The Use of Infliximab to Control Recurrent Cytokine Storms in EBV-Associated Angioimmunoblastic Lymphoma and Hemophagocytic Syndrome

Introduction: Chronic active Epstein-Barr virus infection (CAEBV) has been implicated in several diseases including hemophagocytic lymphohistiocytosis (EBV-HLH) and lymphomas including Angioimmunoblastic T cell lymphoma. The exact mechanism by which EBV infection causes these complications is currently not well understood. EBV-HLH is a syndrome in which T-cells, NK cells and macrophages are aberrantly activated. Cytokine storms play a major role in cellular damage and organ dysfunction. In the event that the body is unable to clear the EBV viremia, dysregulated T, NK cells and macrophages continue to release cytokines leading to the accumulation of lymphohistiocytic infiltrates into organs and organ damage. Cytokine storms can lead to death from multi-organ failure. During a cytokine storm, levels of several cytokines are elevated including TNF-a, IFN-g, sCD25, IL-12, IL-1, IL-10 and IL-18.1–3 Current lines of therapy of EBV-HLH include steroids, etoposide, cyclosporine, ATG and hematopoietic stem cell transplantation. We report successfully controlling frequent cytokine storms in a patient with EBV induced angioimmunoblastic lymphoma and HLH with weekly infliximab after failure to do so with chemotherapy (CHOP-E; cyclophosphamide, daunorubicin, vincristine, prednisone, etoposide), rituximab and bortezomib

Pulmonary Hypertension Is a Frequent Event in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Poster presented at American Society of Clinical Oncology in Chicago Illinois. Background: Tyrosine kinase inhibitors (TKI) are the current standard therapy for patients with chronic myeloid leukemia (CML). Fluid retention and pleural effusions have been reported in patients treated with TKIs, particularly with dasatinib. Although TKIs have been shown to reverse pulmonary hypertension (PH) in animal models, there have been some reports of development of reversible PH with dasatinib. Methods: We conducted a retrospective analysis on 401 patients diagnosed with CML in chronic phase (CP) who were treated with TKIs (imatinib, dasatinib, or nilotinib) as initial therapy for CML and had a transthoracic echocardiogram (TTE) done at some point during the course of therapy. PH was diagnosed if the patient had an estimated right ventricular systolic pressure (RVSP) of 35 mm Hg or greater. Secondary causes of PH (systolic or diastolic dysfunction on TTE, chronic obstructive pulmonary diseases [COPD], obstructive sleep apnea [OSA] and pulmonary embolism) were investigated during chart review. Results: Twenty (23%) out of 87 patients had evidence of PH by TTE; median age 57 years, with 46% being males. Six pts (30%) received nilotinib 400mg twice daily, 4 (20%) patients had imatinib (400mg; n=1, 600mg; n=1 and 800mg daily; n=2), and 10 (50%) patients received dasatinib (dose varied 40-140mg daily). Five (25%) patients had coronary artery disease, 9 (45%) had systemic hypertension, 2 (10%) had COPD and 3 (15%) had OSA. Thirteen pts had serial TTE to compare the progression of PH including 6 (7%) who had a TTE prior to starting TKI. Among these 13 pts with serial TTE, 7 had rising RVSP with one patient having mild global hypokinesia, another with diastolic dysfunction and another with OSA. Four of those 7 patients had normal RVSP on their TTE prior to starting therapy. Six other pts had improvement in the RVSP on serial TTE, 4 of them with systemic hypertension. Two of those 6 patients had elevated RVSP on their TTE prior to starting therapy; one pt had no change. Eleven patients had pleural effusions (7 dasatinib, 3 imatinib, 1 nilotinib) associated with PH. Conclusions: TKI therapy is occasionally associated with development of PH, but RVSP may improve spontaneously in some patients. A prospective study is needed to further investigate the relationship between TKIs and the development of PH

A 2-Step Approach to Myeloablative Haploidentical Stem Cell Transplantation with Optimized T-Cell Dosing: Early Immune Reconstitution Leads to Better Outcomes

We developed a 2-step approach to myeloablative haploidentical HSCT in which patients receive a large fixed dose of cyclophosphamide (CY)-tolerized T cells separately frm the HSC infusion in the hopes of accelerating post HSCT immune reconstitution (IR). The uniformity of the T cell dosing facilitates comparison of patients without (low risk) and with (high risk) active malignancy at HSCT to ascertain the impact of disease status at HSCT on IR with fewer confounding effects from conditioning or T cell dosing

The Presence of a CMV Immunodominant Allele in the Recipient Is Associated With Increased Survival in CMV Positive Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation

Specific major histocompatibility (MHC) class I alleles dominate anti-CMV responses in a hierarchal manner. These CMV immunodominant (IMD) alleles are associated with a higher magnitude and frequency of cytotoxic lymphocyte responses as compared to other human leukocyte antigen (HLA) alleles. CMV reactivation has been associated with an increased incidence of graft-vs.-host disease and non-relapse mortality, as well as protection from relapse in HLA-matched HSCT settings. Less is known about the impact of CMV reactivation on these major outcomes after haploidentical (HI) HSCT, an increasingly applied therapeutic option. In HI HSCT, the efficiency of the immune response is decreased due to the immune suppression required to cross the MHC barrier as well as MHC mismatch between presenting and responding cells. We hypothesized that the presence of a CMV IMD allele would increase the efficiency of CMV responses after HI HSCT potentially impacting CMV-related outcomes. In this retrospective, multivariable review of 216 HI HSCT patients, we found that CMV+ recipients possessing at least 1 of 5 identified CMV IMD alleles had a lower hazard of death (HR = 0.40, p = 0.003) compared to CMV+ recipients not possessing a CMV IMD allele, and an overall survival rate similar to their CMV- counterparts. The analysis delineated subgroups within the CMV+ population at greater risk for death due to CMV reactivation

Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide.

Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P \u3c .001) and chronic (HR, 0.35; P \u3c .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up

An international analysis evaluating frontline bendamustine with rituximab in extranodal marginal zone lymphoma

: Extranodal marginal zone lymphoma (EMZL) is a heterogeneous non-Hodgkin lymphoma. No consensus exists regarding the standard-of-care in patients with advanced-stage disease. Current recommendations are largely adapted from follicular lymphoma, for which bendamustine with rituximab (BR) is an established approach. We analyzed the safety and efficacy of frontline BR in EMZL using a large international consortium. We included 237 patients with a median age of 63 years (range, 21-85). Most patients presented with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (n = 228; 96.2%), stage III/IV (n = 179; 75.5%), and intermediate (49.8%) or high (33.3%) Mucosa Associated Lymphoid Tissue International Prognosis Index (MALT-IPI). Patients received a median of 6 (range, 1-8) cycles of BR, and 20.3% (n = 48) received rituximab maintenance. Thirteen percent experienced infectious complications during BR therapy; herpes zoster (4%) was the most common. Overall response rate was 93.2% with 81% complete responses. Estimated 5-year progression-free survival (PFS) and overall survival (OS) were 80.5% (95% CI, 73.1% to 86%) and 89.6% (95% CI, 83.1% to 93.6%), respectively. MALT-IPI failed to predict outcomes. In the multivariable model, the presence of B symptoms was associated with shorter PFS. Rituximab maintenance was associated with longer PFS (hazard ratio = 0.16; 95% CI, 0.04-0.71; P = .016) but did not impact OS. BR is a highly effective upfront regimen in EMZL, providing durable remissions and overcoming known adverse prognosis factors. This regimen is associated with occurrence of herpes zoster; thus, prophylactic treatment may be considered

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850)