ESMO Consensus Conference on malignant lymphoma: management of 'ultra-high-risk' patients.

The European Society for Medical Oncology (ESMO) consensus conference on malignant lymphoma was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the questions devised by their group. These recommendations were then presented to the entire multidisciplinary panel and a consensus was reached. This manuscript presents recommendations regarding the management of the following 'ultra-high-risk' situations: (1) early central nervous system relapse of diffuse large B-cell lymphoma, (2) primary refractory Hodgkin lymphoma and (3) plasmablastic lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. All expert panel members approved this final article.

Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells.

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

Guideline for diagnosis and treatment of Waldenström's macroglobulinaemia.

On behalf of the lymphoma and multiple myeloma working parties of the Dutch/Belgian Haemato-Oncology Foundation for Adults in The Netherlands (HOVON), we present a guideline for diagnosis and management of Waldenström's macroglobulinemia (WM). Considering the indolent behaviour and heterogeneous clinical presentation of WM, it is crucial to determine the right indications for treatment, as well as to individualise therapeutic options. There are significant differences from the approach to multiple myeloma or the treatment of other indolent non-Hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due to the low incidence of WM. Based on the available data, we provide a practical diagnostic classification, as well as recommendations for first-line therapy and options for treating relapsed disease. Some typical clinical features of WM, such as autoimmune phenomena and 'IgM flare' after rituximab treatment, are highlighted. A more elaborate version of this guideline was published in the 'Nederlands Tijdschrift voor Hematologie' (Dutch Journal for Hematology) September 2012.

High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era: an analysis based on data from the European Blood and Marrow Transplantation Registry.

Autologous stem cell transplantation (ASCT) consolidation remains the treatment of choice for patients with relapsed diffuse large B cell lymphoma. The impact of rituximab combined with chemotherapy in either first- or second-line therapy on the ultimate results of ASCT remains to be determined, however. This study was designed to evaluate the benefit of ASCT in patients achieving a second complete remission after salvage chemotherapy by retrospectively comparing the disease-free survival (DFS) after ASCT for each patient with the duration of the first complete remission (CR1). Between 1990 and 2005, a total of 470 patients who had undergone ASCT and reported to the European Blood and Bone Transplantation Registry with Medical Essential Data Form B information were evaluated. Of these 470 patients, 351 (74%) had not received rituximab before ASCT, and 119 (25%) had received rituximab before ASCT. The median duration of CR1 was 11 months. The median time from diagnosis to ASCT was 24 months. The BEAM protocol was the most frequently used conditioning regimen (67%). After ASCT, the 5-year overall survival was 63% (95% confidence interval, 58%-67%) and 5-year DFS was 48% (95% confidence interval, 43%-53%) for the entire patient population. Statistical analysis showed a significant increase in DFS after ASCT compared with duration of CR1 (median, 51 months versus 11 months; P < .001). This difference was also highly significant for patients with previous exposure to rituximab (median, 10 months versus not reached; P < .001) and for patients who had experienced relapse before 1 year (median, 6 months versus 47 months; P < .001). Our data indicate that ASCT can significantly increase DFS compared with the duration of CR1 in relapsed diffuse large B cell lymphoma and can alter the disease course even in patients with high-risk disease previously treated with rituximab.

Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma.

BACKGROUND: The prognosis of T-cell lymphoma is poor. To explore the addition of the monoclonal antibody alemtuzumab, we studied the efficacy and tolerability of an intensified alemtuzumab-chemotherapy combination for aggressive T-cell lymphoma in a phase II study by Dutch-Belgian Hemato-Oncology Group (HOVON). PATIENTS AND METHODS: Patients (≤65 years) with newly diagnosed T-cell lymphoma received eight CHOP cycles (cyclophosphamide, doxorubicin, vincristine, prednisone) 2-weekly, each cycle with three doses of 30 mg alemtuzumab. Prophylaxis consisted of cotrimoxazole, fluconazole and valaciclovir. Cytomegalovirus (CMV) monitoring took place at least every fortnight. RESULTS: Twenty patients from 10 centers, median age 50 years, were included. Eighty-five percent received six or more cycles. The overall response was 90% [12 complete remissions (CRs), 1 CR unconfirmed, 5 partial remissions]. Median duration of follow-up of patients still alive was 29 months (range 19-41 months). Median overall survival (OS) and event-free survival (EFS) were 27 and 10 months, with 55%/27% OS/EFS at 2 years. Adverse events consisted of neutropenic fever (n = 8) and CMV reactivation (n = 7), with one CMV disease. Three patients developed secondary Epstein-Barr virus (EBV)-related lymphoma, all after end of treatment. CONCLUSIONS: Although intensified alemtuzumab-CHOP induces high responses, many patients relapse, and the scheme is associated with serious infection-related adverse events. EBV monitoring after end of treatment is required.

Prognostic value of comorbidity for auto-SCT eligibility and outcome in relapsed or refractory aggressive non-Hodgkin's lymphoma.

Salvage reinduction therapy followed by high-dose chemotherapy (HDCT) and auto-SCT is the treatment of choice for fit patients with refractory or relapsed aggressive non-Hodgkin's lymphoma (NHL). We assessed the prognostic value of comorbidity at the time of relapse to predict receipt of auto-SCT and outcome. We analyzed 156 consecutive NHL patients, referred to our center between 1999 and 2007 for salvage reinduction therapy, followed by HDCT and auto-SCT. Comorbidity according to the hematopoietic SCT comorbidity index was scored at relapse and directly before HDCT and auto-SCT. Primary end points were actual receipt of auto-SCT and survival. At relapse, comorbidity scores of 0, 1-2 and ≥3 were found among 64 (41%), 62 (40%) and 30 (19%) patients, respectively. Ultimately, 95 patients received auto-SCT. Higher comorbidity scores at relapse were associated with significantly less chance of receiving auto-SCT and with inferior OS, independently from secondary age-adjusted International Prognostic Index (sAAIPI) scores. For transplanted patients, OS rates at 5 years were 62, 30 and 17% for relapse comorbidity scores of 0, 1-2 and ≥3, respectively. In patients with relapsed NHL, comorbidity at relapse is associated with receipt of auto-SCT and subsequent survival independently from the sAAIPI.

[Lymphoma in patients who have undergone organ transplantation: severe and variable clinical presentation]. / Lymfoom bij patiënten na een orgaantransplantatie: ernstig en variabel ziektebeeld.

Two patients presented with post-transplant lymphoproliferative disorder (PTLD). PTLD encompasses a broad range ofoften malignant proliferations of lymphoid tissue arising in the immunocompromised host after transplantation. The first patient, a 62-year-old woman, received a bilateral lung transplant due to end-stage emphysema and was diagnosed with PTLD 27 days after transplantation. Treatment consisted of reduction in immunosuppression and administration of rituximab. The PTLD regressed. The second patient, a 57-year-old woman, presented with a massively disseminated PTLD 12 years after kidney transplantation. Immunosuppression was reduced and rituximab was administered, but no response was observed. Despite salvage chemotherapy, the patient died due to progressive disease. These two cases illustrate the heterogeneous presentation of PTLD. The condition is caused by the proliferation of B lymphocytes infected with Epstein-Barr virus (EBV) that are no longer controlled by EBV-specific cytotoxic T lymphocytes, due to the immunosuppressive medication given to prevent transplant rejection. Regression of the lymphoma may be achieved by reducing the immunosuppression or treating with rituximab, which attacks B lymphocytes.

Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study.

OBJECTIVE: To investigate the safety and efficacy of B cell depletion treatment of patients with active primary Sjögren's syndrome of short duration (early primary SS) and patients with primary SS and mucosa-associated lymphoid tissue (MALT)-type lymphoma (MALT/primary SS). METHODS: Fifteen patients with primary SS were included in this phase II trial. Inclusion criteria for the early primary SS group were B cell hyperactivity (IgG >15 gm/liter), presence of autoantibodies (IgM rheumatoid factor, anti-SSA/SSB), and short disease duration (<4 years). Inclusion criteria for the MALT/primary SS group were primary SS and an associated MALT-type lymphoma (Ann Arbor stage IE) localized in the parotid gland. Patients were treated with 4 infusions of rituximab (375 mg/m2) given weekly after pretreatment with prednisone (25 mg) and clemastine. Patients were evaluated, using immunologic, salivary/lacrimal function, and subjective parameters, at baseline and at 5 and 12 weeks after the first infusion. RESULTS: Significant improvement of subjective symptoms and an increase in salivary gland function was observed in patients with residual salivary gland function. Immunologic analysis showed a rapid decrease of peripheral B cells and stable levels of IgG. Human anti-chimeric antibodies (HACAs) developed in 4 of 15 patients (27%), all with early primary SS. Three of these patients developed a serum sickness-like disorder. Of the 7 patients with MALT/primary SS, complete remission was achieved in 3, and disease was stable in 3 and progressive in 1. CONCLUSION: Findings of this phase II study suggest that rituximab is effective in the treatment of primary SS. The high incidence of HACAs and associated side effects observed in this study needs further evaluation.

Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma.

BACKGROUND: Associations of Hodgkin's lymphoma with HLA have been reported for many years. In 20-40% of patients with this disorder, Epstein-Barr virus (EBV) is present in the neoplastic cells. Because presentation of EBV antigenic peptides can elicit vigorous immune responses, we investigated associations of the HLA region with EBV-positive and EBV-negative Hodgkin's lymphoma. METHODS: In a retrospective, population-based study, patients with Hodgkin's lymphoma were reclassified according to the WHO classification, and EBV status was assessed by in-situ hybridisation of EBV-encoded small RNAs. Germline DNA was isolated from 200 patients diagnosed between 1987 and 2000 and from their first-degree relatives. Genotyping was done with 33 microsatellite markers spanning the entire HLA region and two single-nucleotide polymorphisms in the genes for tumour necrosis factor alpha and beta. Classic association analysis and the haplotype sharing statistic were used to compare patients with controls. FINDINGS: Classic association analysis (but not the haplotype sharing statistic) showed an association of consecutive markers D6S265 and D6S510 (p=0.0002 and 0.0003), located in the HLA class I region, with EBV-positive lymphomas. The haplotype sharing statistic (but not classic association analysis) showed a significant difference in mean haplotype sharing between patients and controls surrounding marker D6S273 (p=0.00003), located in HLA class III. INTERPRETATION: Areas within the HLA class I and class III regions are associated with susceptibility to Hodgkin's lymphoma, the association with class I being specific for EBV-positive disease. This finding strongly suggests that antigenic presentation of EBV-derived peptides is involved in the pathogenesis of EBV-involved Hodgkin's lymphoma. RELEVANCE TO PRACTICE: Polymorphisms in the HLA region could explain ethnic variation in the incidence of Hodgkin's lymphoma. The association of EBV-positive Hodgkin's lymphoma with HLA class I suggests that this polymorphism might affect the proper presentation of EBV antigens to cytotoxic T lymphocytes.

Short intensive sequential therapy followed by autologous stem cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma.

The feasibility and efficacy of up-front high-dose sequential chemotherapy followed by autologous stem cell transplantation (ASCT) in previously untreated adults (median age 33 years; range 15-64) with Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or lymphoblastic lymphoma (LyLy), both without central nervous system or extensive bone marrow involvement was investigated in a multicenter phase II study. Treatment consisted of two sequential high-dose chemotherapy induction courses incorporating prednisone, cyclophosphamide, doxorubicin, etoposide and mitoxantrone, without high-dose methotrexate or high-dose cytarabine. Patients with at least PR went on with BEAM and ASCT. Protocol treatment was completed by 23/27 (85%) BL/BLL and 13/15 (87%) LyLy patients. Median treatment duration until BEAM was 70 (range: 50-116) days. No toxic deaths occurred. Response to treatment was complete response (CR) 81% and partial response (PR) 11% for BL/BLL, CR 73% and PR 20% for LyLy. At a median follow-up of 61 months of patients still alive, six BL/BLL and eight LyLy patients have died. The actuarial 5-year overall and event-free survival estimates are 81 and 73% for BL/BLL vs 46 and 40% for LyLy patients. In conclusion, this short up-front high-dose sequential chemotherapy regimen, followed by ASCT is highly effective in adults with BL/BLL with limited bone marrow involvement, but less so in patients with LyLy.

Changes in salivary gland immunohistology and function after rituximab monotherapy in a patient with Sjogren's syndrome and associated MALT lymphoma.

OBJECTIVES: To report the successful use of rituximab on salivary gland immunohistology and function in a patient with Sjogren's syndrome (SS) and associated MALT lymphoma. CASE REPORT: The patient was a 42 year old woman with primary SS and associated MALT lymphoma located in the parotid gland and the hard palate. Four infusions of rituximab (375 mg/m(2)) weekly resulted in complete remission of the lymphoma. An incision biopsy of the parotid gland before and after treatment showed improvement of the (immuno)histopathological characteristics of SS, with possible regeneration of salivary gland tissue. Furthermore, salivary analysis showed decreased inflammatory characteristics and increased stimulated salivary flow. DISCUSSION: Rituximab is a promising agent in the treatment of SS associated MALT lymphoma. In addition to the effect on MALT lymphoma, B cell depletion by rituximab may also attenuate the activity of SS. This case report is the first to describe the effect of rituximab on histological and sialometric/chemical characteristics of SS. The efficacy of rituximab in the treatment of SS warrants further investigation.

Gender and age-related differences in Burkitt lymphoma--epidemiological and clinical data from The Netherlands.

Although Burkitt's lymphoma (BL) is classified as one entity in the World Health Organisation (WHO) classification, we wondered whether BL should not be considered as a different disease in children compared with adults. Netherlands Cancer Registry (NCR) data were obtained from 1994 to 1998 (n=203). Detailed clinical data from two treatment protocols were compared: one for adults up to the age of 65 years (n=27) and one for children (n=80). All slides of the two clinical studies were centrally reviewed which included immunophenotyping and when necessary breakpoint analysis of MYC/8q24. Only cases with an unambiguous diagnosis of BL (classical and atypical BL) were accepted. The age distribution of BL-patients showed a bimodal distribution with a peak at the paediatric age and a steady increase after approximately 60 years of age. Most of the patients were males (89% for children and 78% for adults) and only male patients showed this bimodality. Children more often had extranodal disease (81% vs. 59%), whereas adults more often had nodal disease (89% vs. 53%). Based on epidemiology and clinical presentation, the concept that BL is one disease should be re-challenged.

[Bilateral swelling of the parotid glands as part of a systemic disease]. / Bilaterale zwelling van de glandulae parotideae als onderdeel van een systeemziekte.

In four patients, a man aged 34 years and three women aged 35, 32 and 55 years respectively bilateral swelling of the parotid glands was caused by systemic disease i.e. HIV-salivary gland disease, mucosa-associated lymphoid-tissue (MALT) lymphoma, sarcoidosis with coexisting Sjögren's syndrome, and sialosis and hypothyroidism, respectively. The HIV patient was treated with antiretroviral therapy, the first two women were treated expectantly and the third woman was given a thyroid hormone supplement which resulted in regression of the bilateral parotid enlargement. Bilateral enlargement of the parotid glands is not necessarily caused by infection, it can also be of systemic origin. Minimal invasive investigations of the salivary glands, such as sialography, measurement of salivary secretion rate (sialometry) and analysis of salivary composition (sialochemistry) can offer valuable information about the origin of the parotid gland swelling. Histopathological investigation of an incision biopsy of the parotid gland is an easy way to confirm the diagnosis. The morbidity associated with parotid biopsy is negligible.

CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

PURPOSE: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study.

BACKGROUND: Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy. METHODS: 195 patients with low-grade glioma (of whom 104 had received radiotherapy 1-22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability. FINDINGS: Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function. INTERPRETATION: Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.