Purpose of Review
Enhancer of Zeste Homolog 2 (EZH2) is histone methyltransferase and catalyzes the methylation of histone 3 lysine 27, a mark of transcriptional repression. Various studies have ...elucidated the complex role of EZH2 in both normal biology and tumorigenesis. Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma.
Recent Findings
Activating mutations and overexpression of EZH2 are found in non-Hodgkin lymphoma (NHL). As a result, several EZH2 inhibitors have been developed and entered clinical investigation. Tazemetostat, first-in-class EZH2 inhibitor, demonstrated enhanced clinical activity in mutant follicular lymphoma and diffuse large B cell lymphoma.
Summary
With the early activity noted by tazemetostat in B cell lymphomas, the role of EZH2 inhibition in NHL is becoming more evident. This can be leveraged in future rationale combinations to enhance the activity of EZH2 inhibitors.
Lessons Learned
Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan‐class inhibitors, and increased ease of use.
ACY‐1215 is well tolerated and led to disease ...stabilization in 50% of patients treated on a twice‐daily dosing schedule.
Rational drug combinations with ACY‐1215 improve efficacy in patients with lymphoma.
Biomarkers such as XBP‐1 level or HDAC6‐score may improve patient selection.
Background
ACY‐1215, ricolinostat, is an oral, first‐in‐class isoform‐selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY‐1215 disrupted proteostasis, triggering apoptosis.
Methods
We translated these findings into a multi‐institution, open‐label, dose‐escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma.
Results
Twenty‐one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10). ACY‐1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1–2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3–4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY‐1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days.
Conclusion
ACY‐1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.
Mature T-cell and NK-cell lymphomas (MTNKL) are rare and heterogeneous lymphoproliferative disorders with poor clinical outcomes despite novel therapeutic advances. Although infrequent, central ...nervous system (CNS) involvement by MTNKL is associated with poor outcomes with a median overall survival (OS) of <12 months based on retrospective studies. We performed a retrospective analysis of patients who developed CNS involvement of MTNKL diagnosed at a single center from 1999 through 2020. Twenty-five patients were identified. Characteristics such as a diagnosis of adult T-cell leukemia/lymphoma, extranodal involvement, and poor performance status were associated with a higher risk of CNS involvement (
< 0.01). The median OS after diagnosis with CNS involvement was approximately 1 month (0.03-103.97 months). Patients exposed to novel therapeutics and/or clinical trial enrollment tolerated treatment without safety concerns and appeared to derive reasonable therapeutic benefit. Despite advances in the field, new therapeutic approaches are needed for patients with MTNKL with CNS involvement.
Brentuximab vedotin is currently approved for patients with relapsed or refractory Hodgkin's lymphoma who previously received an autologous stem cell transplant or two previous multiagent ...chemotherapy regimens, and for patients with relapsed or refractory systemic anaplastic large-T-cell lymphoma who previously received at least one chemotherapy regimen. A high proportion of patients with CD30-expressing relapsed or refractory lymphomas have durable responses to single-agent brentuximab vedotin and show longer progression-free survival than do patients treated with chemotherapy. In patients with Hodgkin's lymphoma and peripheral T-cell lymphoma, treatment with bendamustine alone only achieves modest improvements in progression-free survival compared with that for chemotherapy. The objective of this study was to explore the safety and clinical activity of the combination of brentuximab vedotin plus bendamustine in heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma and anaplastic large-T-cell lymphoma.
In this international, multicentre, single-arm, phase 1–2 trial, eligible patients were aged 18 years or older, had histologically confirmed relapsed or refractory Hodgkin's lymphoma or anaplastic large-T-cell lymphoma, had biopsy-proven CD30-positive tumours, had an Eastern Cooperative Oncology Group performance status of 2 or less, and received at least one previous multiagent chemotherapy regimen. In phase 1, patients were assigned following a 3+3 dose-escalation design to one of four cohorts to receive one dose of either 1·2 mg/kg or 1·8 mg/kg of brentuximab vedotin intravenously on day 1 of a 21 day cycle, plus one dose of bendamustine (70 mg/m2, 80 mg/m2, or 90 mg/m2) on days 1 and 2 of the treatment cycle. In phase 2, all patients were assigned to receive brentuximab vedotin plus bendamustine at the recommended phase 2 dose from phase 1. The primary endpoints were maximum tolerated dose and dose-limiting toxicity for phase 1, and the proportion of patients achieving an overall response in phase 2. For both phases 1 and 2, all patients receiving at least one dose of study drug were evaluable for toxicity and all patients completing at least one cycle of therapy were evaluable for response. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01657331.
Between July 26, 2012, and May 31, 2017, we enrolled and assigned 65 patients to treatment (64 98% with Hodgkin's lymphoma and one 2% with anaplastic large-T-cell lymphoma; 28 43% during phase 1 and 37 57% during phase 2). In the phase 1 part, the maximum tolerated dose of the combination was not reached. Dose-limiting toxicities were observed in three (11%) of 28 patients, including grade 4 neutropenia at 1·8 mg/kg brentuximab vedotin plus 80 mg/m2 of bendamustine in two (7%) patients and diffuse rash at 1·2 mg/kg brentuximab vedotin plus 70 mg/m2 of bendamustine in one (4%) patient. The recommended phase 2 dose was deemed to be 1·8 mg/kg of brentuximab vedotin and 90 mg/m2 of bendamustine, which are the standard doses of the drugs when given as single agents. In the phase 2 part, an overall response was achieved in 29 (78% 95% CI 62–91) of 37 patients. Serious adverse events included grade 3 lung infection in five (14%) of 37 patients in the phase 2, and grade 3–4 neutropenia in 16 (25%) of 65 patients across phases 1 and 2. There were no treatment-related deaths.
This study shows that brentuximab vedotin plus bendamustine, with a favourable safety profile, is an active salvage regimen for heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma. This salvage regimen can potentially serve as an efficacious and safe alternative to platinum-based chemotherapy before autologous stem cell transplant.
Seattle Genetics, Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, and National Institutes of Health.
Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in ...preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.
•Combined oral azacytidine and romidepsin induced high response rates and prolonged remissions in PTCL patients, particularly those with tTFH.•Mutations of genes involved in DNA methylation and histone deacetylation appear more frequently in patients responding to epigenetic therapy.
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The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in ...preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non–T-cell lymphoma. The overall response rate in all, non–T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.
•Combined 5-azacytidine and romidepsin are reasonably well tolerated in patients with relapsed/refractory lymphoid malignancies.•This combination produced overall and complete response rates of 73% and 55%, respectively, in patients with T-cell lymphoma.
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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.
Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used ...for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger.
We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed.
Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio HR, 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2).
In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.
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