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Advanced-Stage Hodgkin Lymphoma: New Approaches Based on Novel Therapeutic Agents or Treatment Intensification

Connors, Joseph M., MD

doi: 10.1097/PPO.0000000000000333
Review Articles

Depending on a variety of prognostic factors including age, stage, laboratory abnormalities, and initial response to treatment, from 70% to 90% of patients with advanced-stage Hodgkin lymphoma can be cured with modern multiagent chemotherapy. Two effective strategies offer the promise to improve on those results. Early intensification of treatment, typically by increasing the doses and frequency of administration of standard chemotherapy agents, induces higher initial response rates but has the major drawback of causing unacceptably severe acute toxicity, increased numbers of secondary neoplasms, and infertility due to oligospermia in men and premature menopause in women. Alternatively, integration of novel therapeutic agents into primary treatment is attractive, especially when the introduction not only improves the frequency and durability of disease response but also does not unacceptably increase acute or long-term toxicity. Finally, widespread availability of functional imaging with positron emission tomography now enables response-adapted therapy, a separate innovation in the treatment of Hodgkin lymphoma that can be incorporated with either intensified chemotherapy or addition of novel agents. This article discusses these exciting new developments in the treatment of advanced-stage Hodgkin lymphoma.

From the BC Cancer Center for Lymphoid Cancer and the University of British Columbia, Vancouver, British Columbia, Canada.

Conflicts of Interest and Source of Funding: J.M.C. received research funding from Amgen, Bayer Healthcare, Bristol Myers-Squibb, Cephalon, F Hoffmann-La Roche, Genentech, Janssen, Lilly, Merck, NanoString Technologies, Seattle Genetics, and Takeda.

Reprints: Joseph M. Connors, MD, BC Cancer Center for Lymphoid Cancer, 600 W 10th Ave, Vancouver, British Columbia, Canada V5Z 4E6. E-mail: jconnors@bccancer.bc.ca.

Treatment results for advanced-stage Hodgkin lymphoma have steadily improved over the past half century, providing a model for oncologic management that has been widely emulated across multiple cancer types. Essential to this model are expert pathologic review of diagnostic biopsies; team-based therapeutic assessment by experts in diagnostic imaging, systemic treatment (chemotherapy), and radiotherapy; meticulous attention to appropriate supportive care; carefully designed prospective randomized clinical trials; and regular revision of treatment protocols focusing on achieving the best possible balance of high-level effectiveness and minimization of toxicity. Today, it is possible to cure most patients with Hodgkin lymphoma, even when the disease is widely disseminated; however, there is still much room for improvement as investigators strive to further increase cure rates without adding to long-term toxicity. The most promising progress recently achieved toward these goals has resulted from either escalation of the intensity of treatment or the introduction of novel therapeutic agents. This section explores what has been achieved using each of those strategies and identify the most promising ways forward.

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ADVANCED STAGE: DEFINITION, STAGE MIGRATION, PROGNOSTIC FACTORS, AND RISK ASSESSMENT

Staging of Hodgkin lymphoma is based on the Ann Arbor system with the addition of a definition of bulky disease often referred to as the Cotswolds modification.1 Positron emission tomography using 18-F-fluorodeoxyglucose (PET) has become essential not only to establish stage at diagnosis but also to provide a running assessment of treatment effectiveness both during and at the conclusion of primary treatment. There is universal acceptance of stage III or IV as advanced-stage disease, and many clinicians also include patients with stage II and B symptoms or bulky disease (largest mass >10 cm in at least 1 dimension). It is important to understand, however, that improvements in imaging techniques have caused “stage migration”2 such that a substantial number of patients previously considered to have limited stage Hodgkin lymphoma are now being found to have advanced-stage disease as illustrated in Figure 1. Inclusion of patients such as this leads to apparent improvement in treatment outcome because patients such as this typically have a relatively low tumor burden and thus a more favorable prognosis.

FIGURE 1

FIGURE 1

Especially in the treatment of patients with advanced-stage disease, prognostic factor scoring systems can be helpful both in identifying patients at higher risk of relapse and comparing clinical trial results. A robust prognostic model that identifies patients with differing risks of primary treatment failure was initially based on outcomes for more than 4500 patients with advanced-stage Hodgkin lymphoma, most of whom had been treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in the 1980s.3 Seven independent predictors based on sex, age, stage, hemoglobin level, white blood cell count, lymphocyte count, and serum albumin were combined in an International Prognostic Factors Project (IPFP) score4 to identify subgroups of patients with increasing likelihood of treatment failure based on the number of factors present at diagnosis (Table 1). Improvements in accuracy of diagnosis, staging based on PET with subsequent stage migration, better supportive care, and widespread use of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auSCT) for relapsed disease have substantially lessened the discriminatory power of the IPFP score, as can be seen in our results at the British Columbia Cancer Agency with 675 consecutive patients treated with ABVD or equivalent chemotherapy through 2009 (Fig. 2).5 In contrast to a range in 5-year freedom from progression (FFP) rates of 42% (IPS score = 0, 5-year FFP = 84%; IPS ≥5, 5-year FFP = 42%) seen in the original publication,4 the spread in 5-year FFP being seen in our patients in British Columbia had narrowed to 17%, ranging from 83% to 66% for the same patient subsets (Fig. 2). This change demonstrates that as overall treatment strategies improve, the impact of clinical prognostic scoring systems diminishes.

TABLE 1

TABLE 1

FIGURE 2

FIGURE 2

Although clinical prognostic factors can be helpful in predicting outcome for advanced-stage Hodgkin lymphoma, they do not provide insight into the basic biology of the disease and therefore do not identify useful therapeutic targets for intervention. In theory, specific biologic characteristics (biomarkers) with demonstrable impact on risk of treatment failure could serve this purpose. Numerous candidate biomarkers have been proposed including antigens expressed on the Hodgkin and Reed-Sternberg (HRS) cells, antigens expressed on circulating lymphocytes, antigens expressed on microenvironmental cells within the tumor, circulating biomarkers detectable in the serum, gene expression profiles of biopsied tumors, and specific germline polymorphisms.6 All are of interest; however, turning these interesting biological observations into clinically relevant biomarkers for purposes of treatment planning has proven difficult, and at present, they do not appear ready for integration into standard management.

An alternative type of risk factor relevant to advanced Hodgkin lymphoma is one that becomes evident during treatment, which is typically completed over at least 6 to 8 months. Poor quality of response during multiple cycles of chemotherapy or absence of a complete response at the end of planned treatment may identify patients at higher risk of relapse. The wide availability of PET imaging provides the opportunity to determine its usefulness during management of advanced-stage disease. Interim PET scanning, typically after 2 to 3 cycles of chemotherapy (PET2), can identify a subset of patients with inferior response, which, in turn, may predict a higher likelihood of eventual treatment failure if treatment is simply completed with the same chemotherapy. ABVD is the multiagent chemotherapy program for which PET2 has been most extensively evaluated.7–14 Table 2 shows the outcome comparing results for those with a positive versus negative PET2 during ABVD chemotherapy. A negative PET2 is found in approximately 80% of patients and appears to be strongly predictive of a favorable outcome and may largely override the prognostic impact of the IPFP score. Risk assessment during treatment clearly has the potential to identify the minority of patients at particularly high risk of treatment failure. There is a clear need for more effective treatment, not only for these special patients at high risk but also for all patients with newly diagnosed advanced-stage Hodgkin lymphoma.

TABLE 2

TABLE 2

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NEW APPROACHES BASED ON TREATMENT INTENSIFICATION

Over the past 2 decades, 2 different approaches to overcoming treatment resistance in advanced-stage Hodgkin lymphoma have emerged, dose intensification and introduction of novel agents. The German Hodgkin Study Group initially developed and refined a dose-escalated and accelerated chemotherapy program, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine), in which, in comparison to ABVD, the doxorubicin and cyclophosphamide doses are increased by 40% and 100%, respectively; etoposide is added; the cycle interval is shortened to 3 weeks; and all patients receive neutrophil growth factors.15,16 Through a series of logical, well-designed clinical trials, this group has demonstrated the superiority of escalated BEACOPP over regimens such as ABVD in terms of progression-free survival (PFS),17–20 but this approach does not lead to superior overall survival (Table 3),21–24 and many clinicians consider the increased short- and long-term toxicity of escalated BEACOPP, including unacceptably severe acute toxicity, increased numbers of secondary neoplasms, and infertility due to oligospermia in men and premature menopause in women, too great to justify its use. This level of toxicity, however, may be justified for the approximately 20% of patients with a positive PET2. A growing body of evidence suggests that the negative prognostic impact of a positive PET2 can be at least partially overcome by then switching to intensified treatment such as escalated BEACOPP. This switch to intensified treatment may as much as double 2- to 3-year failure-free survival.(Table 4) Thus, a substantial improvement in freedom from treatment failure is obtained at the cost of much higher toxicity caused by switching to the intensified regimen. The strategy of PET2-guided intensification of treatment now must be compared with a strategy of reserving intensification with high-dose chemotherapy and auSCT until definite progression occurs following completion of standard-dose chemotherapy.

TABLE 3

TABLE 3

TABLE 4

TABLE 4

A somewhat similar use of interim PET scanning is to justify de-escalation of treatment intensity when PET negativity has been achieved after starting with intensified treatment. In such a strategy, a regimen such as escalated BEACOPP is switched to one with lower intensity, perhaps ABVD, or the number of additional cycles of chemotherapy given after PET2 is reduced. Some investigators have evaluated de-escalation to regimens such as ABVD, and in small, nonrandomized experiences, they have demonstrated excellent outcomes and reduced toxicity for patients with a negative PET2.25 More recently, a PET-adapted strategy in which a negative PET2 is used to prompt de-escalation to a reduced number of cycles of escalated BEACOPP has shown substantial promise.20 In the GHSG HD18 trial, 52% of patients with advanced-stage Hodgkin lymphoma reached a PET-negative response after 2 cycles of escalated BEACOPP.20 Those then randomly assigned to complete treatment with 2 more cycles of escalated BEACOPP (total 4 cycles) had a 5-year PFS of 92%, matching that of those randomized to complete treatment with 4 more cycles (total 6 cycles) of escalated BEACOPP. Other similar de-escalation strategies are being actively investigated.

It is useful to attempt to understand why incorporation of intensified chemotherapy into primary treatment of advanced-stage Hodgkin lymphoma has not led to improved overall survival. Certainly, a contributory factor has been the reliable ability of even more intensified chemotherapy combined with auSCT to cure approximately 50% of patients whose Hodgkin lymphoma relapses after primary chemotherapy, providing an intervention that can rescue patients after failure of standard-dose regimens such as ABVD.26–28 A conceptual model, comparing alternative strategies that use either early intensification (e.g., escalated BEACOPP as part of primary treatment) or late intensification offered only to those patients not cured by primary chemotherapy (e.g., primary treatment with ABVD followed by high-dose chemotherapy followed by auSCT, if primary treatment fails) helps explain the available evidence. Figure 3 shows that at the time of diagnosis patients with advanced-stage Hodgkin lymphoma fall into 1 of 3 groups: (a) patients with disease that can be cured with either standard-dose chemotherapy or intensified chemotherapy, (b) patients with disease that cannot be cured with standard-dose chemotherapy but can be cured with high-dose chemotherapy, and (c) patients with disease that cannot be cured with either standard or intensified-dose chemotherapy. As shown in Figure 3, with strategy 1, patients are first treated with ABVD, and if that fails to cure the lymphoma, those who relapse are treated with high-dose chemotherapy and auSCT. In strategy 2, patients are treated with intensified chemotherapy at the time of diagnosis, the escalated BEACOPP approach. As the figure shows, ultimately the same proportion of patients fail to be cured, those who harbor lymphoma at the time of diagnosis that is resistant to both standard- and intensified-dose chemotherapy. Genuine progress against advanced-stage Hodgkin lymphoma will require a different strategy.

FIGURE 3

FIGURE 3

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NEW APPROACHES BASED ON NOVEL AGENTS

To be of genuine usefulness in curing cancers that have proven resistant to previously used chemotherapy drugs, a novel agent must have a distinct mechanism of action, and it must not add substantially to the overall toxicity already being caused by the backbone of agents to which it will be added. The antibody-drug conjugate, brentuximab vedotin, appears to have these characteristics. It is composed of a monoclonal antibody directed against the CD30 antigen universally expressed by malignant HRS cells joined to several molecules of monomethyl aurostatin E (MMAE), a potent microtubule disruptor. After binding to surface CD30, the brentuximab vedotin is internalized into the cell, and the protein antibody and the linker joining it to the MMAE are digested away, freeing the MMAE to disrupt internal cellular structures and trigger apoptosis. In a large phase II trial, brentuximab vedotin induced an overall response rate of 75% and complete response rate of 34% in patients with Hodgkin lymphoma that had relapsed after prior ABVD treatment and high-dose chemotherapy and auSCT.29 Importantly, without any further treatment, approximately 30% of the complete responders have remained in remission for more than 5 years since receiving the brentuximab vedotin and have probably been cured.30 In the AETHERA trial, adjuvant brentuximab vedotin was able to reduce the likelihood of relapse after high-dose chemotherapy and auSCT for high-risk relapsed Hodgkin lymphoma by approximately 30%, shifting the likelihood of relapse from approximately 60% to less than 40%.31,32 Taken together, those 2 studies imply that brentuximab vedotin is capable of curing Hodgkin lymphoma that cannot be cured by either standard-dose or intensified-dose chemotherapy. From the results in those 2 studies, we can estimate that, if added to the backbone of standard-dose AVD (ABVD without the bleomycin, with which brentuximab vedotin cannot be combined because the combination results in unacceptable pulmonary toxicity), the new combination, A-AVD (brentuximab vedotin [Adcetris; Seattle Genetics], doxorubicin, vinblastine, and dacarbazine) should be able to eliminate approximately 20% to 30% of the treatment failures that would have resulted if standard ABVD had been given. That prediction was put to the test in a recently completed clinical trial. In the ECHELON-1 trial, 1334 patients were randomized to standard ABVD versus A-AVD.33 The novel combination induced a superior freedom from treatment failure of 82% compared with 77% for those treated with standard ABVD, a result implying that approximately 23% of the patients who would have relapsed after ABVD did not do so after A-AVD. This result is closely in line with the prediction implied by the results of the phase II and AETHERA trials. The novel regimen, A-AVD, appeared equally superior across multiple subgroups of patients including those with high IPFP scores, those with stage IV disease, and those with bone marrow or multiple extranodal sites of disease. Also, importantly, the addition of brentuximab vedotin added only moderate toxicity to the AVD backbone consisting primarily of reversible peripheral nerve toxicity and more frequent neutropenia, which could be prevented with the use of neutrophil growth factor. Equally importantly, A-AVD completely eliminated the use of bleomycin and thus the associated risk of pulmonary toxicity. Of note, in the ECHELON-1 trial, treatment was not guided by interim PET scanning. All patients received their randomly assigned chemotherapy regimen. Whether previous insights gained from studies of the use of interim PET scanning can be translated to the use of A-AVD primary chemotherapy remains to be tested in future clinical trials.

Returning to the model described in Figure 3, we can examine the impact of adding the novel agent, brentuximab vedotin, to standard first-line chemotherapy for advanced-stage Hodgkin lymphoma. As shown in strategy 3, the addition of the non–cross-resistant novel agent reduces the proportion of patients left with incurable disease. It also brings the spinoff benefit of reducing the frequency with which it is necessary to rely on secondary treatment with high-dose chemotherapy and auSCT because it reduces the number of relapses after frontline treatment. Conceptually, this reduction in the proportion of patients with advanced-stage Hodgkin lymphoma who cannot be cured with standard or high-dose chemotherapy validates the strategy of depending on novel agents to further increase the likelihood of cure.

There are several candidate novel agents other than brentuximab vedotin currently being studied for Hodgkin lymphoma. Lenalidomide is an immunomodulatory drug that was studied in 36 patients with relapsed Hodgkin lymphoma who had received a median of 4 prior therapies; the ORR was 19%, and 1 patient achieved a complete response.34 It is currently being tested as maintenance therapy for patients who have relapsed after auSCT. The mTOR (mechanistic target of rapamycin) inhibitor everolimus has demonstrated activity in a phase II study of patients with heavily pretreated relapsed Hodgkin lymphoma inducing a partial response in 8 (47%) of 19 patients and a median PFS of 6.2 months.35 Panobinostat, a pan-histone deacetylase inhibitor, produced an overall response rate of 27% and a complete response rate of 4% in a phase II trial including 129 patients with multiply relapsed Hodgkin lymphoma.36 It is currently being evaluated in a phase I–II study in combination with the mTOR inhibitor everolimus.37 Bendamustine, a potent alkylating agent, has been shown to induce short-lived but deep remissions in 53% of patients with heavily pretreated relapsed Hodgkin lymphoma, including 33% complete responses.38 Novel immunologic interventions are also being evaluated including AFM13, a bispecific antibody that binds CD16A on natural killer (NK) cells and CD30 on HRS cells, resulting in NK cell activation and tumor cell lysis and autologous T cells primed to target CD30, CD123, or CD19 on malignant cells (chimeric antigen receptor T cells).39–42 The most promising novel agents, however, are the checkpoint inhibitors of the programmed cell death ligands 1 and 2 (PD-L1, PD-L2), and they are the candidates most likely to succeed in further reducing the proportion of Hodgkin lymphoma patients with incurable disease.

Programmed cell death ligands 1 and 2, which are overexpressed not only by malignant HRS cells but also by nonmalignant tumor-associated macrophages that are localized around PD-L1–positive HRS cells, block cytotoxic T- and NK-cell activity,43 causing an immunologic blockade that promotes tumor survival by protecting HRS cells from the cytotoxic effects of NK cells and tumor-specific cytotoxic T lymphocytes.44,45 This provides a strong biologic rationale for targeting the PD-L1 and PD-L2 pathways in Hodgkin lymphoma. Nivolumab and pembrolizumab are immunoglobulin G4 monoclonal anti–PD-1 antibodies now approved for the treatment of relapsed and refractory Hodgkin lymphoma. In the phase II setting, patients whose lymphoma had progressed after auSCT or brentuximab vedotin or both were treated with nivolumab; high overall response rates of 69% and 87% were seen, including complete responses in 16%, leading to a median PFS of 15 months.46,47 Pembrolizumab was approved based on the phase II trial that divided 210 patients with relapsed and refractory Hodgkin lymphoma into 3 cohorts according to previous treatment with auASCT and/or brentuximab vedotin. All 3 cohorts had an overall response rate of 69% and a complete response rate of 22%.48 It is reasonable to anticipate that the next effective step forward in reducing treatment failures in advanced Hodgkin lymphoma will result from the incorporation of such checkpoint inhibitors as nivolumab and pembrolizumab into frontline treatment regimens.

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FUTURE DIRECTIONS

The treatment of advanced-stage Hodgkin lymphoma continues to evolve. Attractive treatment strategies have emerged from clinical trials incorporating interim PET scan–guided escalation or de-escalation approaches or integration of the novel agent such as brentuximab vedotin into primary chemotherapy. The most promising future approach will most likely be incorporation of checkpoint inhibitors into primary treatment. Treating specialists will need to have a careful discussion of the pros and cons of these different strategies with their patients with a final choice based on a full assessment of how to achieve the greatest efficacy while minimizing both short- and long-term toxicity. The outcome for patients found to have advanced-stage Hodgkin lymphoma will continue to improve.

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Keywords:

Advanced stage; brentuximab vedotin; checkpoint inhibitor; Hodgkin lymphoma; nivolumab; pembrolizumab; response-adapted therapy

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