Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma.

Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT01947140).

Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

How I treat posttransplant lymphoproliferative disorder.

Posttransplant lymphoproliferative disorder (PTLD) is an important and potentially life-threatening complication of solid organ transplant and hematopoietic stem cell transplant (HSCT). Given the heterogeneity of PTLD and the risk of infectious complications in patients with immunosuppression, the treatment of this disease remains challenging. Monomorphic PTLD and lymphoma of B-cell origin account for the majority of cases. Treatment strategies for PTLD consist of response-adapted, risk-stratified methods using immunosuppression reduction, immunotherapy, and/or chemotherapy. With this approach, ∼25% of the patients do not need chemotherapy. Outcomes for patients with high risk or those who do not respond to frontline therapies remain dismal, and novel treatments are needed in this setting. PTLD is associated with Epstein-Barr virus (EBV) infection in 60% to 80% of cases, making EBV-directed therapy an attractive treatment modality. Recently, the introduction of adoptive immunotherapies has become a promising option for refractory cases; hopefully, these treatment strategies can be used as earlier lines of therapy in the future.

Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma.

Interplay between chromatin-associated complexes and modifications critically contribute to the partitioning of epigenome into stable and functionally distinct domains. Yet there is a lack of systematic identification of chromatin crosstalk mechanisms, limiting our understanding of the dynamic transition between chromatin states during development and disease. Here we perform co-dependency mapping of genes using CRISPR-Cas9-mediated fitness screens in pan-cancer cell lines to quantify gene-gene functional relationships. We identify 145 co-dependency modules and further define the molecular context underlying the essentiality of these modules by incorporating mutational, epigenome, gene expression and drug sensitivity profiles of cell lines. These analyses assign new protein complex composition and function, and predict new functional interactions, including an unexpected co-dependency between two transcriptionally counteracting chromatin complexes - polycomb repressive complex 2 (PRC2) and MLL-MEN1 complex. We show that PRC2-mediated H3K27 tri-methylation regulates the genome-wide distribution of MLL1 and MEN1. In lymphoma cells with EZH2 gain-of-function mutations, the re-localization of MLL-MEN1 complex drives oncogenic gene expression and results in a hypersensitivity to pharmacologic inhibition of MEN1. Together, our findings provide a resource for discovery of trans-regulatory interactions as mechanisms of chromatin regulation and potential targets of synthetic lethality.

Targeting CD38 with Daratumumab Plus Chemotherapy for Patients with Advanced-Stage Plasmablastoid Large B-Cell Lymphoma.

Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12-31 months and ongoing).

Addition of Lenalidomide to R-CHOP Improves Outcomes in Newly Diagnosed Diffuse Large B-Cell Lymphoma in a Randomized Phase II US Intergroup Study ECOG-ACRIN E1412.

PURPOSE: 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 AND METHODS: 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). RESULTS: 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% (P = .06) and 73% (P = .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 P = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided P = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided P = .1. CONCLUSION: In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.

First-in-Class Selective HDAC6 Inhibitor (ACY-1215) Has a Highly Favorable Safety Profile in Patients with Relapsed and Refractory Lymphoma.

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.

Can we use epigenetics to prime chemoresistant lymphomas?

Chemoresistance remains a challenging clinical problem in the treatment of many lymphoma patients. Epigenetic derangements have been implicated in both intrinsic and acquired chemoresistance. Mutations in epigenetic processes shift entire networks of signaling pathways. They influence tumor suppressors, the DNA-damage response, cell-cycle regulators, and apoptosis. Epigenetic alterations have also been implicated in contributing to immune evasion. Although increased DNA methylation at CpG sites is the most widely studied alteration, increased histone methylation and decreased histone acetylation have also been implicated in stem-like characteristics and highly aggressive disease states as demonstrated in both preclinical models of lymphoma and patient studies. These changes are nonrandom, occur in clusters, and are observed across many lymphoma subtypes. Although caution must be taken when combining epigenetic therapies with other antineoplastic agents, epigenetic therapies have rarely induced clinical meaningful responses as single agents. Epigenetic priming of chemotherapy, targeted therapies, and immunotherapies in lymphoma patients may create opportunities to overcome resistance.

Hypomethylating Agents in Lymphoma.

OPINION STATEMENT: Epigenetic mutations are frequent and pathogenic in select subtypes of lymphoma, and agents modulating DNA and histone methylation-such as inhibitors of DNMT and EZH2, respectively-have demonstrated promise in treating these diseases. In particular, lymphomas derived from the germinal center-GC-DLBCL, FL, and AITL-are all characterized by epigenetic derangements. In an effort to target these derangements, DNMT inhibitors have been investigated as a means of improving responsiveness to chemotherapy in DLBCL patients, or as monotherapy or in combination with other epigenetic agents in the treatment of TCL. Histone methyltransferase inhibitors have demonstrated effectiveness in R/R FL patients with EZH2-activating mutations. New treatment options that target the pathogenesis of disease are needed. HDAC inhibitors have been in the clinic for over a decade for the treatment of lymphoma, and now methyltransferase inhibitors are finding their niche for this disease.

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure.

BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.

Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study.

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.

Chromatin-Remodeled State in Lymphoma.

PURPOSE OF REVIEW: Emerging evidence has shown that epigenetic derangements might drive and promote tumorigenesis in various types of malignancies and is prevalent in both B cell and T cell lymphomas. The purpose of this review is to explain how the epigenetic derangements result in a chromatin-remodeled state in lymphoma and contribute to the biology and clinical features of these tumors. RECENT FINDINGS: Studies have explored on the functional role of epigenetic derangements in chromatin remodeling and lymphomagenesis. For example, the haploinsufficiency of CREBBP facilitates malignant transformation in mice and directly implicates the importance to re-establish the physiologic acetylation level. New findings identified 4 prominent DLBCL subtypes, including EZB-GC-DLBCL subtype that enriched in mutations of CREBBP, EP300, KMT2D, and SWI/SNF complex genes. EZB subtype has a worse prognosis than other GCB-tumors. Moreover, the action of the histone modifiers as well as chromatin-remodeling factors (e.g., SWI/SNF complex) cooperates to influence the chromatin state resulting in transcription repression. Drugs that alter the epigenetic landscape have been approved in T cell lymphoma. In line with this finding, epigenetic lesions in histone modifiers have recently been uncovered in this disease, further confirming the vulnerability to the therapies targeting epigenetic derangements. Modulating the chromatin state by epigenetic-modifying agents provides precision-medicine opportunities to patients with lymphomas that depend on this biology.

Multicentre retrospective study of intravascular large B-cell lymphoma treated at academic institutions within the United States.

Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.

Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas.

PURPOSE: Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC)-derived lymphomas. We hypothesized that direct inhibition of EZH2 and histone deacetyltransferase (HDAC) would be synergistic in GC-derived lymphomas. EXPERIMENTAL DESIGN: Lymphoma cell lines (n = 21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by excess over bliss. Western blot, mass spectrometry, and coimmunoprecipitation were performed. A SU-DHL-10 xenograft model was utilized to validate in vitro findings. Pretreatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity. RESULTS: Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination were due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and was characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNA methyltransferase were associated with EZH2 activation. CONCLUSIONS: Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.

Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.