First‐line use of rituximab correlates with increased overall survival in late post‐transplant lymphoproliferative disorders: retrospective,single‐centre study

This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single‐centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29–69), median time to diagnosis 50 months (range 0–100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B‐cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non‐rituximab; P = 0.5). R‐CHOP‐like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31–96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58–79 months; non‐rituximab 1–30 months). Post‐transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single‐centre series, and it should be considered as first‐line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.     

Nivolumab maintenance after salvage autologous stem cell transplantation results in long‐term remission in multiple relapsed primary CNS lymphoma

Recurrence of primary central nervous system lymphoma (PCNSL) after high‐dose chemotherapy with autologous stem cell transplantation (ASCT) usually has a poor overall prognosis with limited treatment options. Data on repeated ASCT are sparse. Checkpoint inhibitor maintenance therapy has also not been reported in PCNSL. Here, we report the first documented case of a successful third ASCT in second relapse of PCNSL. Whole‐exome sequencing identified a hypermutated tumor genotype. Additionally, immunohistochemistry on pretreatment tumor tissue revealed infiltrates of PD‐1⁺ cytolytic T cells. These alterations provided a rationale for subsequent nivolumab maintenance treatment. Therapy led to a long‐term, ongoing complete remission. In eligible patients with recurrent MTX‐sensitive PCNSL, multiple long‐term remissions can be induced by repetition of high‐dose MTX‐based chemotherapy followed by autologous retransplantation. Subsequent immune checkpoint inhibitor maintenance therapy might be able to prolong or maintain remission.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

Rewired NFκB signaling as a potentially actionable feature of activated B‐cell‐like diffuse large B‐cell lymphoma

Diffuse large B‐cell lymphoma (DLBCL) is the most common type of aggressive lymphoma in the Western world and remains a clinical challenge. Two types of DLBCL are distinguishable, namely a germinal center B‐cell‐like phenotype (GCB) and an activated B‐cell‐like phenotype (ABC). Particularly ABC‐DLBCL is difficult to treat, as this subentity typically displays resistance against frontline chemo‐immune therapy. Through the availability of novel experimental technologies, such as next‐generation sequencing and cutting‐edge mouse models, we recently caught an unprecedentedly detailed glimpse at the genomic and biological features of ABC‐DLBCL. Currently, a picture is emerging which suggests that ABC‐DLBCL critically depends on sustained activity of the NFκB pathway, which, among others, is achieved through numerous distinct genetic aberrations, including CD79A/B‐, CARD11‐, and MYD88 mutations. Further genomic aberrations include amplifications of BCL2 and inactivating mutations in PRMD1. These molecular insights have spurred the development of novel autochthonous mouse models that faithfully mimic the biology and genetics of human ABC‐DLBCL and could serve as preclinical platforms in future experiments. Furthermore, our genomic understanding of the disease now enables us to develop and validate novel targeted therapeutic intervention strategies that aim at decapitating non‐physiological NFκB activity and repressing anti‐apoptotic BCL2 signaling. In this review, we highlight these recent developments and make suggestions for further tool development and the design and stratification of future clinical trials.     

Primary hepatic anaplastic large cell Ki‐1 non‐Hodgkin's lymphoma and hereditary hemochromatosis: a fortuitous association?1

Summary We report here a case of primary hepatic anaplastic large cell Ki‐1 non‐Hodgkin's lymphoma in a 60 year old patient followed for hereditary hemochromatosis.     

Hepatitis B reactivation in HBsAg‐negative/HBcAb‐positive patients receiving rituximab for lymphoma: a meta‐analysis

Patients with chronic hepatitis B (HBsAg‐positive) are at risk of viral reactivation if rituximab is administered without antiviral treatment, a potentially fatal complication of treatment. Patients with so‐called ‘resolved hepatitis B virus infection’ (HBsAg‐negative/cAb‐positive) may also be at risk. We performed a systematic review of the English and Chinese language literature to estimate the risk of hepatitis B virus (HBV) reactivation in HBsAg‐negative/cAb‐positive patients receiving rituximab for lymphoma. A pooled risk estimate was calculated for HBV reactivation. The impact of HBsAb status and study design on reactivation rates was explored. Data from 578 patients in 15 studies were included. ‘Clinical HBV reactivation’, (ALT >3 × normal and either an increase in HBV DNA from baseline or HBsAg seroreversion), was estimated at 6.3% (I² = 63%, P = 0.006). Significant heterogeneity was detected. Reactivation rates were higher in prospective vs retrospective studies (14.2% vs 3.8%; OR = 4.39, 95% CI 0.83–23.28). Exploratory analyses found no effect of HBsAb status on reactivation risk (OR = 0.083; P = 0.151). Our meta‐analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg‐negative/cAb‐positive patients exposed to rituximab. However, heterogeneity in the existing literature limits the generalizability of our findings. Large, prospective studies, with uniform definitions of HBV reactivation, are needed to clarify the risk of HBV reactivation in HBsAg‐negative/cAb‐positive patients.     

Intralobar pulmonary sequestration in a patient with non-Hodgkin's lymphoma: a cause of confusion

Pulmonary sequestration, a rare congenital pulmonary disorder, is characterized by nonfunctioning lung tissue that is separated from normal tracheobronchial tree. We present a 60-year-old woman with diffuse large cell non-Hodgkin's lymphoma. After 6 cycles of chemotherapy, paratracheal and aorticopulmonary lymphadenopathies had disappeared. However, the size of the pulmonary mass in the left lower lobe had persisted. Percutaneous fine-needle aspiration biopsy of the pulmonary mass was not diagnostic, so thoracotomy was applied. The lesion was defined as pulmonary sequestration, and basal segmentectomy was performed. After proper and sufficient chemotherapy, histopathological diagnosis of any persisting masses should be confirmed prior to overtreatment decision.     

Hepatitis C virus infection and lymphoproliferative diseases: prospective study on 1,576 patients in France

CONTEXT: Discordant data have been reported about the prevalence of hepatitis C virus (HCV) infection in patients with lymphoproliferative diseases and the putative role of HCV in lymphomagenesis. OBJECTIVE: To assess the prevalence of HCV infection in patients admitted to a hematology department in Paris, France. DESIGN: Prospective, controlled study. SETTING: University medical center. PATIENTS: 813 patients admitted to the Hematology department (164 B-cell non-Hodgkin's lymphoma, 34 Hodgkin's diseases, 107 chronic lymphocytic leukemia, 54 multiple myeloma, 12 Waldenstr?m's macroglobulinemia, 17 acute lymphoblastic leukemia, 6 hairy cell leukemia, 189 myeloproliferative diseases, 6 solid organ tumors, and 224 nonmalignant diseases) and 694 patients admitted to the Internal Medicine department (control group). MEASUREMENTS: All patients were tested for antibodies to HCV by a third-generation enzyme-linked immunosorbent assay. RESULTS: HCV antibodies were detected in 20 of 813 (2.46%) patients in Hematology including 11 of 394 (2.79%) patients with lymphoproliferative diseases, 3 of 164 (1.83%) B-cell non-Hodgkin's lymphoma, 2 of 107 (1.87%) chronic lymphocytic leukemia, 1 of 54 (1.85%) multiple myeloma, 1 of 189 (0.5%) myeloproliferative diseases, and 8 of 224 (3.57%) nonmalignant hematologic diseases. HCV antibodies were detected in 3 of 694 (0.43%) patients in the control group. HCV contamination preceded B-cell non-Hodgkin's lymphoma only in 2 of 3 HCV-positive patients. CONCLUSION: The prevalence of HCV infection was low (1.83%) in patients with B-cell non-Hodgkin lymphoma. HCV seems not to play a major role in the pathogenesis of B-cell lymphoma in France. Cofactors should be stressed to explain geographical discrepancies.     

Dual institution experience of extranodal marginal zone lymphoma reveals excellent long‐term outcomes

Extranodal marginal zone lymphoma (EMZL) is a B‐cell lymphoma arising from mucosa‐associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long‐term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12‐year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow‐up of 44·3 months (range 2·2–214·9), median progression‐free survival (PFS) was 68·2 months (95% confidence interval [CI] 54·5–111·3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), ≥4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes.     

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.     

Castleman's disease and lymphoma: report of eight cases in HIV-negative patients and literature review

Castleman's disease (CD) is a rare atypical lymphoproliferative disorder associated with a risk of developing malignant lymphoma. We have recorded 8 HIV-negative patients presenting this association, 6 with non-Hodgkin's lymphoma (NHL) and 2 with Hodgkin's disease (HD). After literature review, we analyzed all reported cases of association CD-NHL (n = 23) and CD-HD (n = 27). NHL is more often associated with multicentric CD, its diagnosis being concurrent with CD diagnosis or occurring within 2 years. B-NHL is predominant (71%), and mantle cell lymphoma represents 40% of these B-NHL cases. NHL displays an aggressive course and is liable for death, especially in multicentric CD. HD occurs in localized CD of plasma cell type, usually in the same areas, is more often of interfollicular subtype, and its clinical course seems better than NHL. The association of CD and lymphoma seems to be more than coincidental, and its pathogenesis is discussed.     

Non‐Hodgkin lymphoma manifesting as massive malignant chylothorax: successful management with chemotherapy and ambulatory drainages using indwelling pleural catheter

Recurrent cancer‐related chylothorax is generally managed by talc pleurodesis or indwelling pleural catheter in the palliative care setting to relieve symptoms and improve quality of life. In chylothorax associated with curable/treatable malignancies like lymphoma, there are scarce data regarding the efficacy and safety of indwelling pleural catheters. We report a case of recurrent massive chylothorax associated with non‐Hodgkin lymphoma who demonstrated long‐term remission of lymphoma and complete regression of chylothorax after treatment with combination chemotherapy and ambulatory drainages using indwelling pleural catheter.     

MONITOR‐GCSF DLBCL subanalysis: Treatment patterns/outcomes with biosimilar filgrastim for chemotherapy‐induced/febrile neutropenia prophylaxis

Objective

Prospective data on the use of granulocyte‐colony‐stimulating factor (G‐CSF) in non‐Hodgkin's lymphoma and its aggressive subtypes, including diffuse large B‐cell lymphoma (DLBCL), are limited. MONITOR‐GCSF is a pan‐European, multicenter, prospective, observational study aiming to describe treatment patterns and clinical outcomes in patients receiving biosimilar filgrastim in the prophylaxis of chemotherapy‐induced neutropenia (CIN) and febrile neutropenia (FN).

Methods

This analysis describes patient characteristics, treatment patterns, and outcomes for 245 patients with stage 3 or 4 DLBCL receiving ≤6 chemotherapy cycles as part of MONITOR‐GCSF study, including patients aged ≥65 years and ≥70 years. Outcomes of interest included the incidence of CIN and FN, antibiotic prophylaxis, biosimilar filgrastim prophylaxis, and adverse events (AEs).

Results

MONITOR‐GCSF included 245 patients with DLBCL. Of these patients, 87 (35.5%) experienced one or more CIN (any grade) episode and 24 (9.8%) experienced FN (any grade). The most frequent AE reported was bone pain (n = 7, 2.9%), followed by arthralgia (n = 2, 0.8%) and back pain (n = 2, 0.8%).

Conclusion

In real‐life practice, biosimilar filgrastim demonstrated clinical effectiveness and safety in patients with DLBCL. The large percentage of patients aged ≥65 years adds to the evidence on how to best treat older patients with DLBCL receiving myelosuppressive chemotherapy.     

Prevalence of hepatitis C virus and hepatitis G virus in patients with non‐Hodgkin's lymphoma

Hepatitis C virus (HCV) and hepatitis G virus (HGV) belong to the same family of flaviviridea. A causative role of HCV infection in the pathogenesis of non‐Hodgkin's lymphoma (NHL) has been discussed widely. Little is known about the possible association between NHL and HGV discovered recently. In this study, anti‐HCV and HGV‐RNA prevalence were investigated in a group of 70 patients with NHL. The results were compared to a control group of 70 age‐ and sex‐matched healthy subjects. One patient in each group (1.4%) was found to be anti‐HCV‐positive; the difference was not statistically significant (P > 0.05). Five subjects in the patient group (7.1%) were positive for HGV‐RNA, while a single subject was positive in the control group (1.4%); the difference was not statistically significant (P > 0.05). Odds ratios for anti‐HCV and HGV‐RNA were 1 and 5.30, respectively. Our findings suggest that neither HCV nor HGV are causative or contributing factors in the aetiopathogenesis of NHL.     

The long‐term functional outcome in Mustard patients study: Another decade of follow‐up

Objective: For over 20 years, we have followed a cohort of patients who underwent the Mustard procedure for d‐transposition of the great arteries. The current study follows the same cohort from our last study in 2007 to reassess their functional ca‐pacity and quality of life.
Participants: Of the original 45 patients, six patients have required cardiac transplant and 10 patients have died, including two of the transplanted patients. Twenty‐five of the remaining patients agreed to participate in this current study.
Design: Patients underwent comparable testing to the previous studies when possi‐ble including exercise stress testing, echocardiography, MRI or CT evaluation of car‐diac anatomy and function, Holter monitor, and quality of life questionnaire.
Results: Thirty‐one percent of patients have experienced cardiac death either in the form of mortality or cardiac transplantation. The major cause of death was systemic right ventricular failure. Sixty‐five percent have continuing abnormalities of rhythm. Exercise time and workload showed a statistically significant decrease from the origi‐nal study (Time 1) to both 10‐year (Time 2) and 20‐year (Time 3) follow‐up points. Right ventricular ejection fraction decreased significantly from the Time 1 to Time 2, and again to this current follow‐up. Quality of life measures of energy level decreased significantly from the original study to both the Time 2 and Time 3.
Conclusion: Cardiac mortality for Mustard patients remains high, and over time, sys‐temic right ventricular ejection fraction, rhythm, exercise tolerance, and quality of life assessments show deterioration. There does not appear to be a single clear pre‐dictor of poor outcome.