A Case of Bing–Neel Syndrome Successfully Treated with Ibrutinib

Bing–Neel syndrome is a rare manifestation of Waldenström macroglobulinemia characterized by lymphoplasmacytic cells’ infiltration into the central nervous system. We present a case of a 74-year-old patient with a known diagnosis of Waldenström macroglobulinemia and newly depressed consciousness. Flow cytology of his cerebral spinal fluid demonstrated a lambda light chain-restricted population of B-cells consistent with a CD5+ CD10+ B-cell lymphoma. Magnetic resonance imaging suggested involvement of the left optic nerve sheath and the bilateral orbital and parietal parenchyma and leptomeninges. He was diagnosed with Bing–Neel syndrome and treated with intrathecal liposomal cytarabine, intravenous high-dose methotrexate, and rituximab without improvement. Subsequently, he started treatment with ibrutinib 560 mg daily and concurrent rituximab. Within three months, he showed clinical and radiologic improvement. The patient has continued on ibrutinib and has now been stable for over 36 months. This represents the longest reported period of successful treatment of Bing–Neel syndrome with ibrutinib

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)

The Integration of PD1 blockade with epigenetic therapy is highly active and safe in heavily treated patients with T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).

8049 Background: Our group has demonstrated that combinations of epigenetic modifiers produce potent synergy in pre-clinical models of PTCL and induce the expression of cancer testis antigen, suggesting a role in the addition of the immune-checkpoint inhibitor, pembrolizumab. Methods: This is a phase 1b study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with relapsed and refractory PTCL and CTCL. A standard 3+3 dose-escalation is applied in the triplet Arm (Arm B) while in the doublet Arms (A and C) de-escalation is applied in case of toxicity. Pharmacokinetic and pharmacodynamic studies are ongoing. Results: We treated a total of 12 patients with 4 patients in each Arm. All patients that received at least one dose of drug were evaluable for toxicity. There was a dose limiting toxicity (DLT) in each arm including prolonged grade 3 thrombocytopenia (Arm A), febrile neutropenia (Arm B), grade 3 hyponatremia, and rash (Arm C). There were no treatment-related deaths. Six patients out of 12 were evaluable for response at the time of this analysis. One patient achieved a complete remission, 2 had partial remission, 1 had stable disease, and 2 experienced progression of disease. Interestingly, all of the responses were seen in the triple combination of pralatrexate, decitabine, and pembrolizumab. Table summarizes the patient characteristics, toxicities, and response rates. Conclusions: These preliminary clinical data suggest that the integration of pembrolizumab on an epigenetic backbone is safe and demonstrates encouraging responses in patient with PTCL and CTCL. Clinical trial information: 03240211 . [Table: see text] </jats:p

Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study

Abstract 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.</jats:p

Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1–2 trial

BACKGROUND: The major objective of this study was to explore the safety and clinical activity of Brentuximab vedotin (Bv) and bendamustine in combination in patients with relapsed or refractory Hodgkin Lymphoma. Bv produces high response rates and durable progression-free survival (PFS) in CD30-expressing lymphomas and is approved for the treatment of relapsed Hodgkin lymphoma (HL) and relapsed ALCL. Bendamustine (B) is active agent across the lymphoproliferative malignancies, though the PFS among patients with HL and PTCL is modest. METHODS: This was an international, multicenter, single-arm, Phase 1–2 study of BvB in patients with relapsed or refractory HL and ALCL. Eligible patients were required to have relapsed/refractory CD30+ biopsy proven HL or ALCL and an ECOG Performance Status ≤2. In the Phase 1, HL patients were deemed eligible if they developed progressive disease following or after declining ASCT, or had at least 2 prior multi-agent chemotherapy regimens. In the Phase 2, patients with HL were eligible if they had relapsed or refractory disease after one line of therapy. Eligible ALCL patients were required to have relapsed after at least one prior multi-agent chemotherapy regimen and if they were not eligible for or have declined ASCT. The primary objective of the Phase I portion of this study was to identify the maximum tolerated dose (MTD) and dose limiting toxicity (DLT). The primary endpoint of the Phase 2 portion was to determine the overall response rate (ORR; complete response [CR] plus partial response [PR])) based on an intention to treat analysis (ITT). Secondary objectives of Phase 1–2 included assessing for duration of response, progression free survival and overall survival. Response was evaluated using International Harmonization Project Group 2007 Revised Response Criteria. Bv was escalated from 1.2mg/kg Day 1, and B from 70mg/m2 Days 1 and 2 every 21 days until the MTD or recommended phase 2 dose (RP2D) was reached. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov number NCT01657331. FINDINGS: 65 patients (only 1 ALCL) were treated, 28 on the Phase 1 and 37 on the phase 2. While the MTD of the combination was not reached, the single agent MTD of Bv (1.8mg/kg Day 1) and RP2D of B (90mg/m2 Days 1 and 2) were identified as the RP2D of the combination. Patients were heavily treated, 65% (42 of 65) had an autologous or allogeneic stem cell transplant or both. The Phase 1 revealed modest toxicity. The major Grade 3/4 toxicities included Grade 3 lung infection in 5 (14%) patients in the Phase 2, and Grade 3/4 neutropenia in 13 (24%) patients across the Phase 1 and 2. The Phase 1 and 2 overall response rates (ORR) were 61% and 78% respectively, with 43% (16 of 27) patients treated in the Phase 2 attaining a complete remission (CR). In the Phase 2, the median PFS has not been reached and duration of response (DOR) was 3.4 months. There was a total of 23 deaths with 21 due to progression of disease, 2 occurring after being transplanted, and none of which were treatment related. INTERPRETATION: This demonstrates that BvB might be an effective salvage regimen for patients with HL, with a favorable safety profile. FUNDING: Seattle Genetics, The Lymphoma Research Fund of Columbia University and National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873 provided support for this investigator initiated sponsored trial. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH

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

The authors report a phase 1 study of romidepsin combined with oral 5-azacytidine in patients with relapsed/refractory lymphomas, including complete remissions in 3 patients with angioimmunoblastic T-cell lymphoma.</jats:p