy; Kite: Consultancy; WindMIL: Honoraria; Notch: Honoraria, Other: Stock; PCYC: Consultancy. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Libby: Genentech: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; GSK: Research Funding. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Flinn: Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Haioun: Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen-Cilag: Consultancy; Miltenyi Biotec: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria; Servier/Pfizer: Honoraria; Novartis: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Bartlett: Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Brice: MSD: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Ribrag: Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Argen-X: Research Funding; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho: Celgene: Honoraria, Other: travel; Celgene/BMS: Consultancy; Janssen: Honoraria, Research Funding; Incyte: Consultancy; Takeda: Honoraria; Novartis: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Eusa Pharma: Consultancy; Clinigen: Consultancy; Kyowa Kirin: Consultancy; Morphosys: Consultancy; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Larouche: Gilead: Consultancy. Ando: Astellas Pharma: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Novartis: Honoraria; Takeda Pharmaceutical: Research Funding. Maria: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Astrazeneca: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). André: Johnson & Johnson: Research Funding; Roche: Other: Travel/accomodation/expenses, Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; AbbVie: Other: Travel/accomodation/expenses; Celgene: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Izutsu: Takeda: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Salles: Velosbio: Consultancy; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Loxo: Consultancy; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy; Rapt: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy; Miltneiy: Consultancy; Genmab: Consultancy; Janssen: Consultancy; Genentech/Roche: Consultancy; Debiopharm: Consultancy; Allogene: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Treatment of indolent B-cell non-Hodgkin lymphomas (iNHL) of renal significance is challenging given the need for deep and prolonged hematological response to restore and control renal function overtime, yet to be balanced with the risk of adverse drug-related events. This prospective single-center study included 20 patients with iNHL of renal significance (tubulointerstitial presentation [n = 8], glomerulopathy with or without monoclonal Ig deposits [n = 12]) who received a steroid-sparing regimen of rituximab plus bendamustine (BR), with either no or

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P 70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

Since the introduction of targeted therapies, specific lymphoma mortality has decreased. Possible long-term toxicities, however, are not known yet. This article describes the implementation of the SIMONAL study that investigates the hypothesis of an overconsumption of care after lymphoma treatment with a 10-year follow-up.