Chemotherapy with or without nivolumab or brentuximab vedotin

A randomized prospective trial (NCT03907488) enrolled 994 patients with previously untreated advanced-stage HL. The study compared BV-AVD with N-AVD.[4]

A randomized prospective trial (NCT03907488) enrolled 994 patients with previously untreated advanced-stage HL. The study compared BV-AVD with N-AVD.[4]

With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) rate favored N-AVD over BV-AVD at 92% (95% confidence interval [CI], 89%–94%) versus 83% (95% CI, 79%–86%) (hazard ratio [HR], 0.45; 95% CI, 0.30–0.65; P = .001).[4][Level of evidence B1]

A randomized prospective trial (NCT03907488) enrolled 994 patients with previously untreated advanced-stage HL. The study compared BV-AVD with N-AVD.[4]

Treatment discontinuation due to side effects was twice as likely for patients who received BV-AVD (22% vs. 11%), mainly because of peripheral sensory neuropathy. Grade 2 or higher sensory peripheral neuropathy occurred in 32% of patients who received BV-AVD and 3% of patients who received N-AVD.

A randomized prospective trial (NCT03907488) enrolled 994 patients with previously untreated advanced-stage HL. The study compared BV-AVD with N-AVD.[4]

A preplanned analysis, published in abstract form, included 97 patients aged 60 years or older. With a median follow-up of 12.1 months, the 1-year PFS favored N-AVD over BV-AVD at 93% versus 64% (HR, 0.35; 95% CI, 0.12–1.02; P = .022).[5] The BV-AVD regimen had substantially worse side effects including septicemia, peripheral sensory neuropathy, nausea, diarrhea, anorexia, and weight loss, compared with rash and hypothyroidism for N-AVD.[5]

A randomized prospective trial (NCT03907488) enrolled 994 patients with previously untreated advanced-stage HL. The study compared BV-AVD with N-AVD.[4]

Based on the substantial PFS advantage across age, stage, and IPS score subgroups, as well as the reduced toxicity from avoiding bleomycin or brentuximab vedotin, N-AVD has become the treatment of choice for patients with stages III and IV HL.

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

With a median follow-up of 73 months, the 6-year OS rate was 93.9% (95% CI, 91.6%–95.5%) for patients who received BV-AVD and 89.4% (95% CI, 86.6%–91.7%) for patients who received ABVD (HR, 0.59; 95% CI, 0.40–0.88; P = .009).[6][Level of evidence A1]

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

With a median follow-up of 73 months, the 6-year PFS rate was 82.3% (95% CI, 79.1%–85.0%) for patients who received BV-AVD and 74.5% (95% CI, 70.8%–77.7%) for patients who received ABVD (HR, 0.68; 95% CI, 0.53–0.86; P = .002).[6]

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

Among patients who received BV-AVD, there was significantly more grade 3 or 4 peripheral neuropathy (67% vs. 43%); however, there was more than 80% partial or complete recovery, with a median time to resolution of 16 weeks for BV-AVD and 10 weeks for ABVD. Pulmonary toxicity led to 11 deaths in the ABVD arm.

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

Although fertility was not directly assessed, pregnancies and live births subsequently occurred in both arms of the trial for female patients and female partners of the male patients.

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

BV-AVD can cost 50 times more than ABVD (in 2018).[7]

A randomized prospective trial (NCT01712490) included 1,334 patients with previously untreated advanced-stage HL. The study compared ABVD with BV-AVD.[6]

BV-AVD is a new standard of care for patients with advanced-stage classic HL.

In multiple prospective trials and a meta-analysis, ABVD therapy for 6 to 8 months for patients with newly diagnosed advanced HL, showed equivalent OS when compared with other regimens (i.e., BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone], escalated BEACOPP, Stanford V [doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone], and MOPP-ABV [mechlorethamine, vincristine, procarbazine prednisone/doxorubicin, bleomycin, and vinblastine]).[8-15][Level of evidence A1]

Three prospective randomized trials did not show a benefit in OS from the addition of consolidative radiation therapy to chemotherapy for patients with advanced-stage disease.[16-18][Level of evidence A1]

In a meta-analysis of 1,740 patients treated in 14 different trials, no improvement was observed in 10-year OS for patients with advanced-stage HL who received combined-modality therapy compared with chemotherapy alone.[19][Level of evidence C1]

No survival advantage is known for the use of radiation consolidation for patients with massive mediastinal disease and advanced-stage disease.[20]A randomized prospective trial with a median follow-up of 5.9 years included 320 patients with advanced-stage HL and a large nodal mass (≥5 cm). Patients were randomly assigned to receive radiation therapy or no further treatment after six cycles of ABVD. For patients with a complete metabolic response on positron emission tomography (PET)–computed tomography (CT) after six cycles of ABVD, there was no difference in the 6-year PFS rate for patients who received radiation therapy (91%; 95% CI, 84%–99%) versus patients who received no further treatment (95%; 95% CI, 89%–100%, P = .62).[21][Level of evidence B1]

The German Hodgkin Lymphoma Study Group HD15 trial showed that a negative PET scan after induction therapy with BEACOPP (escalated or every 14 days) for advanced-stage HL was highly predictive for a good outcome, even with the omission of consolidative radiation therapy (negative predictive value for PET was 94% [95% CI, 91%–97%]).[22] In the German Hodgkin Study Group HD18 trial (NCT00515554), PET scan negativity after two cycles (PET2) of escalated BEACOPP allowed reduction to four cycles of therapy instead of six or eight cycles because of the equivalent 5-year PFS (90.8% vs. 92.2%; difference 1.4%; 95% CI, -2.7 to 5.4).[23][Level of evidence B1] The HD18 trial established a Deauville score of 4 or 5 as PET2 positive based on a 3-year OS.[24]

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine).

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine).

With a median follow-up of 7.3 years for the 937 patients with negative PET-CT results, there was no difference in the 7-year OS rate (93.2%; 95% CI, 90.2%–95.3% for ABVD vs. 93.5%; 95% CI, 90.5%–95.5% for AVD).[26][Level of evidence A1]

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine).

The absolute difference in the 3-year PFS rate (ABVD minus AVD) was 1.3% (95% CI, -3.0% to 4.7%), which falls within the predefined noninferiority margin. This meant that there was no PFS advantage for continuing bleomycin for PET-negative patients on the interim scan.

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine).

However, pulmonary toxicity was worse in the continued ABVD arm, with significantly more grade 3 or 4 respiratory events and worsened long-term diffusing capacity of the lung for carbon monoxide levels persisting beyond 1 year.

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine).

This study concluded that bleomycin may be omitted after the second cycle of ABVD if findings from the PET-CT scan are negative (Deauville score of 1, 2, or 3).

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine).

The patients with positive PET-CT scan results (Deauville score of 4 or 5) after two cycles of ABVD received BEACOPP.

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine). › The patients with positive PET-CT scan results (Deauville score of 4 or 5) after two cycles of ABVD received BEACOPP.

With a median follow-up of 41 months for the 172 patients with positive PET-CT results, the 3-year PFS rate was 67.5% and the OS rate was 87.8%

A randomized prospective trial of 1,214 patients with advanced-stage HL (RATHL [NCT00678327]) investigated the use of PET-CT scans after two cycles of ABVD to modify therapy.[25,26] Patients with negative findings from a PET-CT scan (Deauville score of 1, 2, or 3) were randomly assigned to receive four more cycles of ABVD versus four cycles of AVD (doxorubicin, vinblastine, and dacarbazine). › The patients with positive PET-CT scan results (Deauville score of 4 or 5) after two cycles of ABVD received BEACOPP.

This trial did not establish that switching to BEACOPP was superior to remaining on ABVD.

In a nonrandomized trial (SWOG S0816 [NCT00822120]), 336 patients with advanced HL received two cycles of ABVD and then were evaluated by PET scan.[27] PET2–negative patients (Deauville score of 1 to 3) completed four more cycles of ABVD, while the 60 PET2–positive patients (18% of total) were switched to escalated BEACOPP.

In a nonrandomized trial (SWOG S0816 [NCT00822120]), 336 patients with advanced HL received two cycles of ABVD and then were evaluated by PET scan.[27] PET2–negative patients (Deauville score of 1 to 3) completed four more cycles of ABVD, while the 60 PET2–positive patients (18% of total) were switched to escalated BEACOPP.

With a median follow-up of 5.9 years, the 5-year PFS rate for the PET2–positive patients was 66% (95% CI, 52%–76%).[27][Level of evidence C3]

In a multicenter phase II study, 48 patients older than 60 years, of whom 81% had advanced-stage disease, received brentuximab vedotin for two consecutive doses, followed by six cycles of AVD, followed by four more doses of brentuximab vedotin.[28]

In a multicenter phase II study, 48 patients older than 60 years, of whom 81% had advanced-stage disease, received brentuximab vedotin for two consecutive doses, followed by six cycles of AVD, followed by four more doses of brentuximab vedotin.[28]

The 2-year event-free survival rate was 80%, PFS rate was 84%, and OS rate was 93%.[28][Level of evidence C3]

In a multicenter phase II study, 48 patients older than 60 years, of whom 81% had advanced-stage disease, received brentuximab vedotin for two consecutive doses, followed by six cycles of AVD, followed by four more doses of brentuximab vedotin.[28]

Grade 3 or 4 toxicity was experienced by 42% of patients.

For patients with advanced-stage HL, six cycles of N-AVD is now the standard approach. In situations where immunotherapy might be contraindicated (such as active vasculitis or inflammatory colitis), BV-AVD is a good option.

When the financial toxicity of N-AVD or BV-AVD precludes their use (such as in a nation with constrained health care options), ABVD is still a reasonable and cost-effective approach. For patients with negative PET-CT scan results after the second cycle of ABVD, bleomycin may be omitted from the chemotherapy regimen with little loss of efficacy and improvement in tolerability.