Mantle cell lymphoma (MCL) accounts for 4% to 6% of B-cell non-Hodgkin lymphoma with historically poor outcomes. With the advent of intensive first-line, targeted, and cellular therapies, outcomes ...have improved, and initial remission can be 8 to 10 years or longer. As patients experience longer remissions, this raises the question of the optimal surveillance modality. Peripheral blood minimal residual disease (MRD) analysis offers a potential alternative to surveillance imaging that is sensitive, less costly, and eliminates the risk of radiation exposure.
The clonoSEQ assay (Adaptive Biotechnologies) is an FDA-cleared commercially available Ig-HTS MRD assay with a sensitivity of 1 cell in 1,000,000. We performed a retrospective analysis of 34 patients from 2015 to 2021, who underwent MRD testing after achieving remission with first-line therapy.
With a median follow-up of 6.5 years, 10-year progression free survival (PFS) was 60% and 10-year overall survival was 92% of the entire cohort. Among 12 patients who sustained a radiographic relapse, peripheral blood became MRD+ either at or prior to the time of relapse in 11 patients (92%). The first MRD+ test had a lead time of 0 to 24 months (median 34 days) prior to radiographic relapse. Only 1 patient had a MRD− result while being found to have progressive disease on imaging. Among 22 patients who sustained continuous clinical remission, 21 have remained MRD−. Several patients were able to enjoy 2 to 4-year intervals without surveillance imaging.
Our data suggest that the clonoSEQ MRD assay is an effective surveillance tool for MCL patients following first-line therapy and is predictive of relapse prior to imaging.
Peripheral blood MRD analysis is an alternative surveillance method to radiographic imaging in patients with MCL in first remission. These patients are now experiencing longer remissions with the advent of improved therapies. We performed a retrospective analysis of patients who achieved remission with first-line therapy for MCL, who then underwent monitoring of MRD with the clonoSEQ assay. Our data suggest that the assay is an effective surveillance tool and predictive of relapse prior to imaging.
Background
Advanced‐stage Hodgkin lymphoma (HL) is a curable malignancy, although outcomes remain poor in certain patients. It remains unclear if recent advances have improved their population‐level ...survival over time.
Materials and Methods
Using the Surveillance, Epidemiology, and End Results database, we identified patients aged ≥18 years with stage III or IV classical HL as the first primary malignancy, diagnosed between 2000 and 2014 and treated with chemotherapy. Patients were stratified by date of diagnosis into three groups (2000–2004, 2005–2009, 2010–2014) to assess the trends in overall survival (OS).
Results
A total of 9,042 patients with a median age of 41 years were included. The use of frontline radiation therapy decreased in each period (21.3% 2000–2004 vs. 15.5% 2005–2009 vs. 10.7% 2010–2014; p < .001). Three‐year OS was significantly higher for patients diagnosed between 2010 and 2014 (81.8%) and 2005 and 2009 (80.6%) compared with 2000 and 2004 (78.5%; p = .0008 and .02, respectively). Whereas outcomes were poorest in the age >60 cohort, similar improvements were also seen in 3‐year OS over the three time periods within this patient population. On multivariate analysis, diagnosis in the earlier period and minority race were associated with higher mortality. Females and married patients had significantly lower mortality risk.
Conclusion
Survival of patients with advanced‐stage HL has continued to improve over time, suggesting the impact of evolving treatment approaches. Three‐year OS in the contemporary period remains inadequate at 81.8%, highlighting the need for continued research to improve their outcomes.
Implications for Practice
This article evaluates contemporary outcomes for advanced‐stage Hodgkin lymphoma (HL) in the U.S. using the Surveillance, Epidemiology, and End Results database. Although overall survival (OS) has improved in each 5‐year period since 2000, the 3‐year OS from 2010 to 2014 remains inadequate at 81.8% and is limited by patient demographics. New therapies are indicated to improve clinical outcomes in advanced‐stage HL.
This article reports trends, discrepancies, and determinants of survival in a cohort of patients with advanced stage Hodgkin lymphoma, based on a retrospective analysis of the SEER database.
The reduced risk of chronic graft-versus-host-disease (GVHD) with posttransplant cyclophosphamide (ptCy) in the setting of haploidentical related donor and more recently, with HLA-matched related and ...matched and mismatched unrelated donor allogeneic transplantation has been established. There is, however, paucity of data to show if ptCy impacts chronic GVHD pathogenesis, its phenotype and evolution after HCT regardless of the donor status. We examined the differences in chronic GVHD incidence and presentation in 314 consecutive patients after receiving their first allogeneic transplantation (HCT) using ptCy-based GVHD prophylaxis (ptCy-HCT; n = 120; including 95 with haploidentical related donor) versus conventional calcineurin inhibitor-based prophylaxis (CNI-MUD; n = 194) between 2012 and 2019. The 1-year cumulative incidence of all-grade chronic GVHD and moderate/severe chronic GVHD was 24% and 12%, respectively, after ptCy-HCT and 40% and 23% in the CNI-MUD recipients (p = 0.0003 and 0.007). Multivariable analysis confirmed that use of CNI-based GVHD prophylaxis and peripheral blood stem cell graft as the risk factors for chronic GVHD. The cumulative incidence of visceral (involving ≥1 of the following organs: liver, lungs, gastrointestinal tract, serous membranes) chronic GVHD was significantly higher with CNI-MUD vs. ptCy-HCT (27% vs. 15% at 1 year, p = 0.009). The incidence of moderate/severe visceral chronic GVHD was 20% in CNI-MUD group vs. 7.7% in the ptCy-HCT group at 1 year (p = 0.002). In addition, significantly fewer ptCy-HCT recipients developed severe chronic GVHD in ≥3 organs (0.8%) vs. 8.8% in the CNI-MUD group at 1-year posttransplant (p = 0.004). There was no significant different in relapse, non-relapse mortality, and relapse-free and overall survival between the two groups. Further investigation is needed to confirm that reduced risk and severity of chronic GVHD, less visceral organ distribution with ptCy-HCT leads to improved quality of life.
Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We ...evaluated the safety and activity of combinations of brentuximab vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma.
In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab vedotin 1·8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort D) or 1·8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab vedotin 1·2 mg/kg (cohort G) or 1·8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipilimumab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01896999. The phase 2, randomised portion of the trial is still enrolling.
Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were excluded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3-4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11 (50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53-92) in the ipilimumab group, 89% (65-99) in the nivolumab group, and 82% (60-95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34-78%) in the ipilimumab group, 61% (36-83%) in the nivolumab group, and 73% (50-89%) in the triplet therapy group. With a median follow-up of 2·6 years (IQR 1·8-2·9) in the ipilimumab group, 2·4 years (2·2-2·6) in the nivolumab group, and 1·7 years (1·6-1·9) in the triplet therapy group, median progression-free survival is 1·2 years (95% CI 1·7-not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups.
There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial (NCT01896999).
Eastern Cooperative Oncology Group-American College of Radiology Imaging Network and the National Cancer Institute of the National Institutes of Health.
Chimeric antigen receptor T‐cell (CAR‐T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B‐cell lymphoma (LBCL), remains underutilized in older patients due ...to limited clinical data. We therefore studied the safety and efficacy of CAR‐T therapy in older patients with RR LBCL in the real‐world setting. Patients aged ≥65 years with RR LBCL, treated with anti‐CD19 CAR‐T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65–89). Best objective and complete response rates were 86% and 62%, respectively. Median follow‐up after infusion was 18.3 months. The median progression‐free survival (PFS) was 6.9 months, with 6‐ and 12‐month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR‐T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR‐T in older patients, including those aged ≥80 years. The age at CAR‐T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR‐T therapy solely based on their chronological age.
Summary
Reduced‐intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo‐HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, ...there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)‐matched sibling or unrelated donor allo‐HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0·01. There were no significant differences between regimens in risk for non‐relapse mortality (NRM) (P = 0·54), relapse/progression (P = 0·02) or progression‐free survival (PFS) (P = 0·14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo‐HCT (HR = 0·28; 95% CI = 0·10–0·73; P = 0·009), but beyond 11 months post allo‐HCT it was associated with a significantly higher risk of mortality, (HR = 2·46; 95% CI = 0·1.32–4·61; P = 0·005). Four‐year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0·64), respectively. These data confirm the choice of RIC for allo‐HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo‐HCT (possibly due to late NRM events).
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