Recent advances in antibody‐based therapies for Hodgkin Lymphoma

Although a poster child for the development and refinement of multi‐modal multi‐agent therapeutic strategies, Hodgkin Lymphoma has, until recently, lagged behind other lymphomas in terms of the use of therapeutic monoclonal antibodies. This situation has now changed dramatically, with the rapid emergence both of a toxin‐conjugated tumour‐selective anti‐CD30 antibody, and of antibodies targeting immunological checkpoints, most notably PD‐1 (also termed PDCD1). The former provides an efficient targeting vehicle for delivery of a potent synthetic anti‐mitotic drug, with ultimate efficacy independent of immunological activity. The latter are members of a class of drugs representing a new paradigm in immune‐oncological therapies that are designed to enhance pre‐existent anti‐tumour T cell activities. The role of both in the overall treatment pathway will continue to evolve over coming years. Hodgkin Lymphoma has once again become emblematic of the major trend shifts in cancer therapy.     

The treatment of older Hodgkin lymphoma patients

The outcome of patients with Hodgkin lymphoma (HL) has dramatically improved over the past decades and continues to improve with the development of novel targeted therapies, such as the immunoconjugate brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab. Moreover, with the use of response-adapted strategies using positron-emission-tomography (PET), the overall intensity of treatment for most patients can be reduced, resulting in less acute and late toxicity. However, these advances are mainly restricted to younger patients, as advances in patients above the age of 60 years (‘older’ patients) have been much less pronounced. Furthermore, about one third of all HL patients are among the older population, but only 5–10% of the patients treated in current HL clinical trials are ≥60 years old. HL in older patients is characterized by aggressive disease and unfavourable prognostic features as B symptoms and predominance of advanced stages. In addition, tolerance to curative chemotherapy is drastically reduced in older patients resulting in excessive toxicity and insufficient treatment due to therapy delays and dose reductions. Therefore, there is a significant unmet medical need in older HL patients for less toxic and effective therapies, and an important gap of knowledge concerning this growing population of patients. Recent advances on epidemiology, characteristics and treatment of older HL patients will be summarized in this article.     

Current treatment paradigms for advanced stage Hodgkin lymphoma

The treatment of advanced classical Hodgkin Lymphoma (cHL) has evolved over the last 50 years with a progressive improvement in long term cure rates in patients up to the age of 60 years. However, a minority of these survivors experience severe morbidity and mortality resulting from intensive chemotherapy and radiotherapy, leading to a drive to de-escalate treatment without compromising survival. The early identification of patients with chemoresistant disease by functional imaging allows the modulation of therapy and an efficient means to test new agents in those most in need of more effective therapy. The outcomes of treatment for older patients have not improved at the same rate, and this group requires a different approach, incorporating specialist geriatric support to personalise therapy. Clinical trials that focus on quality of life, comorbidity and survival are needed to improve survival rates for this expanding population with complex needs.     

The role of transplantation in Hodgkin lymphoma

Autologous stem cell transplantation is the standard salvage strategy for young and fit patients with Hodgkin lymphoma failing induction therapy, and is effective in nearly 50% of cases. The quality of response at transplantation is the most relevant prognostic aspect, as patients in complete response can obtain better outcomes. Therefore, first-line salvage treatments applied before transplantation need to produce high quality responses without excessive myelotoxicity and without affecting peripheral blood stem cell mobilisation. In this sense, the incorporation of new agents active in Hodgkin lymphoma, such as brentuximab vedotin and anti-programmed death 1 antibodies, in conventional regimens, may help to enhance complete remission rates. Working on conditioning regimen and applying a post-autologous consolidation treatment (for example with brentuximab vedotin) are two ways for improving transplant outcomes, particularly in patients displaying high-risk features for early relapse or progression. Allogeneic transplantation maintains its curative potential also in the era of new drugs, although its most correct timing and the most suitable sequence of post-autologous salvage treatments still remain to be determined.     

Mini-BEAM is effective as a bridge to transplantation in patients with refractory or relapsed Hodgkin lymphoma who have failed to respond to previous lines of salvage chemotherapy but not in patients with salvage-refractory DLBCL

Patients with relapsed or refractory lymphoma can be cured with stem cell transplantation if they are shown to have disease that is responsive to salvage chemotherapy. Patients who fail to respond to first-line salvage chemotherapy tend to do very poorly. Here we report on 39 such patients who received mini-BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy as second or subsequent-line salvage chemotherapy. Fifty-six percent of these patients had primary refractory disease and a further 28% had responses to first-line therapy that lasted <12 months. Seventy-two percent had progressive disease following the salvage chemotherapy administered immediately prior to mini-BEAM and the remaining 28% had stable disease. Overall there was a 38% response to mini-BEAM (complete response = 28%, partial response = 10%). Patients with Hodgkin lymphoma (HL) had a higher response rate compared to those with diffuse large B cell lymphoma (DLBCL) (63% vs. 20%). Seventy-four percent of HL patients were able to proceed to transplantation compared with 30% of patients with DLBCL. Mini-BEAM is a very effective bridge to transplantation in very poor risk patients with HL who have failed to respond to first-line salvage chemotherapy. Its efficacy in non-Hodgkin lymphoma is more modest.     

Brentuximab vedotin for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplantation

Brentuximab vedotin (BV) is the first approved novel agent for salvage treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after autologous stem cell transplantation (ASCT). In this study, a literature-based analysis was undertaken to assess, via an indirect treatment comparison, the comparative efficacy of BV to salvage chemotherapy as treatment for R/R cHL patients following ASCT. This comparative effectiveness research was undertaken to support a reimbursement submission for BV to the Australian Pharmaceutical Benefits Advisory Committee. Retrospective analysis of individual patient data from four data sources demonstrated that the use of BV as first salvage treatment in cHL patients relapsing or progressing post-ASCT achieved improvements in both clinical response and overall survival. More specifically, BV was associated with an incremental improvement of 22% in overall response rate compared to salvage chemotherapy. Five-year overall survival and progression-free survival rates were 92·2% [95% confidence interval (CI): 85·5–99·3%] and 32·2% (95% CI: 19·1–54·6%) respectively for BV, compared to 30·5% (95% CI: 22·2–42·0%) and 3·2% (95% CI: 1·1–8·9%) respectively for salvage chemotherapy. The encouraging results from this conservative analysis have the potential to support informed clinical management and funding decisions for the first salvage of cHL patients demonstrating recurrence after ASCT.     

Low‐dose pembrolizumab induced remission in patients with refractory classical Hodgkin lymphoma

We aimed to compare hypofibrinogenaemia prevalence in major bleeding patients across all clinical contexts, fibrinogen supplementation practice, and explore the relationship between fibrinogen concentrations and mortality. This cohort study included all adult patients from 20 hospitals across Australia and New Zealand who received massive transfusion between April 2011 and October 2015. Of 3566 patients, 2829 (79%) had fibrinogen concentration recorded, with a median first and lowest concentration of 2·0 g/l (interquartile range [IQR] 1·5–2·7) and 1·8 g/l (IQR 1·3–2·4), respectively. Liver transplant (1·7 g/l, IQR 1·2–2·1), trauma (1·8, IQR 1·3–2·5) and vascular surgery (1·9 g/l, IQR 1·4–2·5) had lower concentrations. Total median fibrinogen dose administered from all products was 7·3 g (IQR 3·3–13·0). Overall, 1732 (61%) received cryoprecipitate and 9 (<1%) fibrinogen concentrate. Time to cryoprecipitate issue in those with initial fibrinogen concentration <1 g/l was 2·5 h (IQR 1·2–4·3 h). After adjustment, initial fibrinogen concentration had a U‐shaped association with in‐hospital mortality [adjusted odds ratios: fibrinogen <1 g/l, 2·31 (95% confidence interval (CI) 1·48–3·60); 1–1·9 g/l, 1·29 (95% CI 0·99–1·67) and >4 g/l, 2·03 (95% CI 1·35–3·04), 2–4 g/l reference category]. The findings indicate areas for practice improvement including timely administration of cryoprecipitate, which is the most common source of concentrated fibrinogen in Australia and New Zealand.     

Immune checkpoint inhibition in lymphoid disease

It has long been understood that the immune system has intrinsic anti‐tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this immune surveillance. A number of attempts have been made to harness this anti‐tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death‐1 (PDCD1, PD‐1)/cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) ‘immune checkpoint’ pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti‐tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies.     

Treatment of newly diagnosed advanced stage Hodgkin lymphoma

ABVD continues to be the standard of care for patients with advanced stage Hodgkin Lymphoma (HL) although escalated BEACOPP has improved survival in one randomized controlled trial (RCT). More intensive regimens have higher rates of acute and late toxicities and this poses significant issues for patients. Consolidation strategies such as radiation or autologous stem cell transplantation (ASCT) have not demonstrated an improvement in overall survival in RCTs. Novel technology and therapeutics are leading us to investigate new questions. Interim FDG-PET scanning is now being tested in prospective studies. Small, typically retrospective trials suggest that interim PET scans are independent markers of outcome and current trials are piloting the use of PET-adapted therapy. Targeted therapeutics have been evaluated in the relapsed and refractory setting and now show promising single agent activity. Agents including brentuximab vedotin (a conjugated anti-CD30 monoclonal antibody) and the histone deacetylase inhibitor panabinostat have reported encouraging single agent activity and a large study of brentuximab vedotin maintenance post ASCT is underway. Combination and maintenance trials are planned or ongoing in the primary treatment setting that will hopefully improve on the treatment standards of the past decade. This review will discuss the current standard of care in advanced stage HL, summarize some of the current data regarding interim FDG-PET scans and will conclude with some issues related to the development of new agents that are likely to be involved in the future standard of therapy.     

Quality of life results from a phase 3 study of brentuximab vedotin consolidation following autologous haematopoietic stem cell transplant for persons with Hodgkin lymphoma

Brentuximab vedotin (BV) significantly improved progression‐free survival in a phase 3 study in patients with relapsed or refractory Hodgkin lymphoma (RR‐HL) post‐autologous‐haematopoietic stem cell transplant (auto‐HSCT); we report the impact of BV on quality of life (QOL) from this trial. The European Quality of Life five dimensions questionnaire was administered at the beginning of each cycle, end of treatment, and every 3 months during follow‐up; index value scores were calculated using the time trade‐off (TTO) method for UK‐weighted value sets. Questionnaire adherence during the trial was 87·5% (N = 329). In an intent‐to‐treat analysis, compared with placebo, TTO scores in the BV arm did not exceed the minimally important difference (MID) of 0·08 except at month 15 (?0·084; 95% confidence interval, ?0·143 to ?0·025). On‐treatment index scores were similar between arms and did not reach the MID at any time point; mixed‐effect modelling showed that BV treatment effect was not significant (P = 0·2127). BV‐associated peripheral neuropathy did not meaningfully impact QOL. Utility scores for patients who progressed declined compared with those who did not; TTO scores between these patients exceeded the MID beginning at month 15. In conclusion, QOL decreased modestly with BV consolidation treatment in patients with RR‐HL at high risk of relapse after auto‐HSCT.     

Novel treatment concepts in Hodgkin lymphoma

Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid‐1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long‐term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18‐ to 65‐year‐old patients diagnosed during the period 1992–2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high‐dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life‐prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first‐ or second‐line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long‐term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.     

Results of a multicentre UK‐wide retrospective study evaluating the efficacy of brentuximab vedotin in relapsed,refractory classical Hodgkin lymphoma in the transplant naive setting

Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti‐CD30 monoclonal antibody‐drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK‐wide retrospective study of 99 SCT‐naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0–1 and advanced stage disease. The median progression‐free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post‐BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non‐toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post‐BV.     

Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study

Tandem stem cell transplantation (SCT) is an option for high‐risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14–56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow‐up was 43 months (4.8–73.7 months). The two‐year progression‐free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46–65%) and 71% (95% CI: 49–84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant‐related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high‐risk relapsed/refractory HL patients, although transplant‐related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin‐based post‐transplant consolidative strategies in high‐risk relapsed/refractory HL patients.     

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.