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Concept: Types of cancer

293

Collectively, lymphoid neoplasms are the fourth most common cancer and the sixth leading cause of cancer death in the United States. The authors provide contemporary lymphoid neoplasm statistics by subtype based on the 2008 World Health Organization classifications, including the most current US incidence and survival data. Presented for the first time are estimates of the total numbers of US lymphoid neoplasm cases by subtype as well as a detailed evaluation of incidence and survival statistics. In 2016, 136,960 new lymphoid neoplasms are expected. Overall lymphoma incidence rates have declined in recent years, but trends vary by subtype. Precursor lymphoid neoplasm incidence rates increased from 2001 to 2012, particularly for B-cell neoplasms. Among the mature lymphoid neoplasms, the fastest increase was for plasma cell neoplasms. Rates also increased for mantle cell lymphoma (males), marginal zone lymphoma, hairy cell leukemia, and mycosis fungoides. Like incidence, survival for both mature T-cell lymphomas and mature B-cell lymphomas varied by subtype and by race. Patients with peripheral T-cell lymphomas had among the worst 5-year relative survival (36%-56%, depending on race/sex), while those with mycosis fungoides had among the best survival (79%-92%). For B-cell lymphomas, 5-year survival ranged from 83% to 91% for patients with marginal zone lymphoma and from 78% to 92% for those with hairy cell leukemia; but the rates were as low as 47% to 63% for patients with Burkitt lymphoma and 44% to 48% for those with plasma cell neoplasms. In general, black men had the lowest survival across lymphoid malignancy subtypes. These contemporary incidence and survival statistics are useful for developing management strategies for these cancers and can offer clues regarding their etiology. CA Cancer J Clin 2016. © 2016 American Cancer Society.

Concepts: AIDS, Cancer, Oncology, B cell, Types of cancer, Neoplasm, Leukemia, Lymphoma

279

Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.

Concepts: Immune system, Medicine, Cancer, Bone marrow, Chemotherapy, Types of cancer, Leukemia, Hematological malignancy

216

Background Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. Methods We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery. Results A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval [CI], 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later. Conclusions CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834 .).

Concepts: Immune system, Protein, B cell, Types of cancer, Major histocompatibility complex, Lymphoma, Follicular lymphoma, B-cell lymphoma

172

Background In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. Methods In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. Results Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. Conclusions In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

Concepts: Medicine, Cancer, Response rate, B cell, Types of cancer, Lymphoma, Thymus, Follicular lymphoma

171

A number of constitutively activated signaling pathways play critical roles in the survival and growth of primary effusion lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt’s lymphoma and diffuse large cell B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored.

Concepts: AIDS, Protein, Cancer, Signal transduction, Types of cancer, Hematology, Lymphoma, B-cell lymphoma

167

Ewing Sarcoma Family Tumours (ESFT) are rare in early childhood. The aim of this study was to report the clinical characteristics and outcome of children under 6 years of age affected by ESFT of the bone in Italy.

Concepts: Oncology, Types of cancer, Childhood, Ewing's sarcoma

167

Hairy cell leukemia is a mature B-cell non-Hogkin lymphoma characterized by unique clinical, morphological and immunhistochemical features. Patients with hairy cell leukemia usually present with splenomegaly, progressive pancytopenia and a relative indolent clinical course. The diagnosis does not always indicate immediate treatment, as treatment depends on the clinical stage of the leukemia. Asymptomatic disease without progression requires a watchful waiting policy, while other categories usually need treatment. The treatment of choice is purin nucleosid analogues (pentostatin, cladribine) which can achieve complete remission even for decades. Interferon and monoclonal CD20 antibodies can also significantly prolong tevent free survival. Unfortunately, only the latter two therapies are easily available in Hungary. Splenectomy, which was suggested as first line treatment before the era of purin nucleosid analogues, is only recommended as ultimum refugium. Although hairy cell leukemia is a well-defined lymphoproliferative disease, sometimes it is difficult to differentiate it from other similar entities such as hairy cell leukema variant, splenic marginal zone lymphoma, small lymphocytic lymphoma etc. Making the correct diagnosis is of utmost importance because of the great difference in treatment modalities. Recently, a somatic mutation was found in all analysed hairy cell leukemia samples, but not in other splenic B-cell lymphomas. This article reviews the significance of this observation and presents the different types of methods for the detection of this mutation. Orv. Hetil., 2013, 154, 123-127.

Concepts: Lymphocyte, Cancer, Types of cancer, Hematology, Leukemia, Lymphoma, Blood disorders, Hairy cell leukemia

166

Soft tissue sarcomas comprise approximately 1% of all adult solid malignancies. While chemotherapy is the mainstay of treatment for patients with metastatic or inoperable disease, overall survival for these patients is approximately 12 months, highlighting the need for novel agents. Both laboratory and clinical data have suggested that antiangiogenic agents may have a role in the treatment of soft tissue sarcomas. Pazopanib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. The randomized, double-blind, placebo-controlled, Phase III PALETTE (pazopanib for metastatic soft-tissue sarcoma) study demonstrated improved progression-free survival in patients receiving pazopanib compared with placebo. In this review, we discuss the rationale and clinical evidence for the use of pazopanib in the treatment of metastatic and inoperable soft tissue sarcomas.

Concepts: Cancer, Signal transduction, Soft tissue sarcoma, Types of cancer, Lymphoma, Soft tissue, Sarcoma, Alveolar soft part sarcoma

166

We introduce a novel computational framework to enable automated identification of texture and shape features of lesions on (18)F-FDG-PET images through a graph-based image segmentation method. The proposed framework predicts future morphological changes of lesions with high accuracy. The presented methodology has several benefits over conventional qualitative and semi-quantitative methods, due to its fully quantitative nature and high accuracy in each step of (i) detection, (ii) segmentation, and (iii) feature extraction. To evaluate our proposed computational framework, thirty patients received 2 (18)F-FDG-PET scans (60 scans total), at two different time points. Metastatic papillary renal cell carcinoma, cerebellar hemongioblastoma, non-small cell lung cancer, neurofibroma, lymphomatoid granulomatosis, lung neoplasm, neuroendocrine tumor, soft tissue thoracic mass, nonnecrotizing granulomatous inflammation, renal cell carcinoma with papillary and cystic features, diffuse large B-cell lymphoma, metastatic alveolar soft part sarcoma, and small cell lung cancer were included in this analysis. The radiotracer accumulation in patients' scans was automatically detected and segmented by the proposed segmentation algorithm. Delineated regions were used to extract shape and textural features, with the proposed adaptive feature extraction framework, as well as standardized uptake values (SUV) of uptake regions, to conduct a broad quantitative analysis. Evaluation of segmentation results indicates that our proposed segmentation algorithm has a mean dice similarity coefficient of 85.75±1.75%. We found that 28 of 68 extracted imaging features were correlated well with SUV(max) (p<0.05), and some of the textural features (such as entropy and maximum probability) were superior in predicting morphological changes of radiotracer uptake regions longitudinally, compared to single intensity feature such as SUV(max). We also found that integrating textural features with SUV measurements significantly improves the prediction accuracy of morphological changes (Spearman correlation coefficient = 0.8715, p<2e-16).

Concepts: Cancer, Lung cancer, Non-small cell lung carcinoma, Spearman's rank correlation coefficient, Types of cancer, Squamous cell carcinoma, Correlation and dependence, Small cell carcinoma

164

The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue appearing. In this trial we evaluated the feasibility, safety and efficacy of R-Hyper-CVAD alternating with R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan. Patients received 6 cycles followed by a single dose of 90Y-Ibritumomab-Tiuxetan. Thirty patients were enrolled. Median age was 59 years. Twenty four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation. In the intent- to- treat population, failure free, progression free and overall survival at 4 years were 40 % (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure free and overall survival were 55% (95% confidence interval 31.48&-78.52) and 87% (95% confidence interval 70-100), respectively. Hematological toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with median duration of 5 and 12 weeks, respectively. Six (20%) patients died, 3 due to secondary malignancies (myelodisplastic syndrome and bladder and rectum carcinomas). In conclusion, our experience with R-Hyper-CVAD/R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan is efficacious although less feasible than expected. The unacceptable toxicity observed, specially secondary malignancies, advise against the indication of this strategy. Trial registration: clinical.gov identifier: NCT2005-004400-37.

Concepts: Cancer, Lung cancer, Chemotherapy, Types of cancer, Interval finite element, Normal distribution, Hematological malignancy, Mantle cell lymphoma