Evolution of North American cooperative and consortium trial results

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy with ABVE [66] for patients with favorable low-stage disease and dose-dense ABVE-PC for patients with unfavorable advanced-stage disease in combination with 21 Gy IFRT.[21]

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy with ABVE [66] for patients with favorable low-stage disease and dose-dense ABVE-PC for patients with unfavorable advanced-stage disease in combination with 21 Gy IFRT.[21]

Children and adolescents with low-risk Hodgkin lymphoma (stages I, IIA, IIIA1) treated with IFRT (25.5 Gy) after achieving CR to two cycles of doxorubicin, bleomycin, vincristine, and etoposide (DBVE) had outcomes comparable to those not in CR after two cycles of DBVE who were then treated with a total of four cycles of DBVE and IFRT (25.5 Gy). This response-dependent approach permitted reduction in chemotherapy exposure in 45% of patients.[66]

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy with ABVE [66] for patients with favorable low-stage disease and dose-dense ABVE-PC for patients with unfavorable advanced-stage disease in combination with 21 Gy IFRT.[21]

A dose-dense, early response–based treatment approach with ABVE-PC permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles.[21][Level of evidence B1]

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy with ABVE [66] for patients with favorable low-stage disease and dose-dense ABVE-PC for patients with unfavorable advanced-stage disease in combination with 21 Gy IFRT.[21]

The 5-year EFS rate was comparable for patients with rapid early responses (86%) and slow early responses (83%) who were treated with three and five cycles of ABVE-PC, respectively, followed by radiation therapy (21 Gy). Patients who received dexrazoxane had more hematological and pulmonary toxicity.[21]

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy with ABVE [66] for patients with favorable low-stage disease and dose-dense ABVE-PC for patients with unfavorable advanced-stage disease in combination with 21 Gy IFRT.[21]

Although etoposide is associated with an increased risk of therapy-related acute myeloid leukemia with 11q23 abnormalities, the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.[18,67]

A large COG study (COG-59704) evaluated response-adapted therapy featuring four cycles of a dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP), followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[64][Level of evidence B4] For girls with rapid early responses, an additional four courses of COPP/ABV (without IFRT) were given. Boys with rapid early responses received two cycles of ABVD followed by IFRT. Patients with slow early responses received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girls' therapy was intended to reduce the risk of breast cancer. Key findings include the following:[64]However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of newer and safer strategies.

A large COG study (COG-59704) evaluated response-adapted therapy featuring four cycles of a dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP), followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[64][Level of evidence B4] For girls with rapid early responses, an additional four courses of COPP/ABV (without IFRT) were given. Boys with rapid early responses received two cycles of ABVD followed by IFRT. Patients with slow early responses received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girls' therapy was intended to reduce the risk of breast cancer. Key findings include the following:[64]However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of newer and safer strategies.

Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four cycles of BEACOPP.

A large COG study (COG-59704) evaluated response-adapted therapy featuring four cycles of a dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP), followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[64][Level of evidence B4] For girls with rapid early responses, an additional four courses of COPP/ABV (without IFRT) were given. Boys with rapid early responses received two cycles of ABVD followed by IFRT. Patients with slow early responses received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girls' therapy was intended to reduce the risk of breast cancer. Key findings include the following:[64]However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of newer and safer strategies.

The 5-year EFS rate was 94%, with a median follow-up time of 6.3 years.

A large COG study (COG-59704) evaluated response-adapted therapy featuring four cycles of a dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP), followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[64][Level of evidence B4] For girls with rapid early responses, an additional four courses of COPP/ABV (without IFRT) were given. Boys with rapid early responses received two cycles of ABVD followed by IFRT. Patients with slow early responses received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girls' therapy was intended to reduce the risk of breast cancer. Key findings include the following:[64]However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of newer and safer strategies.

Early intensification followed by less-intense response-based therapy resulted in high EFS.

The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:

The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:

Nonalkylating-agent chemotherapy (e.g., methotrexate or etoposide) instead of alkylating-agent chemotherapy results in an inferior EFS among patients with unfavorable clinical presentations.[68,69]

The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:

The combination of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) is an effective regimen (10-year EFS rate, 89%) for children and adolescents with favorable-risk disease (low-stage NLPHL and classical Hodgkin lymphoma without B symptoms or bulky disease) when used in combination with response-based LD-IFRT (15–25.5 Gy).[70]

The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:

Patients with favorable-risk Hodgkin lymphoma treated with four cycles of VAMP chemotherapy alone who achieved an early CR had a comparable 5-year EFS rate to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).[71]

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Patients with rapid early responses (defined by CT imaging after two cycles) received two additional ABVE-PC cycles, followed by CR evaluation.

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54] › Patients with rapid early responses (defined by CT imaging after two cycles) received two additional ABVE-PC cycles, followed by CR evaluation.

Patients with rapid early responses with CR at the end of chemotherapy (based on CT imaging and negative PET or gallium scans) were randomly assigned to receive either IFRT or no additional therapy.

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54] › Patients with rapid early responses (defined by CT imaging after two cycles) received two additional ABVE-PC cycles, followed by CR evaluation.

Patients with rapid early responses with less than a CR were nonrandomly assigned to IFRT.

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Patients with slow early responses were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All patients with slow early responses were assigned to receive IFRT.

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Early response was an important prognostic factor. The overall EFS rate was 85.0% and significantly higher (P < .001) for patients with rapid early responses (86.9%) than for patients with slow early responses (77.4%).

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

The OS rate was 97.8% and significantly higher (P < .001) for patients with rapid early responses (98.5%) than for patients with slow early responses (95.3%).

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Approximately 45% of patients had rapid early responses and achieved CR by the end of chemotherapy. For this population, the EFS rate did not differ significantly (P = .11) among those who were randomly assigned to IFRT (87.9%) versus no IFRT (84.3%). The OS rate was 98.8% (95% confidence interval [CI], 96.8%–99.5%) for those receiving IFRT and 98.8% (95% CI, 96.9%–99.6%) for those receiving chemotherapy alone.

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Despite achieving rapid early response or CR, stage I or stage II patients with bulky mediastinal adenopathy and anemia had significantly better EFS when randomly assigned to IFRT after four cycles of ABVE-PC.[57]

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Approximately 20% of patients had slow early responses. For this population, the EFS rate did not differ significantly (P = .11) among those who were randomly assigned to DECA (79.3%) versus no DECA (75.2%).

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of ABVE-PC followed by response evaluation.[20]Key 4-year OS and EFS outcomes from this trial include the following:An analysis of patterns of failure among patients whose disease relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[54]

Study results confirm the prognostic significance of early chemotherapy response and support the safety of no IFRT, based on rapid early response with CR by the end of chemotherapy.

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44]

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44]

At 4 years, the OS rate was 99.6%, with 49.0% in remission after treatment with minimal chemotherapy alone and 88.8% in remission without receiving high-dose chemotherapy with stem cell rescue or more than 21 Gy of IFRT.[44]

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44]

Factors predicting favorable EFS after a limited chemotherapy response-based approach included mixed-cellularity histology, low erythrocyte sedimentation rate, and negative 18F-FDG PET after one cycle.[44]

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44]

Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44] › Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]

For patients with rapid early responses, the 10-year PFS rate was 96.6% with IFRT and 84.1% without IFRT (P = .10).

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44] › Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]

For patients with slow early responses, the 10-year PFS rate was 80.9% with IFRT and 64% without IFRT (P =.03).

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44] › Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]

Among the 90 patients with rapid early responses who did not receive IFRT, all 14 relapses included an initial disease site.

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44] › Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]

Among the 45 patients with slow early responses who did not receive IFRT, 14 of the 16 relapses occurred in the initial disease site.

The COG AHOD0431 (NCT00302003) study used a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after one and three cycles of AV-PC chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[44] › Extended follow-up of this trial confirmed a significantly higher rate of relapse among patients with a slow early response by PET after one cycle, which was mitigated by adding 21 Gy of IFRT.[72][Level of evidence B4]

This 3-year study was amended during the second year. All patients with equivocal or positive PET findings after one cycle were treated with IFRT, even if they achieved a CR after three cycles.

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

After a median follow-up period of 42.1 months, the 3-year EFS rates were 92.1% (95% CI, 88.4%–94.7%) for patients who received Bv-AVE-PC and 82.5% (95% CI, 77.4%–86.5%; P = .0002) for patients who received ABVE-PC.

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

The cumulative incidence of relapse was significantly lower for patients who received Bv-AVE-PC (7.5%; 95% CI, 4.9%–10.9%) than for patients who received ABVE-PC (17.1%; 95% CI, 12.9%–21.8%).

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

Radiation therapy was administered to patients with slow-responding lesions confirmed by PET2 imaging (defined as a five-point scale score >3) and to patients with any large mediastinal masses. The percentage of patients who received radiation therapy was similar between the two arms of the study (52.7% for Bv-AVE-PC and 55.7% for ABVE-PC).

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

Rates of febrile neutropenia, infection complications, and neuropathy were similar between the two arms of the study.

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

In the group of patients who received the novel agent brentuximab vedotin, health-related quality of life improved over the course of initial therapy, earlier, and to a greater extent.[73]

In the COG AHOD1331 (NCT02166463) phase III study, 587 eligible patients with high-risk Hodgkin lymphoma were randomly assigned to receive ABVE-PC or Bv-AVE-PC, a regimen that incorporates brentuximab vedotin, omits bleomycin, and reduces vincristine to one dose per treatment course (see Table 6). Patients aged 2 to 21 years with stage IIB with bulk, stage IIIB, and stage IV Hodgkin lymphoma were eligible.[53]

The U.S. Food and Drug Administration approved brentuximab vedotin in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients aged 2 years and older with previously untreated high-risk classical Hodgkin lymphoma.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

Patients aged 12 to 17 years accounted for approximately 24% of the study's total accrual.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

About 63% of patients had stage IV disease, 68% had B symptoms, and 29% had bulky disease. There were no differences between the brentuximab-AVD group and the nivolumab-AVD group.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

Results for this study were released early at a planned interim analysis because the primary PFS end point crossed the protocol-specified monitoring boundary. However, patients continued to be monitored until a median of 2 years was achieved.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

The 2-year PFS rate favored nivolumab-AVD over brentuximab vedotin-AVD (92% vs. 83%, respectively) after a median follow-up of 2.1 years. The hazard ratio (HR) was 0.45 (95% CI, 0.30–0.65).

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

Less than 1% of patients (n = 7) in either arm received consolidative radiation therapy.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

The nivolumab-AVD regimen was tolerated better than the brentuximab-AVD regimen. In this study, 9.4% of patients discontinued nivolumab, while 22.2% of patients discontinued brentuximab. Neuropathy was more frequent in the brentuximab arm. Hypothyroidism and hyperthyroidism were more common in the nivolumab arm (7% and 3%, respectively), but other autoimmune conditions were not seen more frequently in the nivolumab arm.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

Three age groups were analyzed (12–17 years, 18–60 years, and >60 years). In all age groups, the 2-year PFS rates were significantly increased with the nivolumab-AVD regimen compared with the brentuximab-AVD regimen.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30] › Three age groups were analyzed (12–17 years, 18–60 years, and >60 years). In all age groups, the 2-year PFS rates were significantly increased with the nivolumab-AVD regimen compared with the brentuximab-AVD regimen.

Aged 12–17 years: 95% versus 83%.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30] › Three age groups were analyzed (12–17 years, 18–60 years, and >60 years). In all age groups, the 2-year PFS rates were significantly increased with the nivolumab-AVD regimen compared with the brentuximab-AVD regimen.

Aged 18–60 years: 92% versus 86%.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30] › Three age groups were analyzed (12–17 years, 18–60 years, and >60 years). In all age groups, the 2-year PFS rates were significantly increased with the nivolumab-AVD regimen compared with the brentuximab-AVD regimen.

Aged older than 60 years: 88% versus 65%.

The S1826 (NCT03907488) phase III study included both adolescents (aged ≥12 years) and adults. The study evaluated six cycles of doxorubicin (Adriamycin), vinblastine, and dacarbazine (AVD) with either brentuximab vedotin or nivolumab (see Table 6). A total of 970 enrolled patients with newly diagnosed stage III or stage IV Hodgkin lymphoma were randomly assigned to receive either brentuximab vedotin-AVD or nivolumab-AVD. Granulocyte colony-stimulating factor was required for patients who received brentuximab vedotin-AVD and optional for patients who received nivolumab-AVD. The cardioprotectant dexrazoxane was allowed for all patients, per the investigator's choice. Radiation therapy for pediatric patients was based on the end-of-treatment imaging evaluation after completion of six cycles of systemic therapy. The use of the AVD backbone with either agent was to reduce or avoid radiation therapy and reduce the use of alkylating agents.[30]

The authors suggested that nivolumab-AVD will likely be a new standard therapy for patients with advanced-stage Hodgkin lymphoma.