Lenalidomide maintenance following high-dose therapy and autologous haematopoietic stem cell transplantation in chemo-resistant or high-risk non-Hodgkin lymphoma: A phase I/II study.

Improved maintenance treatments are needed for patients with relapsed/refractory aggressive lymphomas after autologous haematopoietic stem cell transplantation (ASCT). Several studies with lenalidomide have been found to have activity in the treatment of relapsed/refractory aggressive lymphomas. In the present phase I/II, single-arm, open-label study, 59 patients with high-risk relapsed non-Hodgkin lymphoma received pretransplant BEAM chemotherapy and ASCT followed by 12 months of maintenance lenalidomide once daily on Days 1-21 (28-day cycles) beginning at post-transplantation Day 100. The most common histologies were mantle cell lymphoma (56%) and diffuse large B-cell lymphoma (24%). The maximum tolerated dose in the dose-finding part of the study was 15 mg, but cytopenias led to the subsequent adoption of a 10 mg dose in the final study. Sixteen patients (27%) completed 12 cycles of lenalidomide maintenance. The most common reason for discontinuation was adverse events (31%). These were primarily haematologic, and 56% of patients experienced Grade 3-4 events. Two-year PFS rates (95% CIs) were 70% (56%-80%), 45% (19%-68%) and 81% (66%-90%); 2-year OS rates (95% CIs) were 91% (80%-96%), 93% (61%-99%) and 90% (76%-96%) in all patients, patients completing and patients not completing 12-month maintenance respectively. These results do not support the use of lenalidomide maintenance in this setting.

Phase 1 trial of carfilzomib in relapsed/refractory peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m2. Dose-limiting toxicities included anemia and sepsis. Serious adverse events were seen in 45% of patients. Single-agent carfilzomib leads to a complete response in one patient and a partial response in one patient. Overall, the drug was reasonably tolerated for a heavily pretreated population, but the limited response rate and short duration of response demonstrate a lack of promise for carfilzomib as a single agent in this patient population.

Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Radiologic Differentiation of Primary CNS Posttransplant Lymphoproliferative Disorder From Brain Metastasis.

OBJECTIVE. Primary CNS posttransplant lymphoproliferative disorder (PTLD) may present as multiple contrast-enhancing intraaxial lesions, often with central necrosis and surrounding edema. This imaging appearance is similar to the pattern seen in brain metastases. The purpose of this study was to find differences in the radiologic features of primary CNS PTLD lesions and brain metastases. MATERIALS AND METHODS. We retrospectively reviewed the radiologic findings of 51 primary CNS PTLD lesions in 10 patients and 156 metastatic brain lesions in 25 patients. Lesion size, multifocality, location, necrosis, hemorrhage, perilesional vasogenic edema, contrast enhancement, and diffusion and perfusion features were evaluated. We used the chi-square test or Fisher exact test when appropriate to compare the findings between primary CNS PTLD lesions and brain metastases. RESULTS. Primary CNS PTLD lesions occur in the deep gray matter and periventricular locations more frequently than brain metastases (p < 0.0001) and are not present at the gray and white matter junctions and vascular border zones as commonly as brain metastases are (p < 0.0001). Primary CNS PTLD tends to have less frequent hemorrhage (p < 0.0001), more restricted diffusion (p = 0.001), and lower perfusion (p = 0.002) than brain metastases. We did not find statistically significant differences between primary CNS PTLD and brain metastases for lesion size, multifocality, necrosis, and perilesional edema. CONCLUSION. The imaging characteristics of primary CNS PTLD overlap considerably with those of brain metastases, but there are significant differences between primary CNS PTLD lesions and brain metastases in lesion location, diffusion and perfusion features, and tendency to hemorrhage.

NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

NCCN Guidelines Insights: Antiemesis, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.

Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

Venous thromboembolism in patients with hematologic malignancy and thrombocytopenia.

The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty-seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000-45,000/µL) versus 165,000/µL (50,000-429,000/µL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic-dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21-1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. © 2016 Wiley Periodicals, Inc.

Hodgkin lymphoma, version 2.2015.

Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment.

Phase I/II study of bortezomib-BEAM and autologous hematopoietic stem cell transplantation for relapsed indolent non-Hodgkin lymphoma, transformed, or mantle cell lymphoma.

A 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/m(2)) 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/m(2) but it was later decreased to 1 mg/m(2) 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.

MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and "double-hit" DLBCL, with both MYC and BCL2 translocations has a poor prognosis. In this study, we investigated whether MYC and BCL2 protein expression in tissue would predict survival in DLBCL. The study included 106 cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or CHOP-like regimens. The results were validated on an independent cohort of 205 DLBCL patients. Patients with low expression of BCL2 (≤30%) and MYC (≤50%) had the best prognosis, whereas those with high BCL2 (>30%) and MYC (>50%) had the worst outcome. In multivariate analysis, the combination of the BCL2 and MYC was an independent predictor of overall survival (OS) and event-free survival (EFS) (P = 0·015 and P = 0·005, respectively). The risk of death was nine times greater for patients with high BCL2 and MYC compared to those with low expression. High BCL2 and MYC was a strong predictor of poor OS (P < 0·001) and EFS (P = 0·0017) in patients with the germinal centre B-cell (GCB) type, but not in the non-GCB type. In DLBCL, high co-expression of MYC and BCL2 was an independent predictor of poor survival, and could be used to stratify patients for risk-adapted therapies.

Surgery for primary central nervous system lymphoma: is it time for reevaluation?

The overall survival rate for primary central nervous system lymphoma (PCNSL) has improved significantly. This prolongation in survival is related mainly to advances in chemotherapy regimens and radiotherapy. In contrast, the role of surgery in PCNSL has been limited because tumors are frequently not amenable to resection and because most studies have failed to show that resection is beneficial. A recent analysis of the German Primary CNS Lymphoma Study Group 1 (G-PCNSL-SG-1) trial has challenged this convention by showing that the survival of patients with PCNSL may actually be prolonged if tumors are resected. While there are a number of weaknesses in the analysis, many authorities now feel that an attempt at gross total resection is reasonable for patients with solitary lesions that can be removed without morbidity. However, even if resection does benefit some patients, the diagnosis of lymphoma is almost always made in retrospect, and there are few occasions when a neurosurgeon will actually need to make a decision whether or not to resect a known PCNSL.

Phase II trial of 131-Iodine tositumomab with high-dose chemotherapy and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma.

The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information.

Central nervous system cancers.

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.

Novel therapy for therapy-resistant mantle cell lymphoma: multipronged approach with targeting of hedgehog signaling.

Mantle cell lymphoma (MCL) is one of the most aggressive B-cell lymphomas with a median patient survival of only 5-7 years. The failure of existing therapies is mainly due to disease relapse when therapy-resistant tumor cells remain after chemotherapy. Therefore, development and testing of novel therapeutic strategies to target these therapy-resistant MCL are needed. Here, we developed an in vivo model of therapy-resistant MCL by transplanting a patient-derived MCL cell line (Granta 519) into NOD/SCID mice followed by treatment with combination chemotherapy. Cytomorphologic, immunophenotypic, in vitro and in vivo growth analyses of these therapy-resistant MCL cells confirm their MCL origin and resistance to chemotherapy. Moreover, quantitative real-time PCR revealed the upregulation of GLI transcription factors, which are mediators of the hedgehog signaling pathway, in these therapy-resistant MCL cells. Therefore, we developed an effective therapeutic strategy for resistant MCL by treating the NOD/SCID mice bearing Granta 519 MCL with CHOP chemotherapy to reduce tumor burden combined with GLI-antisense oligonucleotides or bortezomib, a proteosome inhibitor, to target therapy-resistant MCL cells that remained after chemotherapy. This regimen was followed by treatment with MCL-specific cytotoxic T lymphocytes to eliminate all detectable leftover minimal residual disease. Mice treated with this strategy showed a significantly increased survival and decreased tumor burden compared to the mice in all other groups. Such therapeutic strategies that combine chemotherapy with targeted therapy followed by tumor-specific immunotherapy are effective and have excellent potential for clinical application to provide long-term, disease-free survival in MCL patients.

Lymph node-induced immune tolerance in chronic lymphocytic leukaemia: a role for caveolin-1.

Emerging evidence indicates that the tumour microenvironment (TME) regulates the behaviour of chronic lymphocytic leukaemia (CLL). However, the precise mechanism and molecules involved in this process remain unknown. Gene expression profiles of CLL cells from lymph node (LN), bone marrow (BM) and peripheral blood (PB) indicate overexpression of a tolerogenic signature in CLL cells in lymph nodes (LN-CLL). Based on their role in B cell biology, the progression of CLL, or immune regulation, a few genes of this 83-gene signature were selected for further analyses. We observed a significant correlation between the clinical outcomes and the expression of CAV1 (P = 0·041), FGFR1 isoform 8 (P = 0·032), PTPN6 (P = 0·031) and ZWINT (P < 0·001). CAV1, a molecule involved in the regulation of tumour progression in other cancers, was seven-fold higher in LN-CLL cells compared to BM- and PB-CLL cells. Knockdown of CAV1 expression in CLL cells resulted in significantly decreased migration (P = 0·016) and proliferation (P = 0·04). When CAV1 was knocked down in B and T cell lines, we observed an inability to form immune synapses. Furthermore, CAV1 knockdown in CLL cells impaired their ability to form immune synapses with autologous T lymphocytes and allogeneic, healthy T cells. Subsequent analyses of microarray data showed differential expression of cytoskeletal genes, specifically those involved in actin polymerization. Therefore, we report a novel role for CAV1 in tumour-induced immunosuppression during the progression of CLL.

Cell of origin fails to predict survival in patients with diffuse large B-cell lymphoma treated with autologous hematopoietic stem cell transplantation.

Diffuse large B-cell lymphoma (DLBCL) includes two prognostically important subtypes, the germinal center B-cell (GCB) and the non-GCB types. The aim of this study was to evaluate immunohistochemical approaches for predicting the survival of patients with DLBCL following autologous hematopoietic stem cell transplantation (AHSCT). We identified 62 patients with DLBCL who either had an initial complete remission (17 patients) or received salvage chemotherapy for relapsed or refractory disease (45 patients), followed by AHSCT. Tissue microarrays were immunostained with monoclonal antibodies against GCET1, CD10, BCL6, MUM1, FOXP1 and LMO2. Using the Hans algorithm, we classified 50% of the cases as GCB type, whereas the Choi algorithm classified 58% as GCB type and LMO2 was positive in 69%. However, no significant differences were found in the 5-year overall or event-free survivals using any of these approaches. In conclusion, cell of origin fails to predict survival of DLBCL patients treated with AHSCT.

Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin Lymphoma (HL) include the clinical management of classical HL and lymphocyte-predominant HL (LPHL). Major changes have been incorporated into these guidelines since their inception. In the 2012 NCCN Guidelines for HL, PET scans are not recommended for interim restaging of patients with stage I to II favorable disease. After reevaluating the available evidence on the use of interim PET imaging, the panel recommends the use of diagnostic CT scan of involved sites for interim restaging after completion of chemotherapy for this group of patients. Maintenance rituximab for 2 years is included as an option for patients with stage IB to IIB or stage III to IV LPHL treated with rituximab alone in the first-line setting. Brentuximab vedotin is included as an option for patients with progressive disease or relapsed disease after second-line chemotherapy or high-dose therapy with autologous stem cell rescue.

Late relapse in patients with diffuse large B-cell lymphoma.

The outcomes for 162 patients with diffuse large B-cell lymphoma treated with a CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like regimen who obtained a complete remission and who subsequently relapsed after ≥5 years of remission (late relapse, N=30), or <5 years of remission (early relapse, N=132), were compared. The late relapsing patients had better prognostic characteristics at diagnosis, such as stage I/II disease (73% vs. 49%, P=0·04), a normal lactic dehydrogenase (77% vs. 48%, P=0·01), and a Karnofsky performance score of ≥80 (100% vs. 86%, P=0·01). The 3-year survival after relapse was better in late relapsing patients (48% vs. 25%, P=0·03), but the survival at 5 years (32% vs. 20%) and 10 years (13% vs. 14%) after relapse was not different. A multivariate analysis of factors predicting survival after relapse found age (P<0·0001) and presence of B-symptoms (P=0·03) to predict survival, but not early versus late relapse. A small percentage of the late relapsing patients can have a prolonged second remission. However, the overall survival from the time of relapse was not different between early and late relapsing patients with most succumbing to lymphoma.

The Meaning of Self-efficacy for Symptom Management in the Acute Phase of Hematopoietic Stem Cell Transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an intensive treatment that offers the potential for longer life or cure for some types of cancer. Hematopoietic stem cell transplant is associated with decreased quality of life and functional status and distressing symptoms. Self-efficacy for symptom management (SESM) is a person's belief in his/her ability to implement behaviors to manage these symptoms. Presence of SESM can affect symptom distress, healthcare utilization, and posttransplantation outcomes. OBJECTIVE: The aim of this study was to explore the meaning of SESM in adults during the acute phase of HSCT. METHODS: Interviews were conducted before and at 30 days after transplantation. Descriptive thematic analysis was performed on verbatim interview transcripts. RESULTS: Themes of confidence, being responsible, and caring for mind, body, and spirit were identified, with subthemes of self-confidence, confidence in others, confidence and symptom level, vigilance, self-advocacy, and normalcy. Participants reported having high SESM before transplantation and having much less or no SESM when symptom distress was the most severe. CONCLUSIONS: This is the first study to examine the patient's perspective of self-efficacy in the acute phase of HSCT. This contributes to existing literature on the concept of symptom management and expands nursing knowledge of SESM in patients undergoing HSCT. IMPLICATIONS FOR PRACTICE: Nurses can assess SESM before transplantation and implement interventions to enhance SESM when symptoms are at their most distressing after HSCT. The findings from this study can provide the basis for creating behavioral interventions to enhance self-efficacy for symptom management in HSCT patients.