Journal of Clinical Oncology
A large number of frontline treatment options exist for mantle cell lymphoma (MCL), making selection of therapy a challenge for the clinician. In this Oncology Grand ...Rounds article, the case of a 73-year-old woman with MCL who attained remission with bendamustine and rituximab is presented. The relevant literature regarding frontline therapy is then reviewed, with particular focus on selection of induction regimen and the potential roles for autologous transplantation and/or rituximab maintenance. This literature primarily consists of prospective phase 2 and phase 3 clinical trials; however, added to this literature now is a growing body of large retrospective real-world cohorts, such as the new analysis by Martin et al,
the manuscript that accompanies this Oncology Grand Rounds article. In some cases, the real-world evidence is at odds with data from prospective clinical trials, such as regarding the role of rituximab maintenance after bendamustine plus rituximab induction. These important new real-world data are put into context of an ever-changing treatment landscape, in hopes of aiding clinicians in frontline treatment selection for patients with MCL.
Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies
. Despite impressive outcomes, relapse with CD19
disease remains a ...challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB-CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10
-2.5 × 10
cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10
cells per kg was chosen for expansion. Grade 3-4 cytokine release syndrome occurred in one (5%) patient, and grade 3-4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10
cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
Given the limited treatment options for relapsed lymphoma post–allogeneic hematopoietic cell transplantation (post–allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin ...lymphoma (cHL) patients, anti–PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti–PD-1 mAbs for relapse post–allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post–allo-HCT and prior to anti–PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti–PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti–PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti–PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post–allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.
•Checkpoint blockade via anti–PD-1 mAbs was associated with a high overall response rate in relapsed Hodgkin lymphoma allo-HCT patients.•Checkpoint blockade via anti–PD-1 mAbs after allo-HCT can be complicated by rapid onset of severe and treatment-refractory GVHD.
Incidence and survival trends in mantle cell lymphoma Epperla, Narendranath; Hamadani, Mehdi; Fenske, Timothy S. ...
British journal of haematology,
June 2018, 2018-06-00, 20180601, Letnik:
181, Številka:
5
Journal Article
Primary bone diffuse large B-cell lymphoma is a rare variant of extranodal non-Hodgkin lymphoma historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It ...remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited stage disease. We conducted a multicenter, retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field. A total of 112 patients were included: 78 received CIT and radiation (RT group), and 34 received CIT alone (no RT group). The overall survival at 10 years was 77.9% in the RT group and 89.0% in the no RT group (P=0.42). The relapse-free survival at 10 years was 73.5% in the RT group and 80.3% in the no RT group (P=0.88). Neither improved overall survival nor relapse-free survival was associated with the addition of consolidative RT. Subgroup analysis of patients only achieving a partial response after CIT suggests that these patients may benefit from consolidative RT.
Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved ...isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies.
We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766.
Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0–14·0) or 133 days (IQR 55–335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 43% of 90 patients), nausea (38 42%), and fatigue (28 31%). The most common grade 3 or 4 adverse events were neutropenia (in 12 13% patients), anaemia (eight 9%) and thrombocytopenia (six 7%). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib.
Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting.
TG Therapeutics.
Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter ...phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. This trial is registered at www.ClinicalTrials.gov as NCT00540007.
Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13q32) translocation, is a clinically heterogenous disease which can range from indolent to highly ...aggressive. Numerous prognostic factors have been identified, including blastoid histology, the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, high proliferation index, p53 deletions and/or mutations, complex karyotype, minimal residual disease, and several others. However, using these prognostic factors to guide treatment selection has largely remained elusive. Given the heterogeneous behavior of this disease and varying patient characteristics, we suggest that the time has come for a more risk-adapted approach to this disease. In this article, we review the numerous prognostic factors that have been described for MCL, both at the time of diagnosis and following first-line treatment. We then propose a risk-adapted approach to first-line therapy for MCL, which would reserve intensive therapy for the highest risk patients and spare others excessive toxicity.
Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation ...(autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.
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