Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma
Abstract
:1. Introduction
1.1. The Journey from Pathobiology to Novel Therapeutic Approaches
1.2. Treatment of Hodgkin Lymphoma in the Past Millennium: Lights and Shades
2. Randomized Trials Incorporating Novel Agents in the First-Line Therapy of Advanced-Stage Classical Hodgkin Lymphoma
2.1. The BV-AVD Combination: Incorporating Brentuximab Vedotin to ABVD
2.2. Novel Combinations with Brentuximab Vedotin and Checkpoint Inhibitors: Moving beyond BV-AVD
3. Brentuximab Vedotin in the First-Line Therapy of Early-Stage Classical Hodgkin Lymphoma
4. Checkpoint Inhibitors in the First-Line Therapy of Classical Hodgkin Lymphoma
5. Brentuximab Vedotin and Checkpoint Inhibitor Combinations in the First-Line Treatment of Classical Hodgkin Lymphoma
6. Novel Agents in the First-Line Treatment of Classical Hodgkin Lymphoma of the Elderly
6.1. BV Combined with AVD
6.2. BV Monotherapy
6.3. Anthracycline-Free BV-Chemo Combinations
6.4. Checkpoint Inhibitor Monotherapy with or without BV for Frail or CT-Ineligible Patients
7. Ongoing and Forthcoming Randomized Trials
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Patients’ Characteristics and Key Outcome and Toxicity Measures | ECHELON-1 | SWOG S1826 | ||
---|---|---|---|---|
ABVD | BV-AVD | BV-AVD | N-AVD | |
Patients (Ν) and patient characteristics [42,44,45] | 670 | 664 | 487 | 489 |
Age (median (range)) | 37 (18–83) | 35 (18–82) | 26 (12–81) | 27 (12–83) |
Stage IV (%) | 63 | 64 | 65 | 62 |
IPS 4–7 (%) | 26 | 25 | 32 | 32 |
Outcome measures [42,43,44,45] | ||||
All patients | ||||
1-year PFS (%) * | 81.4 | 88.6 | 86 m | 94 m |
2-year mPFS per IRC (%) (primary endpoint) [42] | 77.2 a | 82.1 a | ND | ND |
6-year PFS per INV (%) [43] | 74.5 b | 82.3 b | NYA | NYA |
6-year OS (%) [43] | 89.4 c | 93.9 c | NYA | NYA |
Stage IV or III subgroup | ||||
2-year mPFS per IRC, Stage IV (%) [42] | 74.9 d | 82.0 d | ND | ND |
6-year PFS per INV, stage III (%) [43] | NR e | NR e | NYA | NYA |
6-year PFS per INV, stage IV (%) [43] | NR f | NR f | NYA | NYA |
6-year OS, stage III (%) [43] | NR g | NR g | NYA | NYA |
6-year OS, stage IV (%) [43] | NR h | NR h | NYA | NYA |
Interim PET negative status [44] | n = 578 | n = 588 | ||
5-year PFS per INV, all patients (%) | 78.9 i | 84.9 i | NYA | NYA |
5-year PFS per INV, <60 years old (%) | 81.5 j | 86.6 j | NYA | NYA |
Interim PET positive status [44] | n = 58 | n = 47 | ||
5-year PFS per INV, all patients (%) | 45.9 k | 60.6 k | NYA | NYA |
5-year PFS per INV, <60 years old (%) | 49.3 l | 63.1 l | NYA | NYA |
Toxicity [42,45] | ||||
Toxic deaths, all patients [N (%)] | 13 (1.9) | 9 (1.4) | NR | 1 (<%) |
Hospitalization, all patients (%) | 28 | 37 | NR | NR |
Peripheral sensory neuropathy, all patients, all grades (%) | 17 | 29 | 55 | 29 |
Peripheral sensory neuropathy, all patients, grade ≥ 3 (%) | <1 | 5 | 8 | 1 |
Peripheral motor neuropathy, all patients, all grades (%) | 4 | 11 | 7 | 4 |
Febrile neutropenia, all patients (%) | 8 | 19 | 7 | 5 |
Febrile neutropenia, elderly (%) | 17 | 37 | - | - |
Abramson J.S. et al., 2019 [54] | Abramson J.S. et al., 2023 [55] | Park S.I. et al., 2020 [56] | Kumar A. et al., 2021 [57] | Fornecker L.M. et al., 2022 [58] | |
---|---|---|---|---|---|
Patients (N) | 36 | 34 | 39 | 116 | 170 |
Eligible stages | I/II non-bulky ◊ | I/II non-bulky ◊ | I/II non-bulky ± | Stage I, II unfavorable ¶ | Stage I/II unfavorable & |
Initial treatment | BV-AVD × 2 | BV-AD × 2 | ABVD × 2 | BV-AVD × 2 | BV-AVD × 2 vs. ABVD × 2 (113 vs. 57 patients) |
Further treatment | BV-AVD × 4 (#4) (not PET2 directed) | BV-AVD × 2 (#4) vs. ABVD × 2 (#4) (not PET2 directed) | |||
PET2− | BV-AVD × 2 (#4) | BV-AD × 2 (#4) | F: BV × 6 U: ABVD × 2 (#4) + BV × 6 | ||
PET2+ | BV-AVD × 4 (#6) | BV-AD × 4 (#6) | F: ABVD × 2 (#4) + BV × 6 U: ABVD × 4 (#6) + BV × 6 | ||
PET2+ definition | DS 4–5 | DS 4–5 | DS 3–5 | DS 4–5 | DS 4–5 |
PET2+ patients (N) | 0 | 6% | 28% | 13% | 17.7% vs. 24.6% |
RT (% of patients) | No | No | Yes, for EoT PET+ (5%) | Yes, for cohorts 1–3 | Yes, for all patients after treatment (30 Gy) |
PFS | 3-year: 94% | 5-year: 91% | 3-year: 92% (100% for patients with EoT PET−) | 2-year PFS: 93.1%, 96.6%, 89.7%, 96.6% for cohorts 1–4 | 2-year: 97.3% vs. 92.6% For PET2−: 97.8% vs. 97.7% For PET2+: 93.8 vs. 71.6% |
OS | 3-year: 97% | 5-year: 96% | 3-year: 97% (100% for patients with EoT PET−) | 2-year: 99% in the whole population | NR |
Toxicity (% of patients) | |||||
PN grade ≥ 3 | 24% | 0% * | 2.5% | 3% | 3 vs. 2% |
FN | 29% | 0% ** | NR | 8% | 8% vs. 6% |
EoT PET-negative (% of patients) | 91.2% | 97% | 95% | 93%, 100%, 93%, and 97% for cohorts 1–4 | 88% vs. 77% |
Ramchandren R. et al., CHECKMATE-205, Arm D, 2019 [71] | Bröckelmann P.J. et al., NIVAHL, 2023 [72] | Allen P.B. et al., 2022 [73] | Lynch E.C. et al., 2023 [74] | |
---|---|---|---|---|
Patients (N) | 51 | 109 | 30 | 30 |
Eligible stages | Advanced * (III/IV, IIBX/E) | I/II unfavorable * | III/IV, I/II unfavorable ¶¶ | All |
CPI lead-in phase | Nivo × 4 | Nivo × 4 (Only Arm B) | Pembro × 3 | no |
Response to CPI monotherapy [ORR (CR)] | 69% (18%) | NR (51%) | NR (37% + 23%) *** | NA |
Overall Treatment Schedule | Nivo × 4 followed by AVD × 6 | Arm A: Nivo-AVD × 4 + 30 Gy ISRT Arm B: Nivo × 4 → Nivo-AVD × 2 → AVD × 2 + 30 Gy ISRT | Pembro × 3 followed by AVD × 4–6 ** | Pembro-AVD × 2–6 ** |
CR rate at EoT | 80% | Arm A: 83% ¶ Arm B: 84% ¶ | 100% (at EoT) | 78% (at EoT) |
PFS | 92% (9-month) | Arm A: 100% (3-year) Arm B: 98% (3-year) | 100% (2-year) | 97% (2-year) |
OS | 98% (9-month) | 3-year OS 100% in both arms | 100% (2-year) | 100% (2-year) |
Patients’ Characteristics and Outcomes | BV-AVD (Sequential Regimen) [94] | BV-AVD (Concomitant Regimen) [93] | ABVD Comparator [93] |
---|---|---|---|
Patients (N) | 48 | 84 | 102 |
Age [years, median (range)] | 69 (60–88) | 68 (60–82) | 66 (60–83) |
ECOG PS ≥ 2 | 19% | 12% | 10% |
Ann Arbor Stage | |||
II | 19% | 0% | 0% |
III | 37% | 37% | 34% |
IV | 44% | 61% | 66% |
Efficacy | |||
Response to BV × 2 [ORR (CR)] | 82% (36%) | NA | NA |
Interim PET positive | 24% (10/42 pts) | 20% | 18% |
EoT PET-negative | 90% (38/42 pts) | 71% | 74% |
2-year PFS | 84% | 70.3% * | 71.4% * |
5-year PFS | NA | 67.1% | 61.6% |
2-year OS | 93% | NA | NA |
Toxicity | |||
TRM | 2% | 3.6% | 5.1% |
Neutropenia, grade ≥ 3 | 44% | 70% | 59% |
Febrile neutropenia, grade ≥ 3 | 8% | 37% | 17% |
Peripheral neuropathy | |||
any grade | NA | 65% | 43% |
grade ≥ 3 | 4% | 18% | 3% |
grade 2 | 27% | 37% | 16% |
resolution | 69% | 80% | 83% |
Pulmonary toxicity, any grade | NA | 2% | 13% |
Patients’ Characteristics, Outcome, and Toxicity | BV Monotherapy (BREVITY) [95] | BV Monotherapy [96] | BV-Dacarbazine [97] | BV-Bendamustine [97] | BV-Bendamustine (HALO) [98] | BV-Nivolumab [99] |
---|---|---|---|---|---|---|
Patients (total, N) | 35 | 27 | 22 | 20 | 60 | 20 |
Patients (evaluable, N) | 31 | 26 | 19 | 17 | 59 | 19 |
Eligibility criteria | Stage IIBX/III/IV unfit for standard CT * | ≥60 years old | ≥60 years old | ≥60 years old | Stage IIB/III/IV ≥60 years old | ≥60 years old |
Follow-up time (median) | 3-years | 59.4 months | 58.6 months | 51.3 months | 20.6 months | 19.4 months |
Treatment cycles | up to 16 | up to 16 | up to 12 plus BV ≥ 4 | up to 6 plus BV ≥ 10 | up to 6 | NA |
Age [median (IQR or range)] | 77 (72–82) | 78 (64–92) | 69 (62–88) | 75 (63–86) | 70.32 (62–79) | 72 (NR–NR) |
Ann Arbor Stage III, IV | 80% | 63% | 68% | 75% | 80% | 80% |
ECOG PS ≥ 2 | 48% | 22% | 32% | 20% | 10% | 5% |
B-symptoms | 71% | 22% | 29% | 41% | 68% | NA |
CIRS [median (IQR or range)] | 5 (4, 7) | NA | NA | NA | NA | NA |
TRM | 0.35% | 0% | 0% | 0% | NA | 0% |
ORR | 84% ** | 92% *** | 100% *** | 100% *** | 63% | 95% |
CMR | 26% ** | 73% *** | 62% *** | 88% *** | 80.36% | NA |
PFS | ||||||
Median | 7.3 months | 10.5 months | 46.8 months | 40.3 months | NR | NR |
1-year | 14% | ~35% | NA | NA | 84% | NA |
2-year | 7% | ~30% + | NA | NA | 54% | NA |
OS | ||||||
Median | 19.5 months | 77.5 months | 64 months | 46.9 months | 83% | NR |
1-year | 73% | NA | NA | NA | 97% | NA |
2-year | 42% | NA | NA | NA | 83% | NA |
Peripheral neuropathy grade ≥ 3 | NR ++ | 30% & | 26% | 20% | 0% | 35% |
Discontinuation rate | 29% | 42% | 40% | 40% | 30.5% | 30% |
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Share and Cite
Vassilakopoulos, T.P.; Liaskas, A.; Pereyra, P.; Panayiotidis, P.; Angelopoulou, M.K.; Gallamini, A. Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma. Int. J. Mol. Sci. 2023, 24, 13187. https://doi.org/10.3390/ijms241713187
Vassilakopoulos TP, Liaskas A, Pereyra P, Panayiotidis P, Angelopoulou MK, Gallamini A. Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma. International Journal of Molecular Sciences. 2023; 24(17):13187. https://doi.org/10.3390/ijms241713187
Chicago/Turabian StyleVassilakopoulos, Theodoros P., Athanasios Liaskas, Patricio Pereyra, Panayiotis Panayiotidis, Maria K. Angelopoulou, and Andrea Gallamini. 2023. "Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma" International Journal of Molecular Sciences 24, no. 17: 13187. https://doi.org/10.3390/ijms241713187