Front-Line Treatment of Patients with Advanced Hodgkin Lymphoma
Multidrug chemotherapy regimens, with or without radiotherapy, have proved to be highly successful in achieving long-term remissions in the majority of patients with advanced-stage Hodgkin lymphoma.1 However, depending on the treatment given, approximately 30% of patients with advanced-stage Hodgkin lymphoma do not achieve long-term remission with front-line treatment using standard regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).1-3
More effective chemotherapy regimens, such as escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone), can acheive 5-year freedom-from-treatment failure in patients with advanced Hodgkin lymphoma.1,2 In addition, chemotherapy regimens, such as BEACOPP, are generally associated with acute and long-term toxicities, including secondary malignancies, cardiovascular disease, and infertility, which are a major concern, especially given the high survivorship rate and younger patient population.4-12
Furthermore, the prognosis of patients who do not respond to front-line therapy is poor, with only 50% to 60% of patients with relapsed disease able to be rescued with high-dose chemotherapy and autologous hematopoietic stem-cell transplant, underscoring the importance of successful front-line therapies for patients with advanced-stage Hodgkin lymphoma.2
On March 29, 2017, a panel of 5 Hodgkin lymphoma experts convened in Marseille, France, to explore the challenges associated with the current standard of care in the front-line treatment of patients with advanced Hodgkin lymphoma, and outlined unmet medical needs that have been observed in this patient population. This whitepaper captures the highlights from the expert panel discussions.
Front-Line Treatment Options for Advanced Hodgkin Lymphoma
The 4-drug regimen ABVD was developed more than 4 decades ago and continues to be used in patients with advanced Hodgkin lymphoma.1 Contemporary studies have demonstrated the efficacy of the ABVD regimen, showing complete remission rates of 70% to 84% and 5-year freedom from disease progression rates of 61% to 74% in patients with advanced-stage Hodgkin lymphoma.5,13-15
The efficacy of the ABVD regimen was established by the results of the Cancer and Leukemia Group B clinical trial that compared the ABVD regimen and the MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) regimen for 6 to 8 months, and MOPP alternating with ABVD for 12 months in 361 patients with advanced-stage Hodgkin lymphoma; no radiotherapy was administered.13 Patients who received ABVD achieved a complete response rate of 82%; the 5-year failure-free survival was 61% in the ABVD cohort. At a follow-up of at least 20 years, no difference was seen in overall survival (OS) among the 3 cohorts.14
The randomized, phase 3 North American Intergroup Trial E2496 demonstrated complete remission and clinical complete remission rates of 73% with the ABVD regimen versus 69% with the Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) regimen, with or without radiation, in 794 patients with advanced-stage Hodgkin lymphoma.15 At a median follow-up of 6.4 years, the failure-free survival rate was 74% with the ABVD regimen versus 71% with the Stanford V regimen.15 Overall, the efficacy of the ABVD regimen is not optimal, because approximately 30% of patients will ultimately experience treatment failure.3
Several clinical efforts have been made to develop other regimens that can improve on the efficacy of the ABVD regimen; of these, only the escalated BEACOPP regimen, developed by the German Hodgkin Study Group, has demonstrated improvement in progression-free survival (PFS) over ABVD.4-9
The ABVD and BEACOPP regimens are currently included in the European Society for Medical Oncology Hodgkin lymphoma clinical practice guidelines. Members of the expert panel noted that in clinical practice, “Both regimens are being used outside of clinical studies right now, and they both work in the vast majority of cases, achieving long-term remissions in patients,” and that “while ABVD is worse than escalated BEACOPP in terms of efficacy, BEACOPP has more acute toxicity, including leukopenia, thrombocytopenia, higher risk of infection, and it also has more long-term side effects, particularly infertility.”
The 3-arm HD9 clinical trial compared a baseline and an increased dose of BEACOPP versus COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) plus ABVD (COPP-ABVD) in 1196 evaluable patients with advanced-stage Hodgkin lymphoma.4 This clinical trial demonstrated significantly higher 5-year rates of freedom from treatment failure in the baseline BEACOPP group and the escalated BEACOPP group (76% and 88%, respectively) versus the COPP-ABVD group (68%; Table 1).4 This freedom-from-treatment-failure benefit translated into a significantly higher 5-year OS rate
with the escalated BEACOPP regimen (92%) versus the COPP-ABVD regimen (83%) and a lower rate of early disease progression with the escalated BEACOPP regimen compared with COPP-ABVD.4
At 10 years’ follow-up, the escalated BEACOPP regimen was still associated with a higher freedom-from-treatment-failure rate of 82% versus 64% with the COPP-ABVD regimen and an OS rate of 86% versus 75%, respectively (P <.0001).4 These long-term follow-up data are of particular importance in the absence of clinical trials powered to test for OS difference between ABVD and escalated BEACOPP as the primary end point.
Because the ABVD and escalated BEACOPP regimens are the main contenders for the front-line treatment of patients with advanced-stage Hodgkin lymphoma, clinicians are divided about which regimen to use. Several studies have compared the efficacy of the escalated BEACOPP regimen (using 4 cycles of escalated BEACOPP, followed by 4 cycles [4 + 4] or 2 cycles [4 + 2] of baseline-dose BEACOPP) with that of the ABVD regimen; the results have consistently shown that escalated BEACOPP yields significantly higher rates of PFS than ABVD (Table 2).5-9 The data show that, based on the study population and treatment regimen, the 5-year PFS of escalated BEACOPP is 81% to 93% compared with 68% to 75% for ABVD.1
A meta-analysis of 14 randomized clinical trials conducted between 1980 and 2013, involving 9993 patients, showed that the estimated absolute benefit in the 5-year OS was 10% after 6 cycles of escalated BEACOPP versus ABVD.16 However, such an absolute benefit was not reported in the 4 smaller clinical trials that directly compared these 2 regimens, which was attributed to the clinical trials’ limited statistical power to detect even larger differences in OS and the impact of subsequent therapies; none of the studies included in the meta-analysis directly compared the 2 regimens.16
The 10-year data from the HD9 clinical trial also revealed that the benefits of the escalated BEACOPP regimen were offset by considerably increased rates of severe hematologic toxicity, treatment-related mortality, and secondary myelodysplastic syndrome (MDS) and leukemia compared with the COPP-ABVD regimen.4 Overall, 98% of patients who received escalated BEACOPP had grade 3 or 4 leukopenia and thrombocytopenia, and 22% of patients had infectious complications.4
However, at 5-year and 10-year follow-up of the HD9 trial, the differences between the COPP-ABVD regimen versus the baseline BEACOPP regimen in terms of the rate of freedom from treatment failure were not statistically significant; the rate of freedom from treatment failure was 68% versus 76% at 5 years for the ABVD regimen and baseline BEACOPP, and 64% versus 70% at 10 years, respectively. The OS rates were also not significantly different between the 2 regimens. The OS was 83% versus 87% at 5 years for ABVD versus baseline BEACOPP, and 75% versus 80% at 10 years, respectively. These data suggest that baseline BEACOPP is no more effective than ABVD in the treatment of patients with advanced-stage Hodgkin lymphoma.3
Reduced-intensity chemotherapy variations of escalated BEACOPP continue to be developed to reduce the increased risk for toxicities. The parallel-group, open-label, HD15 clinical trial compared 8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, and 8 cycles of baseline BEACOPP in 2182 patients with newly diagnosed advanced Hodgkin lymphoma.10
The HD15 study demonstrated that the 5-year freedom from treatment failure with 6 cycles of the escalated BEACOPP regimen, followed by radiation administered to residual positron emission tomography (PET)-positive disease ≥2.5 cm, was noninferior to and less toxic than 8 cycles of escalated BEACOPP (97.5% confidence interval [CI], 0.5-9.3, for treatment difference).10 The 5-year freedom-from-treatment-failure rates were 84.4% (97.5% CI, 81.0-87.7) for 8 cycles of escalated BEACOPP; 89.3% (97.5% CI, 86.5-92.1) for 6 cycles of escalated BEACOPP; and 85.4% (97.5% CI, 82.1-88.7) for 8 cycles of baseline BEACOPP, with OS rates of 91.9%, 95.3%, and 94.5%, respectively.10
Roundtable participants proposed that the observed treatment regimen bias for ABVD over escalated BEACOPP in clinical practice might stem from several clinical and practical considerations, including increased risk for secondary malignancies, higher rate of infertility, and prohibitive toxicities associated with escalated BEACOPP, as well as physician preferences.
“ABVD has bleomycin-related toxicities, but it’s a well-established regimen, particularly in the United States, among nonhospital private oncologists who treat most of these patients,” said one expert.
Another expert noted that “ABVD is quite an easy regimen to use, so it can be given in the outpatient setting, while patients treated with escalated BEACOPP need more supportive treatment and occasional hospitalization to manage the associated hematologic toxicities, particularly in elderly patients. While this might not be an issue in university hospitals, it becomes an issue for practitioners in the community setting, where they are not used to these intense protocols.”
Given such differences between treatments, the participants agreed that it would be difficult to arrive at a generally accepted induction regimen, and that “the two philosophies will continue to coexist; the countries and groups that use ABVD are not going to change to escalated BEACOPP, and vice versa,” as one participant said; in the absence of evidence-based data in favor of one regimen over another, both regimens will likely continue to be used, despite suboptimal safety and efficacy in advanced disease.
The panel of experts agreed that further refinement of the approaches to Hodgkin lymphoma treatment or risk-stratification strategies will need to be developed to improve patient outcomes. In particular, based on ongoing clinical research trends and available evidence, one expert hypothesized that “first-line therapy in the near future may be modulated by PET-driven strategies in certain cases.”
Failure of Front-Line Therapy
Approximately 30% of patients do not achieve complete remission with front-line ABVD therapy, because of primary refractory disease or relapsed disease.1,2 The expert panel noted that patients with primary refractory disease have a worse prognosis than patients with relapsed disease after primary therapy. Treatment options for these patients include salvage chemotherapy regimens, consolidation therapy, and transplantation. However, only 50% to 60% of patients with relapsed Hodgkin lymphoma will be rescued with standard high-dose chemotherapy,2 followed by transplantation without consolidation, whereas 15% to 30% of patients do not even proceed to transplantation for various reasons, highlighting the importance of successful front-line treatment in patients with Hodgkin lymphoma.2
Front-Line Therapy in Elderly Patients
The ABVD regimen is the current standard of care for older patients (aged ≥60 years) with Hodgkin lymphoma who are fit to receive treatment with multi-agent chemotherapy, because the escalated BEACOPP regimen is associated with an increased rate of treatment-related mortality in elderly patients, as was demonstrated in a 2005 study by Ballova and colleagues.17 These results are consistent with the results of the HD9 study, where escalated BEACOPP was not associated with improved freedom-from-treatment-failure rates over COPP-ABVD in older patients aged >60 years.4
In another study, elderly patients with advanced-stage Hodgkin lymphoma had disproportionately inferior outcomes compared with younger patients, with an associated 5-year failure-free survival rate of 48% in elderly patients compared with 74% in the younger cohort (P = .002) after treatment with ABVD or Stanford V.18 Furthermore, older patients had markedly higher treatment-related mortality compared with younger patients.18 In addition, elderly patients are at an increased risk for dying from bleomycin-related lung toxicity.19
These disparate outcomes may be attributed to biologic differences between younger and older individuals and to an increased risk for dose reductions and treatment toxicity in elderly patients with advanced-stage Hodgkin lymphoma.18,20 Based on these data, there is a critical need for new therapeutic approaches for older patients with Hodgkin lymphoma, particularly regimens that maintain efficacy while improving tolerability.
Long-Term, Treatment-Related Toxicities
The standard chemotherapy regimens ABVD and escalated BEACOPP, along with radiotherapy, are associated with short- and long-term treatment-related toxicities, including secondary malignancies, cardiac toxicities, infertility, and pulmonary toxicities, which have important clinical and quality-of-life (QOL) implications for patients.
The ABVD and the escalated BEACOPP regimens include bleomycin, an agent that can lead to unpredictable and potentially fatal pulmonary toxicity in approximately 10% of patients.21-23
The exact pathogenesis of bleomycin-related lung toxicity is unclear, and no good predictive tests are available to evaluate the risk for this condition in patients with normal baseline pulmonary function.22,23 Evidence supports the discontinuation of bleomycin in all patients with documented or strongly suspected bleomycin-related lung toxicity, because pneumonitis can resolve over time if detected early, but it increases the risk for irreversible pulmonary fibrosis if unchecked.21
The experts endorsed performing baseline pulmonary function tests before initiating bleomycin treatment, noting that “it’s a cheap and quick test that provides a good baseline diffusion capacity for many patients.”
Common abnormalities associated with bleomycin-induced lung toxicity include a reduced carbon monoxide diffusion capacity and a restrictive ventilator defect.20 However, omitting bleomycin from ABVD (ie, AVD) in patients who are at risk for bleomycin-related lung toxicity is associated with inferior outcomes, showing a decrease of approximately 4% in the 5-year freedom from treatment failure with AVD compared with ABVD in early-stage Hodgkin lymphoma, further underscoring the need for more effective and safer front-line treatments for patients with Hodgkin lymphoma.24
A large body of evidence indicates that treatment with escalated BEACOPP carries an increased risk for secondary malignancy (eg, secondary MDS/acute nonlymphocytic leukemia) compared with ABVD (Table 3).4-10
The chemotherapy-induced increased risks for secondary malignancies are further compounded by an elevated risk for solid tumors, such as breast cancer and nonmelanoma skin cancer, in patients who receive concomitant radiotherapy.25
The experts cited a 2003 study that examined the long-term mortality of 1261 patients with Hodgkin lymphoma who were aged ≤40 years at the time of diagnosis and received treatment between 1965 and 1987, to underscore the high mortality rate associated with the effects of long-term treatment of Hodgkin lymphoma, particularly in younger patients.26
In that study, the increased mortality risk was attributed to causes other than Hodgkin lymphoma, 20 years after diagnosis, with approximately 66% of deaths resulting from secondary cancers and 33% of deaths resulting from cardiovascular disease; this increased mortality risk lingered more than 30 years after Hodgkin lymphoma diagnosis, and the greatest excess mortality risk was seen predominantly in the youngest patient cohort (aged <21 years at diagnosis).26
However, encouraging results from more recent studies, including HD15, demonstrated that refining the escalated BEACOPP regimen (ie, 6 cycles vs 8 cycles of escalated BEACOPP), with the intent of balancing efficacy with toxicities, yields a considerably lower rate of secondary malignancies.10 The incidence rate of secondary malignancies in HD15 was 1.8% with 8 cycles of escalated BEACOPP, 0.7% with 6 cycles of escalated BEACOPP, and 1.1% with 8 cycles of baseline BEACOPP.10
The panel of experts agreed that the increased risk for secondary malignancies in patients with Hodgkin lymphoma is a general concern, although the number of secondary malignancies has been reduced as a result of substantial effective dose reductions, such as those used in the HD15 and the HD18 clinical trials.10,27
Evidence indicates that radiotherapy and chemotherapy are associated with increased cardiovascular morbidity and mortality.11 The overall risk for coronary heart disease increased by 7.4% per Gy of radiation administered in long-term Hodgkin lymphoma survivors who received radiotherapy between 1965 and 1995.11
These results, however, may be less relevant in 2017, the experts noted, because radiotherapy techniques have evolved from an era of larger treatment fields and higher radiotherapy doses to more confined fields and lower doses to reduce cardiovascular toxicities. Despite these advances, radiotherapy-induced cardiac toxicity continues to be a relevant clinical concern in the modern era.
With regard to chemotherapy, it is well-established that anthracyclines (eg, doxorubicin) can cause cardiomyopathy in patients with Hodgkin lymphoma and in other cancer types.28 Anthracycline-containing chemotherapy nearly tripled the rate of heart failure, irrespective of the use of radiotherapy.29
“It’s an understated problem: we need to get away from the current situation where anthracyclines are an absolute in lymphoma treatment with curative intent,” noted one expert.
The incidence of gonadal toxicity in patients with Hodgkin lymphoma depends on several factors, including the type and dose of chemotherapy, patient age at treatment onset, and the use of oral contraceptives.12
A large 2013 study involving 1323 men and women survivors of Hodgkin lymphoma showed that chemotherapy-induced gonadal toxicity was highest in patients who received escalated BEACOPP.30 The majority of women who received this regimen showed signs of amenorrhea and reduced hormonal levels, reflecting impaired fertility and reduced ovarian reserve.30
In another study of women with advanced Hodgkin lymphoma, at a median follow-up of 3.2 years, 54.6% of women who received 4 cycles of COPP-ABVD reported continuous amenorrhea after treatment versus 66.7% of women who received escalated BEACOPP.12
The effect of Hodgkin lymphoma treatment on gonadal toxicity is a determinant of treatment decision-making in daily practice, particularly in women of reproductive age, the panel experts explained. Despite the availability of ovarian tissue preservation and sperm bank options to mitigate future fertility issues, “long-term side effects, such as pulmonary and cardiac toxicity, are relevant, but fertility is also a big concern,” said one participant. The experts noted that cultural influences within a country can make infertility issues a bigger concern for some patients.
Quality of Life
It is increasingly being recognized that the treatment of Hodgkin lymphoma is associated with a considerable decline in QOL in survivors.31 In a longitudinal study of 273 long-term survivors of Hodgkin lymphoma (82% with stage I/II disease at presentation, 18% with stage III/IV disease), 59% of the survivors had ≥1 new late effects in a 7-year period.31 The researchers reported a significant decline in the 36-Item Short Form Physical Component Summary score, which was significantly greater among survivors with new cardiac or pulmonary complications than in those without new complications.31 In addition, survivors with a new cardiac complication had significantly greater scores on worsening of fatigue, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire.31
Indeed, recent evidence suggests that 30% to 40% of patients with Hodgkin lymphoma in remission have severe or extreme fatigue, regardless of disease stage and treatment, with a devastating impact on their QOL.32
The debilitating effects of Hodgkin lymphoma treatment on fatigue, said one expert, “is often overlooked. Chronic fatigue and soreness of the muscles is a consequence of anthracyclines, and while it might seem like a very low price to pay for getting cured, it severely impacts quality of life, when at age 30, maybe about 3 to 5 years after chemotherapy, you become extremely tired with small exertion.”
These long-term, treatment-related effects correlate with increased healthcare resource utilization; indeed, previously seldom-reported reasons for excess healthcare use by these patients included chest pain, keratitis, asthma, diabetes, or depression.33 Hodgkin lymphoma survivors had a doubling in outpatient visits for up to 10 years after diagnosis, and a 3-fold increase in “bed days” for up to 4 years, as a result of infectious complications (ie, septicemia, viral infections, and erysipelas), respiratory disorders (ie, pneumonia), genitourinary diseases (ie, nephritis, nephrolithiasis, and urinary infections), or nonspecific symptoms (ie, chest pain and fever).33
Because younger patients with Hodgkin lymphoma have a high likelihood of long-term remission, it is particularly important to consider and minimize the risk for late effects associated with chemotherapy and radiotherapy in Hodgkin lymphoma treatment.34
The International Prognostic Score (IPS) was developed as a risk stratification tool for patients with advanced Hodgkin lymphoma based on 7 baseline prognostic factors, including low albumin levels, anemia, male sex, increasing age, advanced disease stage, leukocytosis, and lymphopenia.35 IPS continues to be predictive of outcomes and is used in everyday practice, but its clinical value in making treatment decisions is limited, because of its reduced discrimination of higher-risk groups, underscoring an unmet clinical need for these patients. Although better biomarkers are needed for guiding treatment decisions in Hodgkin lymphoma, currently no validated markers are available for clinical use.
Recent evidence indicates that the use of 18F-fluorodeoxyglucose PET assessment early in the course of treatment (ie, interim PET) is superior to baseline IPS scoring as a predictive tool to assess long-term treatment outcomes and to modulate subsequent therapy accordingly, by escalating or de-escalating treatment in patients with advanced Hodgkin lymphoma based on interim PET findings.27,36-39 Hodgkin lymphoma shows high 18F-fluorodeoxyglucose avidity (97%-100%), with 18F-fluorodeoxyglucose PET functional imaging considered a validated means of detecting residual, metabolically active disease, and acting as a surrogate biomarker for chemosensitivity.40
RATHL Clinical Trial
Several randomized clinical trials evaluated 2 models of response-adapted therapy based on early interim PET scans in patients with advanced Hodgkin lymphoma (ie, treatment de-escalation in patients with PET-negative findings and a good outlook, or treatment escalation in patients with PET-positive findings who are at highest risk for treatment failure).27,36 These approaches were assessed in the Response-Adjusted Therapy for Hodgkin Lymphoma (RATHL) clinical trial, using interim PET findings after 2 treatment cycles.36
Johnson and colleagues assessed whether 18F-fluorodeoxyglucose PET could guide treatment escalation or de-escalation in 1214 patients with high or low risk for treatment failure after receiving 2 cycles of ABVD.36 Patients with PET-negative findings (N = 937) were randomly assigned to continue ABVD or omit bleomycin (ie, AVD regimen), whereas patients with PET-positive findings received escalated BEACOPP or an accelerated version of BEACOPP that involved growth-factor support (hazard ratio, 0.90; 95% CI, 0.47-1.74; P = .76).36
In early PET-negative patients, at a median follow-up of 41 months, the 3-year PFS was 85.7% with ABVD versus 84.4% with AVD, and the OS was 97.2% with ABVD versus 97.6% with AVD.36 In the RATHL study, no significant difference was seen in 3-year PFS or OS between patients who received ABVD and those who were de-escalated to AVD (ie, without bleomycin), according to baseline characteristics, such as age, sex, disease stage, IPS, or bulky disease status.36 The results in this clinical trial fell short of the prospectively defined specified noninferiority margin for the omission of bleomycin from the ABVD regimen after negative interim PET findings, but preliminary results indicated that the AVD regimen was associated with a more favorable safety profile than ABVD: pulmonary toxicity was less severe with AVD than with ABVD.36
Furthermore, the predictive ability of negative findings on an interim PET scan was significantly reduced in patients with stage III or IV disease.36 The 3-year PFS was 90.0% in patients with stage II disease, 83.1% in those with stage III disease, and 79.6% in patients with stage IV disease (P <.001).36 In addition, of the 172 patients with PET-positive findings who received escalated BEACOPP as part of the dose-escalation strategy, 74.4% had negative findings on a third PET/computed tomography scan; the 3-year PFS rate was 67.5% and the OS rate was 87.8%, highlighting the continued unmet need for more effective treatment approaches.36
“RATHL is really a relevant study, particularly in patients over 50 years or those who are current or ex smokers; the omission of bleomycin in these patients based on PET findings is worthwhile,” one expert said.
HD18 Clinical Trial
Further extending the results of the RATHL and the HD15 studies, the international, open-label, phase 3 HD18 study by the German Hodgkin Study Group included 1100 patients with newly diagnosed, advanced-stage Hodgkin lymphoma who underwent interim PET imaging after completing 2 cycles of escalated BEACOPP.27
Patients with PET-positive findings (N = 440) were randomly assigned to 6 additional courses of escalated BEACOPP, with or without rituximab.27 The addition of rituximab to escalated BEACOPP did not impart additional benefit to the 5-year PFS.27 At a median follow-up of 33 months, the estimated 3-year PFS was 91.4% (95% CI, 87.0-95.7) with escalated BEACOPP versus 93.0% (95% CI, 89.4-96.6) with rituximab plus escalated BEACOPP (log-rank P = .99).27 The PFS rate for patients with PET-positive findings was better than expected, exceeding even the outcome of PET-unselected patients in the HD15 study.10 Further analysis of the efficacy and safety effects of treatment de-escalation in the PET-negative subpopulation are ongoing.
Results from other trials, including the US intergroup S0816 study, the Italian GITIL HD0607 study (NCT00795613), and the AHL2011 LYSA study, support the PET-guided response-adapted treatment strategy in advanced Hodgkin lymphoma.1,38,39
The experts noted that although PET-guided therapy represents an important advancement in personalized treatment of patients with advanced-stage Hodgkin lymphoma, several clinical and practical challenges exist, including the de-escalation of therapy in patients with stage III or IV disease and with PET-negative findings, availability of PET facilities for community-based practitioners, variations in the accurate and reproducible interpretation of PET images, and reimbursement issues in some countries in the European Union.
Given that the interpretation of qualitative visual scans can result in unacceptable inter-reader variability, the experts endorsed the value of appropriate education for risk mitigation. In this context, experts voiced hesitancy in making important treatment decisions based solely on interim PET results outside of a clinical trial or central review, highlighting an unmet need for clinical biomarkers in clinical practice. Because PET assessments can only detect measurable disease, the panel agreed that the development of validated methods to detect minimal residual disease in patients with Hodgkin lymphoma is another important unmet need.
Future Trends in Front-Line Therapy for Hodgkin Lymphoma
The BEACOPP regimen is more effective in prolonging PFS than the ABVD regimen in patients with advanced Hodgkin lymphoma; however, it is associated with more acute and long-term toxicities than the ABVD regimen.
The panel of experts expressed hope for challenging the use of high-dose chemotherapy and moving toward a chemotherapy-free treatment regimen for patients with advanced Hodgkin lymphoma. They noted that such goals are not unrealistic, because chemotherapy-free regimens have been successful in other hematologic malignancies, such as chronic lymphocytic leukemia.
The experts proposed that the concept of “complication-free survival” may offer better front-line treatment options, which is consistent with the demands of all stakeholders, including regulatory agencies and patients.
In light of current advancements with response-guided therapies for patients with Hodgkin lymphoma and the potential development of clinical and molecular biomarkers, the expert panel envisioned tailoring Hodgkin lymphoma treatment to the individual patient in the near future.
The current treatment paradigm for patients with advanced Hodgkin lymphoma involves the use of combination chemotherapy with ABVD or with escalated BEACOPP, with several clinical and practical considerations influencing treatment selection. The benefits of these chemotherapy regimens are tempered by 2 main issues: the recognition that some patients do not achieve cure, and the risk for short- and long-term toxicities associated with these regimens, including secondary malignancies, pulmonary and cardiac toxicities, infertility issues, and compromised QOL.
Therefore, the goals for front-line treatment of advanced Hodgkin lymphoma are 2-fold—to achieve long-term remission, while minimizing acute and long-term toxicities for elderly and younger patients. The front-line treatment landscape for Hodgkin lymphoma is evolving, with the promise of PET response-adapted treatment to maximize efficacy and minimize toxicity, as well as the use of emerging agents with novel mechanisms of action.
- Vassilakopoulos TP, Johnson PW. Treatment of advanced-stage Hodgkin lymphoma. Semin Hematol. 2016;53:171-179.
- Vassilakopoulos TP, Angelopoulou MK. Advanced and relapsed/refractory Hodgkin lymphoma: what has been achieved during the last 50 years. Semin Hematol. 2013;50:4-14.
- Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348:2386-2395.
- Engert A, Diehl V, Franklin J, et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009;27:4548-4554.
- Federico M, Luminari S, Iannitto E, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin’s lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009;27:805-811.
- Merli F, Luminari S, Gobbi PG, et al. Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced Hodgkin lymphoma: a study by Fondazione Italiana Linfomi. J Clin Oncol. 2016;34:1175-1181.
- Viviani S, Zinzani PL, Rambaldi A, et al. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365:203-212.
- Carde P, Karrasch M, Fortpied C, et al. Eight cycles of ABVD versus four cycles of BEACOPPescalated plus four cycles of BEACOPPbaseline in stage III to IV, International Prognostic Score ≥ 3, high-risk Hodgkin lymphoma: first results of the phase III EORTC 20012 Intergroup Trial. J Clin Oncol. 2016;34:2028-2036.
- Mounier N, Brice P, Bologna S, et al; for the Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥4 baseline): ﬁnal results in stage III–IV low-risk Hodgkin lymphoma (IPS 0–2) of the LYSA H34 randomized trial. Ann Oncol. 2014;25:1622-1628.
- Engert A, Haverkamp H, Kobe C, et al; for the German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379:1791-1799. Erratum in: Lancet. 2012;379:1790.
- van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol. 2016;34:235-243.
- Behringer K, Breuer K, Reineke T, et al; for the German Hodgkin’s Lymphoma Study Group. Secondary amenorrhea after Hodgkin’s lymphoma is inﬂuenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2005;23:7555-7564.
- Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327:1478-1484.
- Canellos GP, Niedzwiecki D, Johnson JL. Long-term follow-up of survival in Hodgkin’s lymphoma. N Engl J Med. 2009;361:2390-2391.
- Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31:684-691.
- Skoetz N, Trelle S, Rancea M, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14:943-952.
- Ballova V, Rüffer JU, Haverkamp H, et al. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005;16:124-131.
- Evens AM, Hong F, Gordon LI, et al. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013;161:76-86.
- Böll B, Goergen H, Behringer K, et al. Bleomycin in older early-stage favorable Hodgkin lymphoma patients: analysis of the German Hodgkin Study Group (GHSG) HD10 and HD13 trials. Blood. 2016;127:2189-2192.
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