High dose chemotherapy and autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: Emerging questions,newer agents,and changing paradigm

Primary treatment for adult and pediatric patients with Hodgkin lymphoma (HL) using current multiagent anthracycline-based chemotherapy with or without radiation therapy will cure approximately >70% of the patients; >95% for early stage with a favorable risk profile and 70–75% with advanced stage and high risk features. Managing refractory and relapsed disease, however, remains a challenge. High dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT) can salvage 40–70% of patients with relapsed or refractory HL. Two randomized trials in relapsed and refractory patients showed superior progression free survival. This presentation addresses some of the salient differences and changes in the management that have evolved over the last decade and have either already affected, or are likely to affect the outcome of HDC auto-SCT. The following will discussed. 1. Historic trials and other emerging issues impacting the outcome of HDC auto-SCT. 2. Changes in the primary treatment and response adapted therapy. 3. Evaluation and validation of prognostic factors at the time of first failure. 4. Selection of salvage chemotherapy. 5. Conditioning regimens. 6. Consolidation after HDC auto-SCT. 7. Management of failures of HDC auto-SCT. 8. Availability of financial resources in various healthcare systems. Enrolment in clinical trials should be encouraged.     

Modern principles in the management of nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a unique rare subtype of Hodgkin lymphoma (HL) which differs clinically, pathologically and biologically from classic HL, warranting a nuanced approach to treatment. CD20 expression by malignant lymphocyte-predominant cells, a tendency for late relapses, and the risk of transformation to aggressive large B-cell lymphoma are characteristic features with important implications for treatment and follow-up. Recognition of histopathological variant patterns is also critical, with important implications for prognosis and treatment. The optimal management for NLPHL is unclear and opinions differ as to whether treatment paradigms should be similar to, or differ from, those for classic HL. Therapy differs for early versus advanced stage disease and for frontline versus relapsed or refractory disease. Potential treatment strategies include radiotherapy, combined modality therapy, chemotherapy, rituximab and watchful waiting. Given the excellent overall survival of NLPHL, treatment choices should be geared towards reducing long-term toxicity and optimizing survivorship. In this review, we provide an overview of the current literature and discuss modern principles in the management of NLPHL.     

Therapy-related classical Hodgkin lymphoma after a primary haematological malignancy: a report on 13 cases

The risk of developing Hodgkin lymphoma (HL) is increased in immunodeficiencies or during the treatment of some autoimmune diseases. The development of new therapeutic agents has highlighted the risk of unusual lymphoid proliferations, particularly classical HL (cHL). We report the clinicopathological findings of 13 cHL arising in patients treated for a primary haematological malignancy. Eight patients had received an immunomodulator, protein tyrosine-kinase inhibitor or monoclonal antibody, which may have contributed to the cHL development. Most patients had disseminated disease with poor prognostic factors at cHL diagnosis. Despite the initial presentation, good outcomes were achieved with standard cHL chemotherapy.     

Febrile cholestatic disease as an initial presentation of nodular lymphocyte-predominant Hodgkin lymphoma

Febrile cholestatic liver disease is an extremely unusual presentation of Hodgkin lymphoma(HL).The liver biopsy of a 40-year-old man with febrile episodes and cholestatic laboratory pattern disclosed an uncommon subtype of HL,a nodular lymphocyte-predominant HL(NLPHL).Liver involvement in the early stage of the usually indolent NLPHL's clinical course suggests an aggressiveness and unfavorable outcome.Emphasizing a liver biopsy early in the diagnostic algorithm enables accurate diagnosis and appropriate tre...     

Phase IA/II,multicentre, open‐label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non‐Hodgkin or Hodgkin lymphoma

Despite advancements in the treatment of non‐Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), patients continue to relapse and thus a need for new targeted therapies remains. The CD40 receptor is highly expressed on neoplastic B cells and activation leads to enhanced proliferation and survival. Lucatumumab (HCD122) is a fully human antagonistic CD40 monoclonal antibody. A phase IA/II study was designed to determine the maximum tolerated dose (MTD) and activity of lucatumumab in patients with relapsed/refractory lymphoma. Determination of the MTD was the primary objective of the phase IA dose escalation portion and clinical response was the primary objective of the phase II dose expansion portion. Patients received escalating doses of lucatumumab administered intravenously once weekly for 4 weeks of an 8‐week cycle. MTD was determined at 4 mg/kg of lucatumumab. A total of 111 patients with NHL (n = 74) and HL (n = 37) were enrolled. Responses were observed across various lymphoma subtypes. The overall response rate by computed tomography among patients with follicular lymphoma (FL) and marginal zone lymphoma of mucosa‐associated lymphatic tissue (MZL/MALT) was 33·3% and 42·9%, respectively. Lucatumumab demonstrates modest activity in relapsed/refractory patients with advanced lymphoma, suggesting that targeting of CD40 warrants further investigation.     

Malignancies in beta-thalassemia patients: a single-center experience and a concise review of the literature

Thalassemia represents the world's most common monogenic disease, characterized by absence of or decreased globin chain production. The lifespan of thalassemia patients has been extended as a result of current supportive treatment. We report three cases of cancer (non-Hodgkin lymphoma, Hodgkin disease, and seminoma) in thalassemic patients. Factors that may contribute to the pathogenesis of cancer seem to be infections and iron overload through mechanisms of oxidative damage; immunomodulation or coexistence of the two diseases may only be coincidental.     

Subsequent malignancies among long‐term survivors of Hodgkin lymphoma and non‐Hodgkin lymphoma: a pooled analysis of German cancer registry data (1990–2012)

The increased risk of subsequent primary malignancies (SPM) in survivors of adult‐onset Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) remains a challenging clinical problem worldwide. The German cancer registry database, pooled from 14 federal states, was used to calculate the standardized incidence ratio (SIR) and excess absolute risk (EAR) of SPM in 128 587 patients registered with first primary HL/NHL between 1990 and 2012. Conversely, SIRs were also calculated for a subsequent HL/NHL following other first cancers. The risk of developing SPM was significantly increased over twofold for HL survivors (SIR = 2·14, EAR = 51·87 cases/10 000 person‐years) and 1·5‐fold for NHL survivors (SIR = 1·48, EAR = 55·23) compared with the general German population. For solid cancers, SIRs were significantly elevated (1·6‐ and 1·4‐fold; respectively) and were highest (threefold) in patients below 30 years of age upon initial diagnosis. Overall, SIRs were consistently elevated for lip/oral cavity, colon/rectum, lung, skin melanoma, breast, kidney and thyroid. Significantly increased SIRs for oesophagus, stomach, liver, pancreas, testis, prostate, and brain/central nervous system were observed following NHL only. For certain SPM, SIRs remained significantly elevated more than 10 years following HL/NHL diagnosis. Positive reciprocal associations were demonstrated between HL/NHL and several solid cancers mentioned above; for some, common aetiological mechanisms seem plausible.     

Epstein–Barr Virus Expression in Classic Hodgkin Lymphoma in an Indian Cohort and its Association with Clinical and Histomorphological Parameters

Epstein Barr virus (EBV) associated Hodgkin lymphoma (HL) has been defined as cases with clonal EBV infection, EBV genome and gene products in the Reed Sternberg cells. We evaluated the prevalence and clinico-pathological association of EBV in North Indian HL patients. Eighty-eight cases of histologically confirmed classic HL were evaluated for EBV by both IHC expression of LMP1 and real time PCR on formalin fixed lymph node tissue. The expression pattern was analyzed for any association with clinical and histomorphological parameters. Nodular sclerosis subtype was seen in 79.5% patients and mixed cellularity was seen in the remaining patients. Ninety percent of the cases were positive for EBV. The detection rate of EBV by IHC was higher. The EBV positive cases presented with higher disease stage (p < 0.05). The presence of histomorphological features like granuloma formation (5/5), atypical lymphocytes (8/8), histiocyte clusters (26/28), large area of necrosis (11/12), less prominent inflammatory response (25/27) was associated with EBV positivity (p > 0.05). In our study population a high proportion of HL cases showed positivity for EBV indicating a pathogenic role. The positivity was independent of age, gender and histological subtype. Further evaluation of EBV positivity in modulation of tumor immunity may provide insights into variable treatment outcome in EBV positive cases.     

‘ACOPP’ chemotherapy for older and less fit patients with Hodgkin lymphoma—A multicentre,retrospective study

Management of classical Hodgkin lymphoma in older patients is challenging due to poor tolerance of the chemotherapy regimens used in younger patients. We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co-morbidities. Here we present data from the first 41 patients treated with ‘ACOPP’ across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2-year PFS and OS, 73% (95% CI: 52–94) and 93% (95% CI: 80–100) respectively).     

Lymphoma diagnosis at an academic centre: rate of revision and impact on patient care

Few studies have examined the value of a mandatory second review of outside pathology material for haematological malignancies. Therefore, we compared diagnoses on biopsies referred to an academic medical centre to determine the rate and therapeutic impact of revised diagnoses resulting from a second review. We reviewed 1010 cases referred for lymphoma during 2009–2010. For each case, referral diagnosis and second review diagnosis were compared. Revised diagnoses were grouped into major and minor discrepancies and all major discrepancies were reviewed by a haematologist to determine the effect the diagnostic change would have on therapy. There was no change in diagnosis in 861 (85·2%) cases. In 149 (14·8%) cases, second review resulted in major diagnostic change, of which 131 (12·9%) would have resulted in a therapeutic change. The highest rates of revision were for follicular, high‐grade B‐cell, and T‐cell lymphomas. We found higher rates of major discrepancy in diagnoses from non‐academic centres (15·8%) compared to academic centres (8·5%; P = 0·022), and in excisional biopsies (17·9%) compared to smaller biopsies (9·6%; P = 0·0003). Mandatory review of outside pathology material prior to treatment of patients for lymphoma will identify a significant number of misclassified cases with a major change in therapy.     

Soluble factors produced by activated CD4+ T cells modulate EBV latency

Following infection with Epstein-Barr virus (EBV), the virus is carried for life in the memory B-cell compartment in a silent state (latency I/0). These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental significance to identify how the different EBV expression patterns are established in the latently infected cell. In view of the prompt activatability of CD4(+) T cells in primary EBV infection, and their role in B-cell differentiation, we studied the involvement of CD4(+) T cells in the regulation of EBV latency. Lymphoblastoid cell lines (LCLs) were cocultured with autologous or allogeneic CD4(+) T cells. Activated T cells influenced the expression of two key viral proteins that determine the fate of the infected B cell. EBNA2 was down-regulated, whereas LMP1 was unregulated and the cells proliferated less. This was paralleled by the down-regulation of the latency III promoter (Cp). Experiments performed in the transwell system showed that this change does not require cell contact, but it is mediated by soluble factors. Neutralizing experiments proved that the up-regulation of LMP1 is, to some extent, mediated by IL21, but this cytokine was not responsible for EBNA2 down-regulation. This effect was partly mediated by soluble CD40L. We detected similar regulatory functions of T cells in in vitro-infected lymphocyte populations. In conclusion, our results revealed an additional mechanism by which CD4(+) T cells can control the EBV-induced B-cell proliferation.     

High serum levels of B-lymphocyte stimulator are associated with clinical-pathological features and outcome in classical Hodgkin lymphoma

B-lymphocyte stimulator (BLyS) acts as survival factor for B lymphocytes. As Hodgkin and Reed-Sternberg (HRS) cells express receptors through which BLyS promotes their growth and chemotherapy resistance, we investgated whether this molecule was increased in sera from patients with classical Hodgkin lymphoma (cHL) and whether it correlates with clinical-pathological features and outcomes. Enzyme-linked immunosorbent assay was used to measure soluble BLyS (sBLyS) in sera from 87 patients and 33 donors; higher levels were detected in patients (mean +/- standard error 4493.9 +/- 264.9 pg/ml vs. 2687.0 +/- 200.9 pg/ml; P < 0.0001). Levels above the median value (4242.0 pg/ml) were associated with age > or = 45 years (P = 0.042), advanced stages of disease (P = 0.005), systemic symptoms (P = 0.014) and extranodal involvement (P = 0.009). Five-year failure-free survival (FFS) of patients with sBLyS below or equal to median levels was 88.6% as compared to 65.1% of those with levels above the median (P = 0.009). Statistical analyses confirmed the prognostic significance of sBLyS (P = 0.046). When patients were analysed according to variables associated with high levels, sBLyS showed an independent predictive power in terms of FFS. Our findings support the involvement of BLyS in cHL pathogenesis. The association between high serum levels and an inferior FFS indicates that sBLyS is a possible prognostic predictor with a potential significance as a therapeutic target.     

Molecular Pathogenesis of Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a distinctive lymphoma subtype that accounts for approximately 30% of all lymphomas in the Western world and approximately 5% in Japan. HL is characterized by the giant multinucleated tumor cells called Hodgkin/Reed-Sternberg (H/RS) cells, but the cellular origin had long been unknown. Recent investigations have clarified that H/RS cells have a clonally rearranged immunoglobulin gene in most cases, but it still seems appropriate to differentiate HL from other B-cell neoplasms, because the transforming event rather than its cellular origin is more likely to influence the nature of H/RS cells. Many questions remain to be answered for comprehensive understanding of the pathogenesis of HL. The presence of H/RS cells alone is probably not enough for disease onset, but the immune reaction against these cells appears to be inevitable for generation of HL. Most HL patients are cured with current treatment strategies, but some of them have refractory or recurrent disease, and intensified treatment occasionally induces therapy-related secondary malignancies. Because the growth and survival of H/RS cells are supported by various external stimuli and constitutive intracellular signals, management of HL is expected to be one of the best applications of molecule-targeted therapy.     

Chemotherapy only for localized Hodgkin lymphoma

Radiation therapy (RT) alone and more recently in combination with chemotherapy (combined modality therapy; CMT) has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma (HL) for over 40 years. Because of increasing awareness of the late morbidity and mortality associated with RT, recent treatment regimens have attempted to limit its use. Chemotherapy only has been demonstrated to be a treatment option for most patients with localized HL. Current clinical trials have targeted subgroups of such patients who may be at an increased risk of recurrence for the addition of limited RT to chemotherapy.