Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: A report from The North American Mantle Cell Lymphoma Consortium

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p \u3c 0.0001) and progression-free survival (PFS, p \u3c 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p \u3c 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL

The Cancer Care Workforce in Nebraska

Although cancer is the leading cause of death in Nebraska, the adequacy of Nebraska’s cancer care workforce to care for the cancer population is unknown. Therefore, we used workforce survey data for 2008-2012 from the Health Professions Tracking Service to analyze the cancer care workforce supply in Nebraska. We found that from 2008 to 2012, the cancer care workforce for adults outpaced cancer prevalence. We outline several policy options to improve Nebraska’s cancer care workforce capacity, and we consider the effect the Affordable Care Act may have on Nebraska’s cancer care workforcehttps://digitalcommons.unmc.edu/coph_policy_reports/1005/thumbnail.jp

Phase I/II Study of Bortezomib-BEAM and Autologous Hematopoietic Stem Cell Transplantation for Relapsed Indolent Non-Hodgkin Lymphoma, Transformed, or Mantle Cell Lymphoma

AbstractA phase I/II trial was designed to evaluate the safety and efficacy of adding bortezomib to standard BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (ASCT). Eligible patients had relapsed/refractory indolent or transformed non-Hodgkin lymphoma or mantle cell lymphoma (MCL) that was relapsed/refractory or in first partial (PR) or complete remission (CR). Patients received bortezomib on days −11, −8, −5, and −2 before ASCT. Phase I had 4 dose cohorts (.8, 1, 1.3, and 1.5 mg/m2) and 3 patients were accrued to each. Any nonhematological ASCT-related toxicity >2 on the Bearman scale occurring between day −11 and engraftment defined the maximum tolerated dose (MTD). After the MTD has been reached, another 20 patients were enrolled at this dose to determine a preliminary overall response rate (ORR). Patients who were in CR or PR at day +100 were considered responders. The study enrolled 42 patients through August 14, 2009. The median age was 58 (range, 34 to 73) years, with 33 males and 9 females. The most common diagnoses were MCL (23 patients) and follicular lymphoma (7 patients). The median number of prior therapies was 1 (range, 0 to 6). The median follow-up was 4.88 (range, 1.07 to 6.98) years. Thirteen patients were treated in phase I and 29 patients were treated in phase II. The MTD was initially determined to be 1.5 mg/m2 but it was later decreased to 1 mg/m2 because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100 days and 87% at 1 year. For all 38 evaluable patients at 1 year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1 year, and 32% (15% to 51%) at 5 years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1 year and 67% (50% to 79%) at 5 years. The most common National Cancer Institute grade 3 toxicities were neutropenic fever (59%), anorexia (21%), peripheral neuropathy (19%), orthostatic hypotension/vasovagal syncope (16%), and 1 patient failed to engraft. Compared with 26 MCL in CR1 historic controls treated with BEAM and ASCT, PFS was 85% and 43% for the BEAM group versus 87% and 57% for those who received bortezomib in addition to standard BEAM (V-BEAM) at 1 and 5 years, respectively (log-rank P = .37). OS was 88% and 50% for the BEAM group versus 96% and 72% for V-BEAM at 1 and 5 years, respectively (log-rank P = .78). In conclusion, V-BEAM and ASCT is feasible. The toxicities were manageable and we did not observe any treatment-related mortalities; however, we did observe an excess of autonomic dysfunction and ileus, which is concerning for overlapping toxicity with BEAM conditioning. Determining relative efficacy of V-BEAM compared to BEAM would require a randomized trial

Long-Term Outcomes of Autologous Stem Cell Transplantation for Follicular Non-Hodgkin Lymphoma: Effect of Histological Grade and Follicular International Prognostic Index

AbstractAlthough results of autologous stem cell transplantation (SCT) for recurrent follicular non-Hodgkin lymphoma (NHL) have been previously reported, the long-term results and evaluation of prognostic factors in a large patient population receiving this therapy are difficult to find in the literature. To address these issues, we evaluated 248 patients with recurrent follicular NHL treated with high-dose chemotherapy and autologous SCT between 7/87 and 6/03. According to the World Health Organization (WHO) classification system, 64 patients (26%) had follicular NHL grade 1 (FL 1), 98 (40%) had FL 2, and 86 (35%) had FL 3. At the time of transplantation, 88 of the patients (35%) had a Follicular Lymphoma International Prognostic Index (FLIPI) score of low risk, 87 (35%) had an intermediate-risk FLIPI score, 37 (15%) had a high-risk FLIPI score, and 36 (15%) had at least 1 missing value, preventing calculation of the FLIPI score. The 5-year overall survival (OS) for all patients was 63%, and the 5-year progression-free survival (PFS) was 44%. In a multivariate analysis, a histological grade of FL 3, a high-risk FLIPI score at the time of transplantation, and having received 3 or more previous chemotherapy regimens were significant factors for predicting a worse OS. In addition, the use of a transplantation regimen including a monoclonal antibody decreased the relative risk of progressive lymphoma. These data suggest that transplantation earlier in the course of the disease for patients with follicular lymphoma with use of a monoclonal antibody–based regimen may lead to improved outcomes

Autologous hematopoietic stem cell transplantation for mantle cell lymphoma

AbstractThis study evaluated the outcomes of patients who underwent high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (autoHSCT) for mantle cell non-Hodgkin's lymphoma and the effect of clinical and treatment characteristics. The clinical outcome and prognostic factors in 40 patients who underwent HDC and autoHSCT for mantle cell lymphoma between June 1991 and August 1998 were analyzed. With a median follow-up of 24 months for the surviving patients (range, 4-68 months), the 2-year overall survival was 65% and the 2-year event-free survival (EFS) was 36%. In univariate analysis, characteristics predictive of a poor EFS were blastic morphology (P = .019) and the patient having received 3 or more prior chemotherapy regimens (P = .004). In a multivariate analysis, the only factor associated with a poor EFS was the number of prior chemotherapy regimens. Those patients who received 3 or more prior therapies had a 2-year EFS of 0%, and those who received <3 therapies had a 2-year EFS of 45% (P = .004). Patients with mantle cell lymphoma can obtain prolonged EFS with HDC and autoHSCT; however, this strategy for prolonged EFS appears to work optimally in patients who are less heavily pretreated. Whether this therapy will increase the overall survival or EFS in patients receiving transplants in first complete remission will need to be tested in prospective randomized clinical trials.Biol Blood Marrow Transplant 2000;6(6):640-5

Genome-wide miRNAprofiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n =7) and compared them with small lymphocytic leukemia/ lymphoma (n =12), aggressive B-cell lymphomas (n =138), normal B-cell subsets, and stromal cells.We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNAclassifier showed consistent results in formalinfixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators

Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 106 CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population