CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET

A majority of patients with early-stage nonbulky classical Hodgkin lymphoma (HL) are cured with radiation therapy (RT) or chemotherapy and RT (combined modality therapy; CMT). However, treatment approaches that include RT are associated with high rates of serious morbidity and mortality in long-term survivors, particularly second primary malignancies and cardiovascular disease.¹  Although decreases in the size of RT portals and doses have been made through the years, it has been difficult to completely abrogate these risks.²  Good outcomes are also achieved with chemotherapy employing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone without RT, thereby eliminating the risks associated with RT.^3-5  Positron emission tomography (PET) predicts outcome during and at the end of treatment (EOT) with ABVD with or without RT. A relapse rate <15% has been observed for patients with limited-stage disease whose EOT PET is negative,^5,6  and a similar low relapse rate has been seen in patients with a negative interim PET after 1 to 2 cycles of ABVD or variants of ABVD.^6,7  It may be lower with a negative interim PET after 1 rather than after 2 cycles.^7,8  Higher relapse rates are seen in patients with a positive interim PET: 13% to 23% after completion of ABVD plus RT and 50% to 60% after completion of ABVD/variants alone.^6,7  Salvage treatment of patients with early-stage disease relapsing after ABVD alone is excellent, even with RT only for local relapses in initial nodal sites of involvement,⁵  and a survival advantage has never been demonstrated for the addition of RT to initial ABVD chemotherapy.^4,5  Encouraging data suggest that dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) after standard-dose BEACOPP or ABVD in patients with interim positive gallium scan or PET improves outcomes.⁹ 

On the basis of these considerations, a phase 2 trial, CALGB 50604, was conducted by the US Intergroup (Cancer and Leukemia Group B [CALGB]), Southwest Oncology Group, Eastern Cooperative Oncology Group) led by CALGB of response-adapted chemotherapy or chemotherapy/RT based on interim PET/computed tomography (CT) for newly diagnosed patients with stage I or II HL without initial tumor bulk. CALGB is now part of the Alliance for Clinical Trials in Cancer.

Previously untreated patients 18 to 60 years of age with a confirmed histological diagnosis of classical HL stage I or II without tumor bulk, as defined by mediastinal mass <0.33 cm in maximum intrathoracic diameter on standing posteroanterior chest x-ray or peripheral or retroperitoneal adenopathy <10 cm in largest diameter, were eligible if they were considered fit to receive chemotherapy and RT. Staging procedures included contrast-enhanced CT of neck, chest, abdomen, and pelvis and PET/CT. Contrast-enhanced CT was permitted for the PET/CT when available. All patients signed an institutional review board–approved, protocol-specific, written informed consent document before enrollment. Patients who did not meet eligibility criteria after enrollment for screening or who withdrew consent before beginning treatment or before completing 2 cycles of chemotherapy were not included in the progression-free survival (PFS) analysis for patients who underwent postchemotherapy cycle 2 PET/CT (Figure 1). Procedures for registration are described in the supplemental Protocol Document, available on the Blood Web site (section 5.1).

Therapy consisted of 2 cycles of full-dose ABVD¹⁰  regardless of absolute neutrophil count. After the first 2 cycles of ABVD, PET/CT was performed and submitted for central review (cycle 2, days 23-25) and results returned to the treating physicians before initiation of cycle 3. Patients with a negative PET/CT (Deauville 1, 2, or 3¹¹ ) received 2 additional cycles of ABVD (4 total). Patients whose interim PET was positive received 2 cycles of escalated BEACOPP¹²  and involved-field RT (IFRT) as described in the supplemental Protocol Document. Primary growth factor prophylaxis was used for all patients treated with escalated BEACOPP but was only used as secondary prophylaxis after a febrile event with grade 3 or 4 neutropenia with or without infection with ABVD. PET/CT and contrast-enhanced CT were performed at EOT. Patients with a negative EOT PET/CT were followed without further treatment. For patients with a positive EOT PET/CT, biopsy was performed if medically necessary at the discretion of the treating physician. If biopsy was not clinically indicated or medically appropriate, repeat PET/CT was performed 3 months later. Follow-up visits with CT imaging were scheduled every 3 months for year 1, every 6 months for years 2 to 3, and then annually for a maximum of 5 years from study entry.

Before patient enrollment, institutions were credentialed to participate by the CALGB Imaging Core Laboratory. Baseline, interim, and EOT PET/CT studies were electronically submitted to the Imaging Core Laboratory for review. Interim PET/CT images after the initial 2 ABVD cycles were interpreted by 2 reviewers, with a possible third reviewer to adjudicate disagreements. Post–cycle 2 PET/CT results were provided to the treating physicians before the third cycle of chemotherapy for further treatment assignment. Post–cycle 1 PET/CT results were not published at the time of trial design. PET/CT interpretations were made according to Deauville criteria,¹¹  with negative defined as scores of 1 to 3 ([¹⁸F]fluorodeoxyglucose [FDG] uptake ≤ liver) and positive as scores of 4 to 5.

The primary objective was to show that PFS in post–cycle 2 ABVD PET⁻ patients was long enough, even with omission of RT, to meaningfully define the outcome of continued ABVD without RT by estimating the 3-year PFS with a sufficiently narrow 95% confidence interval (CI). PFS was measured as the time from study entry to disease progression or death. The definitions of progression and relapse are provided in the supplemental Protocol Document (section 13.1.4). Patients alive and progression free were censored at the time of their last clinical follow-up visit.

A secondary objective was to determine if, by receiving 2 cycles of escalated BEACOPP plus IFRT, post–cycle 2 ABVD PET⁺ patients would have a similar PFS to that of post–cycle 2 ABVD PET⁻ patients receiving an additional 2 cycles of ABVD. Target accrual was 149 patients, assuming a 10% attrition rate. Complete response (CR) was defined as a negative EOT PET/CT by the same criteria as for interim PET (CR).¹³ 

CALGB 50203, a phase 2 trial of 6 cycles of doxorubicin, vinblastine, and gemcitabine (AVG) in the same patient population, which also included baseline and interim after 2 chemotherapy cycles and EOT PET/CT, was used as a comparator because there was no other published prospective or retrospective database available for interim PET/CT in patients with nonbulky early-stage HL treated with chemotherapy only at the time of the study design.⁶  The estimated 3-year PFS for post–cycle 2 AVG PET⁻ patients was 85% (95% CI, 74%-92%), whereas it was 54% (95% CI, 33%-71%) for PET⁺ patients. On the basis of this previous study, a positive result for the post–cycle 2 ABVD PET⁻ group would be an estimated 3-year PFS >85% (95% CI, 33%-71%) in the current trial.

In CALGB 50203, a hazard ratio (HR) of 3.84 was observed in comparison of the PFS of post–cycle 2 AVG PET⁻ patients with post–cycle 2 AVG PET⁺ patients, all receiving a total of 6 cycles of AVG. Because the expectation was that interim PET⁻ PFS results would be similar for patients treated with ABVD and AVG, an HR ≥3.84 in the comparison of 3-year PFS between post–cycle 2 ABVD PET⁻ and PET⁺ groups, with change of treatment in the latter, would not be considered promising.

Other secondary objectives included determination of CR rate, predictive value of semiquantitative PET/CT with different standard uptake values after 2 and 4 cycles of chemotherapy with or without IFRT, predictive value of volumetric changes on CT after 2 and 4 cycles of chemotherapy with or without RT, and comparison of predictive value of PET/CT, CT, baseline and posttreatment serum biomarkers (thymus- and activation-related chemokine, macrophage-derived chemokine, interleukin-10, tumor necrosis factor), tissue microarrays, and clinical feature including PFS. With the exception of CR rate, these results will be reported separately. Additional details on the statistical design are provided in the supplemental Protocol Document and a separate publication.¹⁴  Statistical analyses were conducted by the Alliance Statistics and Data Center using SAS version 9.3 software (Cary, NC).

The authors designed the study and attest to the accuracy of the data and adherence to the protocol document, which is available in the supplemental Material. Data were collected and stored at the Alliance (CALGB) Statistics and Data Center. Data review was completed by the Alliance Statistics and Data Center and study chair according to Alliance policies and procedures. The data cutoff for this report was 23 January 2017. There was neither commercial support nor any commercial role in the design, conduct, analysis, or reporting of this trial.

From 15 May 2010 through 21 February 2013, 164 patients were accrued. Results were analyzed for 149 patients who underwent post-ABVD cycle 2 interim PET/CT for whom there was adequate follow-up (Figure 1). Patient characteristics are described in Table 1. The median age was 31 years; 7% of patients were age ≥50 years. Twenty-two patients (13%) had stage I disease, 133 (81%) had stage II disease, and 9 (5%) had no disease stage documented; stage B disease was reported in 26%.

On central review, 135 (91%) of 149 patients were interim PET⁻ and 14 (9%) were interim PET⁺ using the predetermined cutoff of Deauville scores of 1 to 3 to define PET⁻ (FDG uptake ≤ liver).

In a secondary analysis, Deauville scores of 1 to 2 (FDG uptake ≤ mediastinal blood pool) were used to define PET⁻ as used in another trial using PET/CT to tailor treatment in patients with early-stage disease.⁵  With this approach, 113 patients (76%) were interim PET⁻ and 36 patients (24%) interim PET⁺.

All interim PET⁻ patients (Deauville scores 1-3) received 2 additional cycles of ABVD (total 4). Thirteen interim PET⁺ patients received BEACOPP plus IFRT. One patient refused BEACOPP and continued to receive ABVD off study but agreed to continue follow-up. This patient achieved a CR 6 months after starting treatment and then experienced progression 9 months after achieving the CR.

Clinical features of the interim PET⁺ and PET⁻ patients are described in Table 2. According to German Hodgkin Study Group criteria (at least 1 of the following: involvement of ≥3 nodal sites, massive mediastinal involvement, extranodal extension, erythrocyte sedimentation rate ≥50 mm/h for stage A, and ≥30 mm/h for stage B), 60% were early stage unfavorable.¹⁵  According to the European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfomi criteria (age ≥50 years, >3 involved nodal areas, presence of mediastinal bulk, or ESR ≥50 mm without B symptoms or ≥30 mm with B symptoms), 41% were early stage unfavorable.¹⁶ 

With a median follow-up time of 3.8 years (range, 0.1-5.7 years), the overall estimated 3-year PFS was 89% (95% CI, 84%-93%). The estimated 3-year PFS for interim PET⁻ patients was 91% (95% CI, 84%-95%), and for interim PET⁺ patients, it was 66% (95% CI, 34%-86%; HR, 3.84; 95% CI, 1.50-9.84; P = .01; Figure 2). Using Deauville scores of 1 to 2 to define interim PET negativity in the secondary analysis rather than Deauville scores of 1 to 3 as in the primary analysis, the estimated 3-year PFS was 94% (95% CI, 87%-97%; Figure 3). PFS for patients with interim PET/CT Deauville scores 1 to 2 vs 3 (treated with ABVD) vs 4 to 5 (treated with escalated BEACOPP and RT) is shown in Figure 4.

The EOT CR rate was 97% (95% CI, 94%-100%) for interim PET⁻ patients and 85% (65%-100%) for those who were interim PET⁺.

Characteristics of patients with relapsed disease are shown in Table 3, including the sites of relapse. All interim PET⁻ patients received chemotherapy only, whereas interim PET⁺ patients received CMT. New sites of relapse were seen in 3 interim PET⁻ patients and in no interim PET⁺ patients. There were no statistically significant differences in estimated PFS between various patient characteristics including German Hodgkin Study Group and European Organisation for Research and Treatment of Cancer risk groups and stage A and B patients (Figure 5), although the number of relapses was small.

There was one death as a result of suicide in an interim PET⁺ patient. Data are available on sites of relapse for 14 of the 16 patients experiencing relapse. Eleven of the relapses were in nodal sites of initial involvement, and 3 were only in new sites. Details of the subsequent treatment of patients experiencing relapse are not available.

Grade 3 and 4 adverse events (AEs) are listed in Table 4. For patients receiving only 4 cycles of ABVD, the most common grade 3 or 4 toxicity was neutropenia, which occurred in 70% of patients. Febrile neutropenia was observed in only 5% and sepsis in 1%. Grade 3 pulmonary toxicity was observed in 1%. For interim PET⁻ patients (ABVD only), grade ≥3 AEs seen in ≥10% of patients were neutropenia and leukopenia. For interim PET⁺ patients (ABVD, BEACOPP, and RT), grade ≥3 AEs seen in ≥10% of patients were anemia, febrile neutropenia, neutropenia, and leukopenia.

The primary end point of CALGB 50604 was 3-year PFS for patients whose interim PET/CT was negative. This is a standard end point employed in many clinical trials of HL treatment. Other end points such as event-free survival¹⁷  and modified PFS¹⁸  have been used in other trials that may differ slightly in determining events. For example, a patient who is started on a new treatment without measurable progression would be considered as having an event in an event-free survival or modified PFS analysis. No such patients were seen in the present trial.

Opinions and interpretation of clinical trial results differ on the relative merits of chemotherapy alone or CMT as initial treatment of patients with early-stage nonbulky HL. Treatment decisions must balance optimal cancer control with minimal AEs or late effects, as highlighted by Meyer¹⁹  in a recent editorial. Currently, physician and patient preferences guide treatment approaches for these patients. Treatment decisions for individual patients may differ according to their clinical features.

Two randomized trials in early-stage nonbulky HL compared 6 cycles of ABVD alone in early-stage nonbulky HL vs RT with or without ABVD. Both showed approximately a 5% decrease in freedom from progression with the omission of RT.^3,4  The HD.6 trial showed a significantly inferior 12-year survival in the RT arm because of deaths resulting from complications of RT, which was the primary end point. Both trials demonstrated that excellent results can be achieved in early-stage nonbulky HL with 4 to 6 cycles of ABVD without exposing a majority of patients to the long-term risks of RT.⁴ 

An approach to determining which patients with early-stage nonbulky HL would benefit from a more intensive approach than ABVD alone is the use of an interim response assessment for treatment selection. Interim PET/CT after 1 to 2 cycles of ABVD is a powerful predictor of outcome; the negative predictive value for PFS is approximately 90%. CALGB 50203 used 6 cycles of AVG in the same population of patients as in CALGB 50604. This provided a large prospective data set with interim PET/CT results in that population, although interim PET/CT did not direct a change in treatment. The overall PFS with AVG was inferior to that reported with ABVD, although survival was not. Despite these results, the strong negative predictive value of interim negative PET/CT in predicting a low rate of relapse with AVG was similar to that reported for ABVD. It seems that achievement of interim PET negativity is possibly more important in predicting PFS than the regimen used to achieve it. In addition, the CALGB 50203 comparator was used to determine the secondary objective of comparing PFS between interim PET⁻ and PET⁺ groups. An earlier small trial tested the concept of altering treatment based on interim gallium or PET/CT scans with promising results that helped provide a rationale for the study design.⁹ 

RAPID (Randomized Phase III Trial to Determine the Role of FDG-PET in Clinical Stages IA/IIA Hodgkin Lymphoma)⁵  made an important contribution to the use of PET as a biomarker for treatment selection in patients with nonbulky HL. Patients received 3 cycles of ABVD followed by PET. PET⁺ patients received an additional cycle of ABVD and IFRT. PET⁻ patients were randomly assigned to receive either IFRT or no further treatment. By intent to treat, the 3-year PFS for the IFRT group was 94.6%, compared with 90.8% for the group that did not receive further treatment (P = .16). This was considered to be an excellent outcome for chemotherapy alone, although noninferiority criteria were not met as compared with addition of IFRT. Only 7 of 22 patients who experienced relapse without further treatment underwent chemotherapy with autologous stem-cell transplantation, whereas 5 patients received only RT as salvage treatment. There was no difference in overall survival. PET was negative in 75% of patients, defined by Deauville scores of 1 to 2 rather than 1 to 3 as in the current trial.

The H10 trial randomly assigned patients with stage I or II disease, stratified according to favorable or unfavorable risk factors, to ABVD and involved-node RT (INRT; standard arm) or risk-adapted treatment with ABVD alone for post-ABVD cycle 2 PET⁻ patients or escalated BEACOPP and INRT for those who were PET⁺ (experimental arm). The randomization was discontinued at a median follow-up time of approximately 1 year because of a preset excess of events in the risk-adapted arms, but the PFS was 95% in both favorable and unfavorable groups in these arms.¹⁶  With further follow-up, the 5-year PFS in the risk-adapted interim PET⁻ groups was 87.1% for ABVD alone vs 99.0% for CMT in the favorable and 89.6% for ABVD alone vs 92.1% for CMT in the unfavorable groups, respectively.²⁰  Both results exceeded the 85% bar set as the criterion for a positive result in CALGB 50604. There was no overall survival difference. For interim PET⁻ patients, PFS noninferiority of the risk-adapted vs CMT approaches could only be found in the favorable but not the unfavorable group. The reason for that finding was not obvious.

Although the PFS results were similar for interim PET⁻ patients with ABVD alone in the H10 and CALGB 50604 trials with the risk-adapted approach, interpretation may differ. Our interpretation of CALGB 50604 is that the 91% PFS is acceptable for ABVD without RT for interim PET⁻ patients in view of the potential late risks of IFRT or INRT. The latter approach shrinks the size of the posttreatment portals but still treats all the initial nodal sites of involvement, regardless of response to chemotherapy, thereby resulting in significant off-target tissue and organ exposure.^2,21,22  Further follow-up will be necessary to determine the long-term survival in patients treated chemotherapy and INRT.

Salvage treatment is successful in achieving second durable unmaintained remissions in patients experiencing relapse after chemotherapy only, even with RT alone for patients who have limited nodal regions as sites of relapse.⁵  In CALGB 50604, 11 of 14 relapses, where information was available, were in initial nodal sites only. Such relapses could be considered for local RT only as initial treatment with subsequent systemic treatment only if necessary.

CALGB 50604 successfully met the primary end point by demonstrating that 91% of patients with stage I or II HL without tumor bulk whose PET/CT became negative after 2 cycles of ABVD achieved an estimated 3-year PFS of 91%, exceeding the target of >85% (Figure 2). Use of Deauville scores 1 to 3 rather than 1 to 2 to define a negative interim PET/CT increased the PET⁻ rate from 76% to 91%, thereby reducing the number of interim PET⁺ patients who would have received more toxic chemotherapy and RT. The PFS for patients with interim negative PET/CT was 94% using Deauville 1 to 2 criteria (Figure 3). PFS for patients with Deauville score of 3 approached that for those with Deauville score of 4 or 5 (Figure 4), but the numbers of patients were too small for this have a major impact on 3-year PFS. Moreover, although the PFS for Deauville 3 patients approached that for Deauville 4 to 5 patients, the Deauville 3 group received ABVD alone, whereas the Deauville 4 to 5 group received more intensive BEACOPP and RT. It is possible that interim PET Deauville score of 3 would have had a greater negative impact on the PFS of interim PET Deauville scores 1 to 3 with a larger number of patients. Nevertheless, the results further confirm the excellent PFS with limited chemotherapy and omission of RT in a majority of patients with early-stage nonbulky HL using interim PET/CT as an indicator of response, reducing the risks of RT. This approach could be considered as a treatment option for these patients.

The trial did not meet the secondary objective of improving the expected estimated 3-year PFS from 54% to 85% (HR <3.84) for interim PET⁺ patients, although numbers were probably too small to draw firm conclusions. Fewer patients than expected were interim PET⁺, which limited the statistical power of the comparison of interim PET⁺ with interim PET⁻ patients. Although escalated BEACOPP may be a promising treatment option for interim PET⁺ patients with advanced disease,^23,24  it is less compelling for those with early-stage disease in view of the short-term and anticipated long-term toxicities of this approach. The recently reported HD18 trial in advanced-stage HL randomly assigned interim PET⁺ patients after 2 cycles of escalated BEACOPP to 6 additional cycles of escalated BEACOPP alone or with additional rituximab. PFS rates at 3 years were 91% and 93%, respectively, suggesting that more cycles of escalated BEACOPP abrogated the adverse effect of an interim positive PET/CT on PFS after 2 cycles of escalated BEACOPP.²⁵  However, toxicity limits the attractiveness of this approach in patients with early-stage disease. Fortunately, new opportunities are now available for investigation in clinical trials for this group of patients, including antibody-drug conjugates (brentuximab vedotin)²⁶  and immune checkpoint blockade inhibitors (nivolumab, pembrolizumab).^27,28 

CALGB 50604 was designed to show that the PFS of interim PET⁻ patients without RT is close to that with CMT with IFRT added to standard chemotherapy (ABVD; primary objective). A secondary objective was to determine if the PFS for interim PET⁺ patients receiving an aggressive chemotherapy (BEACOPP) plus IFRT is close to that of interim PET⁻ patients treated only with ABVD. This statistical design is described in the supplemental Protocol Document (section 15.0) and the novel features in a publication on the design for the secondary objective.¹⁴  A standard trial design to answer the study objectives would be a randomized phase 2 trial, but it would require a large sample size. The much larger H10 trial chose such an appropriate randomization in a phase 3 design. Although the small number of interim PET⁺ patients in CALGB 50604 precluded strong conclusions for the secondary objective, this study demonstrated that the phase 2 design efficiently met the primary objective with a limited number of patients.

This work was supported by the National Cancer Institute of the National Institutes of Health under Awards U10CA180821 and U10CA180820 (to the Alliance for Clinical Trials in Oncology); U10CA007968, U10CA077597, U10CA077651, U10CA077658, U10CA180791, U10CA180833, U10CA180850, and U10CA180799 (ECOG-ACRIN); and U10CA180888 (SWOG). Additional support was provided by the Lymphoma Foundation, Rob and Karen Schneider and the Louis Schneider and Harry Davis Memorial Trust, the Adam R. Spector Foundation, and the David R. and Patricia D. Atkinson Foundation and Mr and Mrs Ernest Dicker (D.J.S.).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Contribution: All authors enrolled patients and/or analyzed data and read and approved the submitted manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: David J. Straus, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 406, New York, NY 10065; e-mail: strausd@mskcc.org.