Treatment Of Advanced Stage Hodgkin Lymphoma Research Articles

PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial

The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1-3], 100 mg/m2 oral procarbazine [day 1-7], 40 mg/m2 oral prednisone [day 1-14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]). Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. For the German translation of the abstract see Supplementary Materials section.

Cost-effectiveness of first-line treatment options for patients with advanced-stage Hodgkin lymphoma: a modelling study

Several strategies are available for the initial treatment of advanced-stage Hodgkin lymphoma, but the optimal strategy in terms of cost-effectiveness is unclear. The aim of this study was to compare the quality-adjusted effectiveness and costs of five modern treatment options for transplantation-eligible patients with newly diagnosed advanced-stage Hodgkin lymphoma. A Markov decision-analytic model was developed using a 20-year time horizon. Five of the most common treatment approaches were selected based on clinical experience and expert opinion: (1) six cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), including data from the HD2000 trial, Viviani and colleagues, and EORTC trial; (2) six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP; from the HD15 trial or PET-adapted as in the HD18 trial, two initial cycles of BEACOPP followed by four additional cycles for patients with a positive PET and either two or four additional cycles of BEACOPP for patients with a negative PET); (3) PET-adapted escalation (as in the RATHL trial, two cycles of standard ABVD chemotherapy followed by an additional four cycles of ABVD or AVD in PET-negative patients and four cycles of BEACOPP in PET-positive patients); (4) six cycles of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A-AVD) or ABVD as in the Echelon-1 trial; and (5) PET-adapted de-escalation (as in the AHL2011 trial, two cycles of BEACOPP followed by PET2 scan; PET-positive patients received two additional BEACOPP cycles and PET-negative patients received two cycles of ABVD; at PET4, PET-negative patients completed two further cycles of either ABVD or BEACOPP depending on what they received after PET2, and PET-positive patients received salvage therapy). Note that all uses of BEACOPP in these strategies were BEACOPPescalated. The randomised groups of interest from these studies comprised 4255 patients enrolled between April, 2000, and January, 2016. Baseline probability estimates and utilities were derived from the included trials in addition to a systematic review of published studies. A Canadian public health payer's perspective was considered (CAN$1=US$0·74) and adjusted for inflation for 2018. All costs and benefits were discounted by 1·5% per year because life-years now are more valuable than future potential life-years. Probabilistic analyses (10 000 simulations) showed that, for a willingness-to-pay threshold of CAN$50 000, a PET-adapted de-escalation strategy based on AHL2011 was more cost-effective 87% of the time. This strategy had the highest number of life-years (14·6 years [95% CI 13·7-15·1]) and quality-adjusted life years (13·2 years [95% CI 10·2-14·4]), and the lowest direct costs ($53 129 [95% CI 31 914-94 446]) compared with the other treatment regimens. Sensitivity analyses showed that the model was robust to key variables, including probability of treatment-related mortality, relapse, frequency of secondary malignancy, death from secondary malignancy, and probability of infertility after BEACOPP. Our results suggest that, when considering cost, effectiveness, and short and long-term toxicities, the preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is the PET-adapted de-escalation regimen starting with BEACOPP and de-escalating to ABVD as appropriate. Although our findings do not provide an absolute best treatment approach for clinicians to follow for all patients, they can contribute to shared decision making between patients and treating physicians. None.

Updates in Treatment Strategies for Hodgkin Lymphoma.

Several options are available for frontline treatment of advanced-stage Hodgkin lymphoma (HL) and treatment of relapsed HL, each with inherent advantages and disadvantages. Clinicians must balance risk with benefit for the individual patient. At the NCCN 2019 Annual Congress: Hematologic Malignancies, Dr. Ranjana H. Advani summarized the current frontline treatment options for advanced-stage HL and outlined novel and emerging agents that may be incorporated as therapy options for relapsed disease.

Health-Related Quality of Life (HRQL) Trajectories during Treatment for Advanced Stage Pediatric Hodgkin Lymphoma (HL)

Introduction: The treatment of advanced stage HL typically includes dose-dense chemotherapy with or without involved field radiation. However, little is known about the HRQL of pediatric patients during initial treatment. We describe the HRQL trajectory over time by child and parent-proxy rater and examine baseline patient characteristics associated with the trajectory.Methods: Children and adolescents, ages 5-17.9 years newly diagnosed with advanced stage HL and enrolled in Children's Oncology Group AHOD 1331, and their parents were co-enrolled in an embedded study to assess HRQL (n=310). Children (age ≥11 years) and parent proxies (of children 5-17.9 years) reported on the child's global HRQL using the Child Health Rating Inventories (CHRIs) at four times: (1) baseline, (2) cycle 2, (3) cycle 5, and (4) end of therapy, approximately 6-7 months following initial diagnosis. The 7-item CHRIs-Global yields scores that range from 0-100, with higher scores indicating better HRQL. A repeated measures linear regression model was fit with categorical time (reference, baseline), rater, child race, ethnicity, and continuous age. An interaction of rater and time was tested and predicted means were plotted.Results: 97% of age-eligible patients and parents completed baseline HRQL assessments with 93% completing planned follow-ups. Median child age was 15.5 years (q1=5.4, q3=18.9) and 50.3% were female. Most children were white (76.1%) and non-Hispanic (82.6%). There was no significant interaction between rater and time (Figure), so this was subsequently excluded from the model. Scores improved slightly at time 2 (β=2.5, 95%CI=0.3, 4.6) and 3 (β=2.8, 95%CI=0.3, 5.3) compared to baseline; larger improvements were seen by time 4 (β=10.6, 95%CI=7.9, 13.3) after completion of therapy. Children reported higher HRQL than their parent proxies (β=5.6, 95%CI=3.9, 7.2), males had higher HRQL than females (β=4.6, 95%CI=1.0, 8.3), and older age was associated with lower HRQL (β=-0.8, 95%CI=-1.5, -0.1). There was no significant effect of race or ethnicity.Conclusions: Completion rates of HRQL were high across all time periods and for both raters. HRQL, impaired at baseline, likely from the disease process, improved slightly during treatment, with larger improvements by the end of initial therapy. Future research will examine how clinical and treatment factors impact the HRQL trajectory. [Display omitted] DisclosuresParsons:Seattle Genetics: Research Funding. Rodday:Seattle Genetics: Research Funding. Henderson:Seattle Genetics: Research Funding.

Cost-Effectiveness and Cost-Utility Analysis of ABVD Versus Beacopp in the Treatment of Advanced-Stage Hodgkin Lymphoma

Background:Treatment options for advanced-stage Hodgkin lymphoma include ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or combinations of BEACOPPbaseline and BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, hereinafter referred to as BEACOPP). There remains clinical equipoise over the best initial treatment strategy, as both strategies have similar 10-year overall survival in long-term clinical trial follow-up. There is a trade-off that occurs with inferior progression-free survival in the ABVD strategy, but higher rates of hematologic toxicity, infertility, and second malignancy in the BEACOPP strategy. The overall lifetime cost of each strategy is also unknown.Methods:We developed a Markov decision-analytic model to compare ABVD versus BEACOPP for a hypothetical cohort of transplant-eligible patients with newly-diagnosed advanced-stage Hodgkin lymphoma. The model simulates their clinical course over a 20-year time horizon. Baseline probability estimates and utilities were derived from a systematic review of published studies. Direct medical costs were obtained from publicly available administrative databases or from the literature and applied to the health states. All costs and benefits were discounted by 1.5%. A Canadian public health payer's perspective was considered and costs are presented in 2018 Canadian dollars (Table 1). Sensitivity analyses were performed for key variables.Results:Based on a 20-year model, life expectancy was 12.6 years with ABVD and 13.6 years with BEACOPP, yielding an expected survival benefit with BEACOPP of 1.0 years. The quality-adjusted life expectancy (QALY) was 10.4 years with ABVD and 11.4 years with BEACOPP, leading to an expected quality-adjusted survival benefit with BEACOPP of 1.0 QALYs. The direct costs were $98,081 for ABVD and $81,296 for BEACOPP, making BEACOPP the cost-saving strategy with a net benefit of $16,785. In the base-case analysis, BEACOPP was associated with both cost-savings and improved quality-adjusted outcomes over ABVD, making it the dominant treatment strategy. Sensitivity analyses demonstrated that the model was robust to key variables including probability of death from secondary malignancy, probability of relapse post-primary and salvage therapy, and probability of infertility secondary to BEACOPP. In sensitivity analysis of treatment-related mortality secondary to BEACOPP, the threshold value was found to be 6.5% mortality over the 6-month treatment period, a value much greater than that reported in the literature. The threshold utility of infertility was found to be 0.72 for ABVD to have a greater QALY than BEACOPP, a value lower than the utility derived from a systemic review of the literature (0.87). We assumed all infertile patients underwent a cycle of fertility preservation or IVF, which is a conservative approach, and likely overestimates BEACOPP costs. In sensitivity analysis of costs, the BEACOPP strategy was non-dominant if the cost of three months of brentuximab was decreased to $19,360 (compared to its current price of $59,110 per three months), or if the cost of fertility preservation was greater than $37,615 per patient, which is higher than the average amount for this treatment in Canada. In these scenarios, BEACOPP was still more effective, but more expensive; however, the maximum ICER was still less than $10,000 per QALY for both costs, considerably lower than conventional willingness to pay (WTP) thresholds of $50,000. Probabilistic sensitivity analyses (10,000 simulations) were performed. For the WTP threshold of $50,000, BEACOPP was the dominant strategy 72% of the time, and overall the most cost-effective strategy 87.5% of the time (Figure 2).Conclusions:The preferred treatment strategy for patients with newly diagnosed advanced-stage Hodgkin lymphoma is a BEACOPP regimen. This strategy maximizes life expectancy, quality-adjusted life years, and is the most cost-effective strategy, accounting for increased rates of hematologic toxicity, secondary malignancy, and infertility in patients receiving the BEACOPP strategy. The model was robust to sensitivity analyses of key variables tested through plausible ranges obtained from the published literature. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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

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.

Update on the role of brentuximab vedotin in classical Hodgkin lymphoma.

Brentuximab vedotin (BV) is an effective and well-tolerated treatment for patients with classical Hodgkin lymphoma (HL). It was initially approved by the US FDA for the treatment of HL after failure of autologous hematopoietic stem cell transplant (autoHSCT) or after failure of at least two prior lines of multiagent chemotherapy in patients who are not transplant candidates, and then subsequently, as consolidation therapy after autoHSCT in patients who are at high risk for relapse. However, the role of BV in the treatment of HL is evolving. BV has shown promising efficacy as a salvage treatment in the second-line setting prior to autoHSCT. Most recently, the ECHELON-1 trial demonstrated that BV combined with AVD for the treatment of newly diagnosed advanced stage HL improved modified progression-free survival (mPFS) compared with standard ABVD. Based on these results, the US FDA has approved BV as part of the initial treatment of advanced stage HL. With the approval of BV as front-line therapy, depending on how widely the use of BV plus AVD is adopted, the role of BV in the treatment of patients with relapsed or refractory (rel/ref) HL may need to be redefined. BV retreatment can be effective, and studies of rational BV-based combination regimens may help to improve response rates and overcome BV resistance. Furthermore, BV has been demonstrated to be effective in the initial treatment of elderly or unfit patients, and ongoing studies are evaluating the addition of BV to initial chemotherapy in patients with early stage HL.

Relapse Analysis of Irradiated Patients Within the HD15 Trial of the German Hodgkin Study Group

To determine, in the setting of advanced-stage of Hodgkin lymphoma (HL), whether relapses occur in the irradiated planning target volume and whether the definition of local radiation therapy (RT) used by the German Hodgkin Study Group (GHSG) is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL. All patients with residual disease of ≥ 2.5 cm after multiagent chemotherapy (CTX) were evaluated using additional positron emission tomography (PET), and those with a PET-positive result were irradiated with 30 Gy to the site of residual disease. We re-evaluated all sites of disease before and after CTX, as well as the PET-positive residual tumor that was treated in all relapsed patients. Documentation of radiation therapy (RT), treatment planning procedures, and portal images were carefully analyzed and compared with the centrally recommended RT prescription. The irradiated sites were compared with sites of relapse using follow-up computed tomography scans. A total of 2126 patients were enrolled, and 225 patients (11%) received RT. Radiation therapy documents of 152 irradiated patients (68%) were analyzed, with 28 irradiated patients (11%) relapsing subsequently. Eleven patients (39%) had an in-field relapse, 7 patients (25%) relapsed outside the irradiated volume, and an additional 10 patients (36%) showed mixed in- and out-field relapses. Of 123 patients, 20 (16%) with adequately performed RT relapsed, compared with 7 of 29 patients (24%) with inadequate RT. The frequency and pattern of relapses suggest that local RT to PET-positive residual disease is sufficient for patients in advanced-stage HL. Insufficient safety margins of local RT may contribute to in-field relapses.

Could BEACOPP Be the New Standard for the Treatment of Advanced Hodgkin's Lymphoma (HL)?

In 1992, the German Hodgkin Study Group (GHSG) developed the BEACOPP regimen for further improving the outcome of patients with advanced Hodgkin's lymphoma (HL). Since then, BEACOPP has been introduced in 3 different prospective randomized clinical trials of the GHSG to find an equilibrium between maximal efficacy and least toxicity with the BEACOPP principle for the treatment of advanced stage HL. In the HD9 trial of the GHSG, with 1,186 patients, after a median observation time (mot) of 7 years, the rates for freedom from treatment failure (FFTF) are 85 percent, and for overall survival (OS) 90 percent for dose-escalated BEACOPP, and for COPP/ABVD (C/ABVD comparable to ABVD) the rate for FFTF is 67 percent, and for OS it is 79 percent. These superior BEACOPP results are obtained inspite of a higher rate of secondary AML/MDS in the esc. BEACOPP arm. The number of toxic deaths during treatment, however, was lower for esc. BEACOPP (1.6 percent) than for C/ABVD (1.8 percent). The majority of patients were treated in outpatient setting, in a multicenter study with more than 400 centers, including 120 private doctors, in Germany and 9 other European countries. The reduce acute and longterm toxicity, the GHSG started in the consecutive studies HD12 and HD15 for advanced stage HL to de-escalate BEACOPP by reducing the number of escalated BEACOPP cycles and by applying the baseline-dose BEACOPP, a time-dense regimen, called BEACOPP-14. The excellent results obtained with the BEACOPP principle challenge the seemingly global consensus that ABVD is the gold standard treatment strategy for advanced stage HL.

Could BEACOPP Be the New Standard for the Treatment of Advanced Hodgkin's Lymphoma?

In 1992, the German Hodgkin Study Group (GHSG) developed the BEACOPP regimen for further improving the outcome of patients with advanced Hodgkin's lymphoma (HL). Since then, BEACOPP has been introduced in 3 different prospective randomized clinical trials of the GHSG to find an equilibrium between maximal efficacy and least toxicity with the BEACOPP principle for the treatment of advanced stage HL. In the HD9 trial of the GHSG, with 1,186 patients, after a median observation time of 7 years, the rates for FFTF are 85 percent and for overall survival 90 percent for dose-escalated BEACOPP, and for COPP/ABVD (C/ABVD comparable to ABVD) the rate for FFTF is 67 percent and for overall survival it is 79 percent. These superior BEACOPP results are obtained inspite of a higher rate of secondary AML/MDS in the escalated BEACOPP arm. The number of toxic deaths during treatment, however, was lower for escalated BEACOPP (1.6 percent) than for C/ABVD (1.8 percent). The majority of patients were treated in an outpatient setting, in a multicenter study with more than 400 centers, including 120 private doctors, located in Germany and 9 other European countries. To reduce acute and long-term toxicity, the GHSG started in the consecutive studies HD12 and HD15 for advanced stage HL to de-escalate BEACOPP by reducing the number of escalated BEACOPP cycles and by applying the baseline dose BEACOPP, a time dense regimen, called BEACOPP-14. The excellent results obtained with the BEACOPP principle challenge the seemingly global consensus that ABVD is the gold standard treatment strategy for advanced stage HL.