A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse <12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

Good Outcome after R-Hyper-CVAD/R-MA in High-Risk Aggressive B-Cell Lymphoma: A Single-Center Experience

INTRODUCTION Patients with high-risk aggressive B-cell lymphoma exhibit poor survival after R-CHOP-like immunochemotherapy. More intensive regimens yield higher rates of remission but also of complication, which have hindered their use, particularly in older patients. At Karolinska, the standard intensive regimen has been R-Hyper-CVAD/R-MA for patients with high-risk characteristics, such as high age-adjusted international prognostic index (aaIPI) and extranodal disease. METHODS In this analysis, high-risk disease was defined as aaIPI ≥ 2 or any extranodal involvement. We examined Karolinska's 136 patients who received at least one cycle of R-Hyper-CVAD/R-MA in first-line therapy for high-risk disease, excluding Burkitt, transformed, and primary CNS lymphoma. Patients were diagnosed between 2006 and 2020; 89 were diffuse large B-cell lymphoma, 23 high-grade B-cell lymphoma, 17 primary mediastinal B-cell lymphoma, 4 T cell/histiocyte-rich B-cell lymphoma, 2 aggressive B-cell lymphoma unspecified, 1 lymphomatoid granulomatosis grade 3. For outcome, we investigated progression-free survival (PFS). RESULTS In this cohort of 136 patients with high-risk disease treated with at least one cycle of R-Hyper-CVAD/R-MA, the median age was 52 years (range, 19-69); 36 patients (26%) were 61-69 years old. Lactate dehydrogenase was elevated in 92%, stage III-IV disease was seen in 93%, WHO performance status ≥2 in 49%, aaIPI = 3 in 38%, extranodal disease in 30%, CNS involvement in 17%, and Charlson comorbidity index ≥2 in 11%. At 5 years, the PFS in all patients was 72% and in the 50 patients with aaIPI = 3, 66% (Figure 1). In patients ≤60 years old, 5-year PFS was 76% (aaIPI = 3, 69%). In patients 61-69 years, the 5-year PFS was 58% (aaIPI = 3, 59%). Six out of 136 patients (4%) died from toxicity during induction therapy (3/6 were 61-69 years old). CONCLUSIONS This is to our knowledge the largest published single-center series of patients treated with R-Hyper-CVAD/R-MA for high-risk aggressive B-cell lymphoma. Outcome in these patients aged 19-69 years was excellent, with 5-year PFS 72%. Particularly patients with aaIPI = 3 showed rather good outcome with 5-year PFS 66%. For comparison, in Sweden the 5-year overall survival of R-CHOP-treated patients ≤60 years with aaIPI = 3 is 40% (Melén CM et al. Brit J Haematol. 614-622. 2016). We will continue to explore R-Hyper-CVAD/R-MA as primary therapy for high-risk aggressive B-cell lymphoma. Figure 1 Figure 1. Disclosures Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding.

Updates in the Management of Early-Stage Diffuse Large B-Cell Lymphoma

Several important updates have emerged in the management of early-stage diffuse large B-cell lymphoma. Three trials resulted in the approval of rituximab + cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) for use in these patients internationally. Furthermore, studies have been initiated to determine whether 4 or 6 cycles of this regimen should be administered without radiation therapy (RT). Six cycles of R-CHOP plus central nervous system (CNS) prophylaxis and prophylactic testicular RT are recommended for patients with extranodal disease occupying the testicles. Although controversial, there is a reasonable consensus in the literature to consider 6 cycles of R-CHOP plus involved-site RT and CNS prophylaxis for patients with extranodal disease of the breast. Patients with primary bone and gastric extranodal disease do not seem to derive a significant survival benefit from RT. Molecular subtype evaluations may change treatment approaches.

Successful Treatment of Diffuse Large B-cell Lymphoma Presenting as Acute Liver Failure

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common histologic subtype of lymphoma. Affected patients most commonly present with rapid lymph node enlargement in the neck, abdomen, or chest, with extranodal disease occurring in up to 40% of all cases. Generally, DLBCL is a clinically aggressive malignancy and the presence of extranodal disease is a poor prognostic indicator. Acute Liver Failure (ALF) is a rare presentation of extranodal DLBCL that is typically associated with a bleak prognosis; however, the impact of prompt diagnosis followed by initiation of appropriate chemotherapy in this setting is not well understood. Further complicating treatment, first-line chemotherapy regimens for DLBCL are typically contraindicated in the setting of liver failure. In this case report, we describe the successful treatment of DLBCL originally presenting as ALF through bridging therapy with a non-standard bendamustinebased approach.

Clinical and morphological characteristics or immunohostochemical factors determine the results of treatment for diffuse large B-cell lymphoma?

e19539 Background: Diffuse large B-cell lymphoma (DLBCL) is and aggressive heterogeneous tumor. The treatment is ineffective in more than 30% cases: primary resistance is observed in 20%, and relapses in 10%. Clinical prognostic indices do not allow assessing the DLBCL course and treatment outcomes. The purpose of the study was to evaluate the results of treatment of DLBCL patients depending on clinical and immunohistochemical factors of the disease prognosis. Methods: Patients with DLBCL (n = 48): men – 25 (52.1%, mean age 52±3.8 years), women – 23 (47.9%, mean age 60±4.3 years) received standard treatment R-CHOP, R-CHOEP, R-EPOCH. Results: After the treatment, 27 (56.2%) patients were in remission for 3 years, 10 (20.8%) patients developed relapses, and 11 (23%) patients were refractory to the therapy. All groups demonstrated Ki-67 > 80%, overexpression of Bcl2, Bcl6, CD10, MUM-1 on tumor cells, C-MYC gene rearrangements. Patients with stage I and II nodal spread were more likely to be in remission; refractory patients and those with early relapses had stages III and IV. Relapses were detected at different periods after treatment: early relapses (n = 5) within 6 months and late relapses (n = 5) after 12 months or later. Among patients with early relapses, 2 (40%) had extranodal disease and 3 (60%) nodal disease; high/medium IPI was noted in 3 patients, low/medium and low IPI – 1 patient each. Among patients with late relapses, 3 patients had nodal disease and 2 – primary extranodal disease; high/medium IPI was noted in 2 patients, low/medium – in 3 patients. Among recurrent patients, 9 had non-germ cell DLBCL and 1 - germ cell DLBCL. Among refractory patients, 8 (73%) had nodal disease and 3 (27%) - extranodal disease; low/medium IPI was registered in 4 patients, high/medium IPI in 2, low IPI in 5 patients; germ cell tumors in 2 patients, non-germ cell tumors in 9 patients. Conclusions: 33% of DLBCL patients did not benefit from the treatment. Molecular markers such as Ki-67, Bcl2, Bcl6 and CD10 were not prognostically significant. The tumor type had a prognostic value only in the group of patients with relapses - non-germ cell tumors were found in 90% of cases.

Presentation of External Ear Rosai-Dorfman Disease With Laryngeal Involvement

Rosai-Dorfman disease (RDD) is a rare benign systemic histiocytic proliferation characterized by massive lymph node enlargement and sometimes associated with extranodal involvement. Even though it is considered to be benign, death can occur depending on the extent and location. Our case highlights a primary extranodal site of the right pinna with extension through the Eustachian tube to the subglottis. A previously healthy 15-year-old female presented with 1-year right pinna swelling, slowly enlarging and becoming more bothersome. An incisional biopsy was performed on the ear along with S100 staining yielding a diagnosis. After multidisciplinary case discussion, clofarabine monotherapy and systemic therapy for Langerhans cell histiocytosis has started. Rosai-Dorfman disease can be a general disorder, often affecting the lymph nodes. Unlike a nodal disease, extranodal disease could involve any site on the patient’s anatomy. Head and neck lesions are the most common extranodal lesions. Rosai-Dorfman disease is self-limited in more than 20% of the cases with spontaneous regression without intervention; 70% of the patients have noticeable symptoms and vital organ involvement requiring treatments such as surgery, steroids, radiation, and chemotherapy. In our case, the patient had wide involvement and presented without any serious breathing difficulties; we decided to start with monotherapy with chemotherapy and systematic glucocorticoid treatment.

Impact of Genetic Polymorphism of Myeloid Differentiation Primary Response Gene 88, Enhancer of Zeste Homolog 2, and B-cell Lymphoma 2 like 11 in Patients with Diffuse Large B Cell Lymphoma Treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristin

BACKGROUND: Despite the growing landscape of genetic drivers in Diffuse Large B-cell Lymphoma, yet their clinical implication is still unclear and R-CHOP regimen remains a “one size fits all” therapy. We aimed in this study to examine the prevalence of EZH2, BCL211 and MYD 88 genetic polymorphisms in DLBCL patients and correlate the results with various clinical and survival outcomes. METHODS: Genotyping of MYD88 (rs387907272 T/C), EZH2 (rs3757441 C/T), and BCL2L11 (rs3789068 A/G) polymorphisms were conducted using real time polymerase chain reaction analysis in a total of 75 DLBCL patients. RESULTS: Most of our cases carried the wild TT genotype of MYD88 gene (64%), the mutant TT genotype of EZH2 gene (52%) and the wild AA genotype of BCL2L11 gene (48%). Regarding cell of origin, Germinal Centre (GC) phenotype was present in 56% of cases while 44% expressed the Post-GC (PGC) phenotype. Poor response outcome to first line R-CHOP was significantly correlated with the mutated CC genotype of MYD 88 (p=0.02), while better response to R-CHOP was significantly associated with younger age <50 years (p <0.0001), good PS (p=0.046), normal LDH level (p=0.003), earlier stage (p <0.0001), good IPI score (p=0.009), absence of extranodal disease (p <0.0001) and absence of bulky disease (p=0.004). The median PFS and the 2 year OS were significantly higher in younger age, earlier stage, good IPI score, absence of extranodal disease, absence of bulky disease and in GC phenotype. CONCLUSIONS: Our results emphasized that the mutated genotype of MYD 88 gene polymorphism is significantly associated with poor response to R-CHOP therapy.