Nehočkinski limfom

COVID19, Hočkinov limfom, Hronična limfocitna leukemija, Leukemije, Multipli mijelom, Nehočkinski limfom

FINDINGS FROM A RETROSPECTIVE CASE STUDY OF COVID-19 INFECTION IN CANCER PATIENTS IN WUHAN: AN EMPHASIS ON SEVERE EVENTS

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Analysis of risk factors associated with admission to an intensive care unit, the use of mechanical ventilation or deathDate:30 Mar 2020Topics:Cancer in Special Situations / Population A study team composed from clinicians from three hospitals in Wuhan, China, led by Dr Min Zhou of the Department of the Respiratory and Critical Care Medicine, Tongji Hospital, performed a retrospective case study of clinical features among 28 patients with cancer and COVID-19 infection. In particular, they analyzed the risk factors associated with admission to an intensive care unit, the use of mechanical ventilation or death. Their series was associated with poor outcomes. There was increased risk of developing severe events, especially if the last antitumour treatment was within 14 days of COVID-19 diagnosis. The findings are published on 23 March 2020 in the Annals of Oncology. Like the other coronaviruses, SARS-CoV-2 primarily causes respiratory tract infection. The study team wrote that data published in The Lancet Oncology on 18 patients with cancer diagnosis from a cohort of 2007 cases with COVID-19 disease in China represents a relatively small sample with limited clinical information and high heterogeneity of the course of the disease. Therefore, critical issues concerning treatment principles for cancer patients with COVID-19 infection are unclear. There is an urgent need to answer whether cancer patients with COVID-19 infection will have distinct clinical course and worse outcomes, such as death from the infection or severe pneumonia, and whether cancer patients should receive antitumour treatments as usual. The study team aimed to explore these issues by conducting a rapid retrospective case study on critical COVID-19-infected cancer patients. They analyzed cancer patients with laboratory confirmed COVID-19. The clinical data were collected from medical records from 13 January 2020 to 26 February 2020. In total, 28 cancer patients with COVID-19 infection were included. Of those, 17 patients (60.7%) were male. Median age was 65.0 years. Lung cancer was the most frequent cancer type in the cohort with 7 patients (25.0%), followed by oesophageal cancer in 4 patients (14.3%) and breast cancer in 3 patients (10.7%). Ten patients (35.7%) were diagnosed with stage IV cancer. Eight patients (28.6%) were suspected to be from hospital-associated transmission. All the patients had a history of antitumour therapy. Within 14 days of COVID-19 diagnosis, 6 patients (21.4%) were treated by at least one kind of antitumour therapy, such as chemotherapy in 3 patients (10.7%), targeted therapy in 2 patients (7.1%), radiotherapy in 1 patient (3.6%), immunotherapy in 1 patient (3.6%); one of them received treatment combining chemotherapy and immunotherapy. There were two main clusters of patients: 8 patients (28.6%) who developed COVID-19 undergoing antitumour therapy in hospitals and 20 patients (71.4%) in their communities. In addition to cancer, 11 patients (39.2%) had at least one or more comorbidities. The following clinical features were present in studied cohort: fever in 23 patients (82.1%), dry cough in 22 patients (81%) and dyspnoea in 14 patients (50.0%), along with lymphopaenia in 23 patients (82.1%), high level of high-sensitivity C-reactive protein in 23 patients (82.1%), anaemia in 21 patients (75.0%) and hypoproteinaemia in 25 patients (89.3%). The common chest CT findings were ground-glass opacity in 21 patients (75.0%) and patchy consolidation in 13 patients (46.3%). In total, 22 patients (78.6%) received oxygen therapy, 10 patients (35.7%) were put on invasive mechanical ventilation, with 2 patients (7.1%) requiring endotracheal intubation and invasive ventilation because of progressive hypoxia. Significantly more severe cases were subjected to mechanical ventilation (non-invasive: 53.3% vs 0%, p < 0.001; invasive: 13.3% vs 0%, p < 0.001) as compared to non-severe cases. The median period of mechanical ventilation for non-invasive and invasive ventilation was 2.5 days. None of the severe patients received extracorporeal membrane oxygenation. In the series, 20 patients (71.4%) were prescribed at least one antiviral agent, while 9 patients (32.1%) received combinations of antiviral agents. Empirical antibiotic therapy was given to 23 patients (82.1%). Systemic corticosteroids were given to 15 patients (53.6%). Administration of corticosteroids was more frequent in patients with severe events (12/15, 80%) than non-severe cases (3/13, 23.1%). Seven of 8 patients with acute respiratory distress syndrome (ARDS) received systemic corticosteroids. The dosage and period of corticosteroids in the severe cases was higher than in non-severe cases, but the difference was not significant. Moreover, intravenous immunoglobin was prescribed to 12 patients (35.7%). As of 26 February 2020, 15 patients (53.6%) developed severe clinical events, 6 patients (21.4%) were admitted to intensive care unit, 10 patients (35.7%) had life-threatening complications and 8 patients (28.6%) died. Of the 10 stage IV cancer patients, 7 patients (70%) had developed severe events, while 44.4% of the non-stage IV patients had such events. Among 6 cancer patients who received antitumor treatment within 14 days of COVID-19 disease diagnosis, 5 patients (83%) developed severe events. Additionally, 11 of 13 patients (84.6%) with patchy consolidation on CT on admission had developed severe events. The most common complication was ARDS in 8 patients (28.6%), followed by septic shock in 1 patient (3.6%), and acute myocardial infarction (AMI) in 1 patient (3.6%). Two patients (7.1%) were suspected to have pulmonary embolism. Ten of 28 patients (35.7%) had been discharged with a median hospital stay of 13.5 days; 10 patients (35.7%) were still inpatients with a median stay of 19.0 days. Of the 28 patients, 8 patients (28.6%) died, with a median time of 16.0 days from admission to death. The cause of death included ARDS in 5 patients (62.5%), followed by pulmonary embolism in 1 patient (12.5%), septic shock in 1 patient (12.5%) and AMI in 1 patient (12.5%). In univariate Cox proportional hazards model, cancer patients who received antitumour treatment within 14 days of COVID-19 diagnosis had a higher risk of developing severe events. Moreover, patchy consolidation on the first CT on admission suggested an elevated risk of developing severe events than those cases without consolidation. Similar results were observed in the multivariate-adjusted Cox proportional hazards model after being adjusted for age and gender. If the last antitumour treatment was within 14 days, it significantly increased the risk

Hronična limfocitna leukemija, Nehočkinski limfom

Implementation of CAR T-cell therapy in the real world – A round table discussion

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The Lymphoma Hub is pleased to report a summary of real-world experiences of chimeric antigen receptor (CAR) T-cell implementation as discussed at the 2nd European CAR T-Cell Meeting. Contributors included Stephan Mielke, Karolinska Institute, Stockholm, SE, Gilles Salles, South Lyon University Hospital, Lyon, FR, and Marcelo C. Pasquini, Medical College of Wisconsin, Wisconsin, US. To begin, Professor Stephan Mielke focused on the progression of CAR T implementation in Sweden. He explained that there are four CAR T-cell treatment centers, only two of which offer CAR T therapy as standard of care (SOC). The centers, Lund, Gothenburg, Stockholm and Uppsala, have formed the basis for Sweden’s CAR T-cell competence network (SWECARNET). SWECARNET stands as a cooperative network between academia, healthcare providers and the industry aiming to deliver education and quality assurance through meetings and lectures. Professor Mielke made it clear that access to CAR T-cell therapy is not equally distributed throughout Europe and hopes that SWECARNET will assist in overcoming the complexities of CAR T-cell implementation.1 We were also pleased to speak to the chair of our Lymphoma Hub, Professor Gilles Salles, who discussed real-world data from the French cohort study previously presented by Catherine Thieblemont at the 24th Congress of the European Hematology Association (EHA).2 The Lymphoma Hub interviewed Professor Thieblemont at EHA 2019 and the video is available here. French cohort study design2 Retrospective data from five centers across France: Lille, Lyon, Montpellier, Nantes and Paris (Saint-Louis), were collected from July 17th – December 31st, 2018 Patients with relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL) were treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel Objectives: Organization of CAR T-cell implementation in France Measure the outcome of CAR T-cell therapy in the real world Results Characteristics of patients receiving ‘real world’ CAR T therapy and those involved in the clinical trials, ZUMA 1 and JULIET, are compared in Table 1 Table 1. Patient characteristics from real world, ZUMA and JULIET studies Characteristics Real world, LYSA2 ZUMA 13 JULIET4 Median age(range), years 53 (18—77) 58 (23—76) 56 (22—76) Male, % 66 67 61 Histology: DLBCL, PMBCL/TFL, % 43/8/9 76/8/16 79/19/0 ECOG PS 0/1, %ECOG PS 2-4, % 937 42/58 55/45 IPI score 3/4, % 53 46 72 Disease stage III/IV, % 80 85 76 Median prior therapies (range), n 4 (2—8) 3 (1—10) 3 (2—6) Refractory to ≥2 lines of therapy, % 68 (primary refractory) 76 55 Relapse <1-year post-auto-SCT, % 30 21 49 Auto-SCT, autologous stem-cell transplantation; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, International Prognostic Index; LYSA, The Lymphoma Study Association; PMBCL, primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma At a three-month follow-up (n= 53): Progression free survival (PFS) was 53.7% (95% CI, 41.6—69.2) Overall survival (OS) was 82.2% (95% CI, 72.3—93.5) Prognostic factors found to have a significant impact on OS following CAR T infusion were: Number of prior lines of therapy, hazard ratio (HR)= 1.80 (95%CI, 1.26—2.58) p= 0.001 Eastern Cooperative Oncology Group performance status (ECOG PS) at screening, HR= 3.69 (95%CI, 1.51—9.03) p= 0.004 Absence of infection, HR= 0.10 (95%CI, 0.01—0.89) p= 0.039 Professor Salles also presented data from studies reporting CAR T-cell therapy experiences in the UK, Spain and Germany (Tables 2 and 3). Table 2. Reported experience of tisagenlecleucel and axi-cel treatment in the UK   Tisagenlecleucel (n= 24) Axi-cel (n= 56) CR, % 17 24 PR, % 12 16 PD, % 71 59 Death, % 0 4 CR, complete response; PR, partial response; PD, progressive disease Table 3. Reported experience of tisagenlecleucel and axi-cel treatment in Spain and Germany   Spain5 Germany2 Study design 5 centersn= 36 infused Single center; Munichn= 21 infused Median age, years 51 60 Treatment Tisagenlecleucel (n= 36) Tisagenlecleucel (n= 9) or axi-cel (n= 12) CR*, % 26 25 Median PFS, months 3 – Axi-cel, axicabtagene ciloleucel; CR, complete response; PFS, progression free survival*CR is representative of patients receiving CAR T-cell infusion Aside from delivering valuable data from a number of European studies, the key message from Professor Salles was the urgent need for a uniformed system worldwide, particularly between Europe and the US. As shown by the studies presented, CAR T-cell data remain incomplete, with countries using different readout measures for clinical efficacy, prognosis and toxicities. Availability of patient data through collaboration is required to provide a greater picture regarding factors contributing to CAR T-cell therapy outcome. A summary of novel routine guidelines was presented by Ibrahim Yakoub-Agha, Lille University Hospital, Lille, FR, at the 2nd CAR T meeting and was recently covered by the Lymphoma Hub, see more here.  Finally, Professor Marcelo C. Pasquini emphasized the need for an efficient CAR T-cell registry (CT registry) to maximize the utilization and coordination of CAR T-cell therapy worldwide. Not only is the CT registry important in managing regulatory requirements, such as long-term follow-up and post approval safety studies (PASS), but also in developing a uniform grading system for CAR T-cell toxicities like cytokine release syndrome (CRS) and neurological events (NE). It has been extremely difficult to compare safety data across clinical trials due to the variations between toxicity grading systems. Professor Pasquini hopes that the CT registry and implementation of the novel American Society for Blood and Marrow Transplantation (ASTCT) consensus grading system will help to lower the incidences of serious toxicities through correct evaluation and treatment approach.6 The Lymphoma Hub covered toxicity grading systems reported during the 45th Meeting of the European Society for Blood and Marrow Transplantation (EBMT) in Frankfurt, DE, which can be accessed here. Professor Pasquini also highlighted how the rapid increase in CAR T-cell therapy is already impacting worldwide practices. Since 2016, 2058 patients have received CAR T-cell therapy across 123 CAR T centers worldwide, over half of which taking place in 2019. It was made very apparent that the level of hematopoietic cell transplantation (HCT) is declining in line with a rise in CAR T-cell therapy. To date, the primary indication for CAR T therapy in the US, comprising 71% of applications, is non-Hodgkin lymphoma (NHL), followed by acute lymphocytic leukemia (ALL; 22%) and multiple myeloma (MM; 6%).6 Take home message All three contributors highlighted the demand for European and worldwide collaboration to increase the availability, effectiveness and

Hočkinov limfom, Hronična limfocitna leukemija, Nehočkinski limfom

Body size and obesity during adulthood, and risk of lympho-haematopoietic cancers: an update of the WCRF-AICR systematic review of published prospective studies

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Overweight and obesity are a global health problem. During the last 40 years, the number of obese adults increased from 100 million in 1975 (69 million women, 31 million men) to 671 million in 2016 (390 million women, 281 million men) [1]. Excess weight and obesity have been linked to several chronic diseases including cardiovascular disease [2, 3], diabetes [3] and many types of cancers including lympho-haematopoietic cancers [4]. The age standardized incidence rates worldwide (per 100 000 inhabitants) were estimated of 1.0 for Hodgkin’s lymphoma (HL), 6.7 for non-Hodgkin’s lymphoma (NHL), 2.1 for multiple myeloma (MM) and 5.7 for leukaemia in 2018 [5]. Although, lympho-haematopoietic cancers are not as frequent as other cancers such as lung, breast, colorectal and prostate cancers, it is very important to investigate their association with overweight and obesity, which are the major public health issues. Consequently findings can add to the existing literature about the importance of lifestyle modification specifically weight management in prevention of haematological cancer incidence and mortality [4]. Previous meta-analyses published up to 2014, showed that greater body mass index (BMI) may increase the risk of HL [6], NHL [6], diffuse large beta-cell lymphoma (DLBCL) [7], myeloma [8] and leukaemia [9]. Since the publication of these metaanalysis, several additional large prospective studies with large number of cases have been published [10–16]. The accumulated evidence has greatly enhanced the investigation of how these modifiable risk factors influence the development of the many different types of lympho-haematopoietic cancers. Moreover, whether BMI in early adulthood (age 18–21 years), height and abdominal obesity increase the risk of lympho-haematopoietic cancers have not been summarized in a meta-analysis. Therefore, we conducted a systematic literature review and meta-analysis of prospective studies of BMI, BMI in early adulthood, height, weight, waist circumference (WC) and waist-to-hip ratio (WHR), and the risk of lymphoma, myeloma and leukaemia, and their main types to provide an up-to-date and comprehensive assessment of the existing evidence. We aimed to clarify the strength and shape of dose–response relationship between the general and abdominal adiposity and lympho-haematopoietic cancers and investigate any potential differences by sub-sites, sex, geographical locations, size of cohort, number of cases, years of follow-up, exposure assessment methods and adjustment for potential confounders. Search strategy and inclusion criteria The CUP team at Imperial College London searched in PubMed for studies on anthropometric measures including BMI, BMI in early adulthood (age 18–21 years), height, weight, WC and WHR, and lympho-haematopoietic cancer risk up to December 2017. The specific search criteria and the review protocol can be seen in supplementary materials, available at Annals of Oncology online. Study selection Our study selection was restricted to cohort (prospective, retrospective, case–cohort or nested case–control studies) studies which investigated the link between anthropometric measures and lympho-haematopoietic cancer risk and mortality, and reported estimates of the relative risk (RR) (e.g. hazard ratio, risk ratio or odds ratio) and 95% confidence intervals (CIs) for the exposures of interest [BMI, BMI in early adulthood (aged 18– 21 years), weight, WC and WHR]. In case of studies reporting only categorical results, number of cases and denominator data (person-years of follow-up or number of subjects) were required for inclusion in the meta-analysis. If there were multiple publications from the same study, the newest publication that included the largest number of cases was selected. Data extraction We extracted the following data from each study: authors, year of publication, country of origin, cancer type, length of study and loss of follow-up, sample size, numbers of cases and population at risk/controls, age, sex and other characteristics, anthropometric measures, RRs and 95% CIs or P-values for each exposure category and adjustment variables. A second reviewer checked at least 10% of the work. Statistical analysis We calculated the summary RRs and 95% CIs using random-effect models that takes into account heterogeneity between studies [17]. Q and I 2 statistics were used to determine heterogeneity [18], potential sources of which were explored in stratified analyses by sex, geographical location, exposure assessment methods, years of follow-up, number of cases, size of cohort and adjustments for confounders including alcohol consumption, smoking and physical activity. We used RR estimates and CIs for continuous increments directly from the articles if provided, and for studies that only reported categorical data, dose–response associations and 95% CIs were derived using generalized least-squares for trend estimation [19], which required the RRs and CIs associated with at least three categories of anthropometric measures, and the number of cases and non-cases or person-years of follow-up per category to be available. If only the total number of cases or person-years was reported in the articles, and the exposure was categorized in quantiles, the distribution of persons or person-years was calculated by dividing the total number of persons or person-years by the number of quantiles. We used the mean or median values per each anthropometric category if available in the articles, or the midpoint was calculated for studies that only reported a range by category. If the range of the highest or lowest category was open-ended, its width was assumed to be the same as the adjacent category. In case of close-ended lowest and highest categories with category widths substantially greater than those of the middle-categories (e.g. highest category of 35–60 kg/m2 of BMI), the Cheˆne and Thompson [20] method was used to estimate the midpoints. The Hamling method was used to recalculate the RR estimates when the first category was not used as reference [19]. If the results were reported for men and women separately, they were combined using a fixed effects meta-analysis before being pooled with other studies in linear, but not non-linear, analyses. We assessed small-study effects, such as publication bias, by using funnel plots and Egger’s test [21]. We assessed a potential nonlinear dose–response association between anthropometric measures and risk of lympho-haematopoietic cancers when we had 3 studies by calculating restricted cubic splines for each study, using three fixed knots at 10th, 50th and 90th percentiles of distribution of the exposure to account for a wider exposure range

Hočkinov limfom, Hronična limfocitna leukemija, Nehočkinski limfom

BMT Societies Issue Recommendations on Posttransplant Maintenance in HL/NHL

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The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) have released consensus recommendations on the use of maintenance therapies after autologous transplantation for patients with Hodgkin (HL) or non-Hodgkin lymphoma (NHL).1 Use of maintenance therapy as a therapeutic strategy in posttransplant patients with HL and NHL is increasing in frequency, according to panel member Mehdi Hamadani, MD, of CIBMTR and Medical College of Wisconsin in Milwaukee. This joint panel was tasked with reviewing available data from clinical trials and summarizing evidence about the contemporary use of maintenance therapy in these patients to help guide therapy in a rapidly advancing field. “Clinical trials evaluating maintenance treatments in lymphoma patients undergoing autologous transplantation cannot keep pace with the speed of drug development; which effectively means, by the time these trials are published the results are no longer applicable to modern patient population[s],” Dr Hamadani told Cancer Therapy Advisor. For example, the large AETHERA clinical trial of brentuximab vedotin consolidation after autologous transplant in high-risk patients with HL showed that patients derived a disease-free survival benefit from that therapy.2 However, 1 of the main eligibility criteria for that trial was that patients could not have had prior exposure to brentuximab vedotin. “The problem is that in 2018, brentuximab got approval for frontline therapy in HL and is also now commonly used in second-line therapy,” Dr Hamadani said. “The population that the AETHERA trial used is becoming less relevant in the real world and we have no trial data available on how to handle those patients.” To issue its recommendations, the panel used the RAND-modified Delphi method, which generates consensus statements where at least 75% of a panel vote in favor of a recommendation. The panel issued 22 consensus recommendations. Several grade A recommendations, indicating good research-based evidence to support the recommendation, are discussed below. The first consensus statement for HL was use of post-autologous hematopoietic stem cell transplantation (HCT) consolidation/maintenance with brentuximab vedotin for 16 cycles in brentuximab vedotin-naive classic HL with at least 1 or more high-risk features as defined by the AETHERA study. A second grade A recommendation was rituximab maintenance therapy in patients with mantle cell lymphoma undergoing auto-HCT after first-line therapy. In these patients, a randomized trial has shown improved progression-free and overall survival with this maintenance regimen compared with observation alone.3 Rituximab maintenance was also recommended in rituximab-naive patients with follicular lymphoma. This recommendation was based primarily on data from the EBMT study,4 which showed that rituximab maintenance after transplant was safe and significantly prolonged progression-free (but not overall) survival. “However, the panel acknowledges that rituximab-naive status at the time of auto-HCT in patients with FL in the current era would be rare, thus limiting the clinical impact of this statement,” the panelists wrote. According to Henry Chi Hang Fung, MD, FACP, director of the Fox Chase-Temple University Hospital Bone Marrow Transplant Program in Philadelphia, Pennsylvania, these recommendations do not necessarily offer up any new data, but instead represent the opinion of bone marrow transplant experts. “These are all based on studies that have already been published, some quite some time ago,” Dr Fung noted. “Because these are from multiple transplant societies, the target audience is definitely transplant doctors, who are highly specialized.” “It is good to get everyone on the same page with recommendations like these, where there is consensus, and of equal importance are the areas where there is no consensus, like in DLBCL [diffuse large B-cell lymphoma],” Dr Fung said. Dr Fung was referring to a final grade A consensus statement recommending against post-transplant maintenance therapy in patients with DLBCL. According to Dr Hamadani, in patients with DLBCL, some clinicians may give maintenance therapy off-label, but there is a lack of evidence base for this. “Maintenance therapies, even with older drugs like rituximab, are not free from side effects and are expensive,” Dr Hamadani said. “We reviewed all trials looking at rituximab after transplant in DLBCL and the studies were negative. They don’t show any survival benefit.” Ongoing clinical trials looking at target therapies in DLBCL may change this recommendation in the future, but clinical trial data are not yet mature.   Source: www.cancertherapyadvisor.com

Nehočkinski limfom

Next-generation therapy for follicular lymphoma

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Morschhauser et al report the safety and efficacy of lenalidomide in combination with obinutuzumab and establish the recommended phase 2 dose (RP2D).1 Rituximab in combination with lenalidomide (R2) has favorable efficacy and toxicity in relapsed and untreated follicular lymphoma (FL) and is now entering the treatment landscape of FL.2⇓–4 Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC), may be an attractive partner to lenalidomide that can exert immunomodulatory effects via natural killer (NK) and T cells for the treatment of relapsed or refractory (R/R) FL. The question is whether the potentially enhanced ADCC activity of obinutuzumab will translate into enhanced synergism with lenalidomide and result in an improved next-generation R2. Outcomes for FL have improved over the past few decades, and many patients diagnosed in the modern era can anticipate a normal life expectancy.5 However, FL remains a disease associated with continued risk for relapse. Currently, the greatest unmet need in new drug development is to alter the natural history among those who experience early relapse (<24 months) following frontline chemoimmunotherapy.6 Identifying effective, well-tolerated therapies that result in meaningful remission duration without negatively impacting quality of life remains fundamental to clinical research in this field. Providing insight into treatment selection and sequencing of therapy is also desirable given the list of therapeutic approaches is nearly as long as the natural history of this disease. With those ground rules, how do we interpret/incorporate the findings of this phase 1b dose-escalation study into the ever-expanding treatment landscape of FL? Obinutuzumab is US Food and Drug Administration (FDA) approved for R/R patients with FL based on the GADOLIN study, which compared obinutuzumab in combination with bendamustine followed by obinutuzumab maintenance to bendamustine alone in patients with rituximab-refractory indolent lymphoma. With a median progression-free survival (PFS) of 25.8 months vs 14.1 months, the obinutuzumab-containing arm was superior to chemotherapy alone.7 Neutropenia, an adverse event associated with obinutuzumab was one of the most common grade 3 or higher adverse events observed at 27.5%. GADOLIN provides a snapshot of the efficacy and safety of obinutuzumab in combination with bendamustine in rituximab-refractory. Though superior to chemotherapy alone, it is less clear whether obinutuzumab is superior to rituximab in this setting based on the study design. Targeted therapies have been promising in R/R FL. Idelalisib, a phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, and copanlisib, a pan-PI3K inhibitor with predominant activity against α and δ isoforms, are both approved for the treatment of R/R FL patients who have failed at least 2 prior lines of therapy. Idelalisib was associated with a 57% objective response rate (ORR) and 11-month PFS among patients refractory to rituximab and an alkylating agent.8 Copanlisib was associated with an ORR of 59% and median PFS of 11 months.9 Though similar in efficacy, the safety profile of these 2 PI3K inhibitors is different, with less gastrointestinal toxicity and higher rates of hyperglycemia and hypertension associated with copanlisib. The toxicity profile of PI3K inhibitors (ie, pneumonitis, colitis, transaminitis, rash, and infection) has likely impacted the uptake of these drugs despite their efficacy profile in poor-risk patients. R2 is under active exploration for relapsed indolent lymphoma. The phase 3 AUGMENT study met its primary end point of superior PFS of R2 compared with rituximab monotherapy in relapsed follicular and marginal zone lymphoma. The details are forthcoming but will likely lead to FDA approval of R2 for R/R FL. The control arm is likely to impact the excitement surrounding this study, but it is important nonetheless to allow exploration of the impact of combination over R monotherapy. The MAGNIFY study is examining 12 cycles of R2 followed by R2maintenance vs rituximab maintenance in indolent and mantle cell lymphoma. Preliminary efficacy has been reported for the FL subgroup including cohorts of early-relapse or double-refractory (CD20 monoclonal antibody and alkylating agent) patients.4 R2 was associated with an ORR of 66% and 1-year PFS estimates of 70% for R/R FL. The early-relapse and double-refractory cohorts had less favorable but meaningful outcomes, with ORRs of 47% and 45% and 1-year PFS estimates of 49% and 65%, respectively. Neutropenia was one of the most common grade 3 or 4 adverse events at 29%. R2 appears to be an effective, manageable strategy for R/R FL. It remains unknown whether the greatest uptake will be in third-line or earlier lines of therapy. This leads us to the current study: obinutuzumab in combination with lenalidomide in R/R FL. This dose-escalation study established the RP2D of lenalidomide at 20 mg in combination with a fixed dose of obinutuzumab (1000 mg). Only 19 patients were evaluable for safety and efficacy and had favorable features. Mean age was 61.5 years, and most had excellent performance status (80% Eastern Cooperative Oncology Group 0), responded to prior rituximab (60%) or prior lymphoma therapy (80%), and had nonbulky disease (75% with lymph nodes <5 cm in size). With a median follow-up of 38.1 months, the 3-year PFS was 52% and ORR was 63%. The most common grade 3 or higher adverse event was neutropenia at 26%. Therefore, the combination appears effective and manageable, with no new safety signals. Commendable is the schedule (6 cycles of therapy). In an era where longer duration of therapy is commonly pursued, this is an important distinction for this study. Larger studies are necessary to understand whether this is a superior option to the available therapies, most importantly, its predecessor (R2). Where do we go from here? The importance of this study is establishing the RP2D for the potentially practice-changing trials. An important study, SWOG S1608, is a randomized phase 2 study exploring 3 arms for early-relapsing FL. One arm is obinutuzumab and lenalidomide. The other arms include a PI3Kδ inhibitor in combination with obinutuzumab and a chemoimmunotherapy arm. Understanding how to approach early-relapse FL is critical and will address the greatest unmet need. Obinutuzumab and lenalidomide have a critical role in one of the most important modern-day FL studies. Source: Blood 2018 132:1465-1467

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