Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory ...agent lenalidomide could increase the activity of rituximab.
A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.
A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63%
49%), neutropenia (58%
23%), and cutaneous reactions (32%
12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50%
13%) and leukopenia (7%
2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62;
< .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.
Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
Abstract
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to ...the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations.
It is important for clinicians to understand the optimal use of tafasitamab + lenalidomide and how treatment-emergent toxicities may be managed in the broader population to prevent early treatment discontinuation. This review provides a practical clinical guide for the management of patients with relapsed/refractory diffuse large B-cell lymphoma treated with tafasitamab + lenalidomide in routine clinical practice.
Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was ...to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.
Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common subtype of large B-cell lymphoma group, with differences in prognosis, reflecting heterogeneity in pathological, ...molecular, and clinical features. Current treatment standard is based on multiagent chemotherapy including anthracycline and monoclonal antiCD20 antibody, which leads to cure of 60% patients. Recent years have brought new insights to the lymphoma biology and helped to refine risk groups. Results of these studies inspired design of new clinical trials with targeted therapies and response-adapted strategies and allowed to identify groups of patients potentially benefiting from new agents. This review will summarize recent progress in identifying high-risk DLBCL patients with employment of clinical and biological prognostic factors assessed at diagnosis and during treatment in the front line setting It will also discuss new treatment strategies with the application of targeted agents and immunotherapy, including response-adapted strategies.
Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, ...particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL.
Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS).
Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell-like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% (
= .06) and 73% (
= .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio HR, 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided
= .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided
= .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided
= .1.
In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.
•Modifying R-CHOP for DLBCL has been challenging and not reached goal efficacy.•Polatuzumab vedotin led to a breakthrough but did not achieve a universal cure rate.•Advances in genomic and molecular ...technology has improved understanding of DLBCL.•New technologies have also allowed for developing targeted, precise therapies.•DLBCL treatment must evolve to incorporate individualized and targeted approaches.
In treating diffuse large B-cell lymphoma (DLBCL), oncologists have traditionally relied on the chemotherapy backbone of R-CHOP as standard of care. The two dangers that the hematologist must navigate between are the aggressive disease (Charybdis that in the absence of therapy systematically destroys all the ships) and the toxicity of the therapies (Scylla with its six monstrous heads that devours six crew members at a time), and hematologists have to navigate very carefully between both. Therefore, three different strategies were employed with the goal of improving cure rates: de-escalating regimens, escalating regimens, and replacement strategies. With a replacement strategy, a breakthrough in treatment was identified with polatuzumab vedotin (anti-CD79B antibody/drug conjugate) plus R-CHP. However, this regimen still did not achieve the elusive universal cure rate. Fortunately, advances in genomic and molecular technologies have allowed for an improved understanding of the heterogenous molecular nature of the disease to help develop and guide more targeted, precise, and individualized therapies. Additionally, new pharmaceutical technologies have led to the development of novel cellular therapies, such as chimeric antigen receptor (CAR) T-cell therapy, that could be more effective, while maintaining an acceptable safety profile. Thus, we aim to highlight the challenges of DLBCL therapy as well as the need to address therapeutic regimens eventually no longer tethered to a chemotherapy backbone. In the intersection of artificial intelligence and multi-omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics), we propose the need to analyze multidimensional biologic datato launch a decisive attack against DLBCL in a targeted and individualized fashion.
Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, ...vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL.
Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review.
A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60%
48%), anemia (22%
14%), thrombocytopenia (17%
11%), and leukopenia (14%
15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and
= .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease.
ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically ...aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.
Purpose
This study sought to characterize transformation incidence and outcome for patients with follicular lymphoma (FL) in a prospective observational series begun after diffusion of rituximab use.
...Patients and Methods
Patients with newly diagnosed FL were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2009. Patients were actively followed for re-treatment, clinical or pathologic transformation, and death. Risk of transformation was analyzed via time to transformation by using death as a competing risk.
Results
In all, there were 631 patients with newly diagnosed grade 1 to 3a FL who had a median age at enrollment of 60 years. At a median follow-up of 60 months (range, 11 to 110 months), 79 patients had died, and 60 patients developed transformed lymphoma, of which 51 were biopsy proven. The overall transformation rate at 5 years was 10.7%, with an estimated rate of 2% per year. Increased lactate dehydrogenase was associated with increased risk of transformation. Transformation rate at 5 years was highest in patients who were initially observed and lowest in patients who initially received rituximab monotherapy (14.4% v 3.2%; P = .021). Median overall survival following transformation was 50 months and was superior in patients with transformation greater than 18 months after FL diagnosis compared with patients with earlier transformation (5-year overall survival, 66% v 22%; P < .001).
Conclusion
Follicular transformation rates in the immunochemotherapy era are similar to risk of death without transformation and may be lower than reported in older series. Post-transformation prognosis is substantially better than described in older series. Initial management strategies may influence the risk of transformation.
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