Treatment effect modifiers for venetoclax in CLL, myeloma, and AML
| Disease line, regimen . | Biomarker . | Improvements in treatment outcomes vs control arm (in comparison with absence of marker) . | Predict benefit vs control arm? . | Prognostic with Ven? . | |||||
|---|---|---|---|---|---|---|---|---|---|
| Chemo-Ab (Chl-Obin or Benda-R) → Ven-Ab | |||||||||
| CLL | Name | Status | CR | uMRD (<10–4) | 2-y PFS | 3-y PFS | CR and uMRD | PFS | |
| First line43,44,47 Ven-Obin | del(17p) | Present Absent | 7% → 44% (24% → 50%) | 7% → 71% 38% → 76% | 23% → 65% (∼71% → 91%) | 12% → 49% (>50% → ∼84%) | Yes ↑↑ | Yes ↑ | Yes ↓ |
| Relapsed39,48 Ven-R | Present Absent | NR | 5%* → 60% (20%* → 76%) | 28% → 82% (41% → 86%) | 0% → 40% (∼30% → 80%) | Yes ↑↑ | Yes ↑↑ | Yes ↓ | |
| First line | TP53 mut | Present Absent | 5% → 48% (25% → 50%) | 21 → 65 (37% → 77%) | 37% → 73% (∼73% → 93%) | 35% → 60% (53% → 85%) | Yes ↑↑ | Yes ↑ | Yes ↓ |
| Relapsed | Present Absent | NR | 5% → 57%† (20% → 66%) | HR 0.19† (HR 0.15) | ∼10% → 63% (∼25% → 80%) | Yes ↑↑ | Yes ↑ | Yes ↓ | |
| First line | Unmutated IGHV | Unmutated Mutated | 15% → 61% (16% → 64%) | 28% → 79% (43% → 74%) | 51% → 89% (86% → 90%) | 34% → 81% (75% → 87%) | Yes ↑↑ | Yes ↑↑ | Probably‡ ↓ |
| Relapsed | Unmutated Mutated | NR | 15% → 61% (16% →64%) | HR 0.16 HR (0.11) | NR | Yes ↑↑ | Yes ↑ | NR | |
| Pbo-BortDex → Ven-BortDex | |||||||||
| Myeloma | Name | Status | ≥vGPR | uMRD (<10–5) | PFS | Survival HR | ≥vGPR & PFS | OS | |
| Relapsed99 Ven-BD | t(11;14) | Present Absent | 27% → 75% (38% → 58%) | 0% → 25% (1% → 12%) | HR 0.11 (HR 0.67) | 0.34 (2.5) | Yes ↑↑ | No | Yes ↑ |
| High BCL2§ | First quartile Fourth quartile | 28% → 71% (40% → 52%) | 0% → 18% (2% →11%) | HR 0.24 (HR 0.76) | 1.0 (>2.0) | Yes ↑↑ | No | Yes ↑ | |
| Pbo-Aza → Ven-Aza | |||||||||
| AML | Name | Status | CR/Cri | ΔCR/Cri | 2-y OS | HR OS | CR | OS | |
| First line74 Ven-Aza | IDH1/2 mut | Present Absent¶ | 11% → 75% 32% → 66% | +64% +34% | 14% → 52% (14% → 41%) | 0.34 | Yes ↑↑ | Yes ↑↑ | Yes ↑ |
| TP53 mut | Present Absent¶ | 0% → 55% 31% → 68% | +55% +37% | 7% → 11% 27% → 49% | 0.76 | Yes ↑↑ | No | Yes ↓ | |
| Disease line, regimen . | Biomarker . | Improvements in treatment outcomes vs control arm (in comparison with absence of marker) . | Predict benefit vs control arm? . | Prognostic with Ven? . | |||||
|---|---|---|---|---|---|---|---|---|---|
| Chemo-Ab (Chl-Obin or Benda-R) → Ven-Ab | |||||||||
| CLL | Name | Status | CR | uMRD (<10–4) | 2-y PFS | 3-y PFS | CR and uMRD | PFS | |
| First line43,44,47 Ven-Obin | del(17p) | Present Absent | 7% → 44% (24% → 50%) | 7% → 71% 38% → 76% | 23% → 65% (∼71% → 91%) | 12% → 49% (>50% → ∼84%) | Yes ↑↑ | Yes ↑ | Yes ↓ |
| Relapsed39,48 Ven-R | Present Absent | NR | 5%* → 60% (20%* → 76%) | 28% → 82% (41% → 86%) | 0% → 40% (∼30% → 80%) | Yes ↑↑ | Yes ↑↑ | Yes ↓ | |
| First line | TP53 mut | Present Absent | 5% → 48% (25% → 50%) | 21 → 65 (37% → 77%) | 37% → 73% (∼73% → 93%) | 35% → 60% (53% → 85%) | Yes ↑↑ | Yes ↑ | Yes ↓ |
| Relapsed | Present Absent | NR | 5% → 57%† (20% → 66%) | HR 0.19† (HR 0.15) | ∼10% → 63% (∼25% → 80%) | Yes ↑↑ | Yes ↑ | Yes ↓ | |
| First line | Unmutated IGHV | Unmutated Mutated | 15% → 61% (16% → 64%) | 28% → 79% (43% → 74%) | 51% → 89% (86% → 90%) | 34% → 81% (75% → 87%) | Yes ↑↑ | Yes ↑↑ | Probably‡ ↓ |
| Relapsed | Unmutated Mutated | NR | 15% → 61% (16% →64%) | HR 0.16 HR (0.11) | NR | Yes ↑↑ | Yes ↑ | NR | |
| Pbo-BortDex → Ven-BortDex | |||||||||
| Myeloma | Name | Status | ≥vGPR | uMRD (<10–5) | PFS | Survival HR | ≥vGPR & PFS | OS | |
| Relapsed99 Ven-BD | t(11;14) | Present Absent | 27% → 75% (38% → 58%) | 0% → 25% (1% → 12%) | HR 0.11 (HR 0.67) | 0.34 (2.5) | Yes ↑↑ | No | Yes ↑ |
| High BCL2§ | First quartile Fourth quartile | 28% → 71% (40% → 52%) | 0% → 18% (2% →11%) | HR 0.24 (HR 0.76) | 1.0 (>2.0) | Yes ↑↑ | No | Yes ↑ | |
| Pbo-Aza → Ven-Aza | |||||||||
| AML | Name | Status | CR/Cri | ΔCR/Cri | 2-y OS | HR OS | CR | OS | |
| First line74 Ven-Aza | IDH1/2 mut | Present Absent¶ | 11% → 75% 32% → 66% | +64% +34% | 14% → 52% (14% → 41%) | 0.34 | Yes ↑↑ | Yes ↑↑ | Yes ↑ |
| TP53 mut | Present Absent¶ | 0% → 55% 31% → 68% | +55% +37% | 7% → 11% 27% → 49% | 0.76 | Yes ↑↑ | No | Yes ↓ | |
The table summarizes the randomized trial data for genetic markers with the most robust evidence informing treatment effect modification: either abrogation of previously established negative treatment effect modification by venetoclax or the presence of novel positive treatment effect modification with venetoclax therapy. In CLL, the established negative treatment effect modifiers for chemo-immunotherapy (del(17p), TP53 mutations and unmutated IGHV status) do not affect responsiveness to venetoclax, and their presence predicts major benefit from use of venetoclax over chemo-immunotherapy, but they remain negatively prognostic. In multiple myeloma, the presence of either t(11;14) or high BCL2 RNA expression is a strong positive treatment effect modifier, with the magnitude of response and PFS benefits for venetoclax significantly exceeding that seen in marker-negative myeloma. In AML, the presence of mutations in IDH1 or IDH2 is a strong positive treatment effect modifier with the magnitude of benefits for venetoclax significantly exceeding that seen in marker-negative AML. Although TP53 mutations in AML are associated with magnified benefit with respect CR/CRi rate, improved survival has not been shown; the presence of TP53 mutations is associated with a lower CR/CRi rate with venetoclax and a negative prognosis compared with AML with normal TP53. ∼, estimated from Kaplan-Meier plots;
Aza, azacytidine; BD, bortezomib + dexamethasone; Benda, bendamustine; Chl, chlorambucil; CRi, CR, including with hematologic incomplete recovery; HR, hazard ratio for progression vs control, included when actual rates were not provided, and italicized when not statistically significantly different from control therapy; NR, not reported; Obin, obinutuzumab; Pbo, placebo; R, rituximab; Ven, venetoclax.
Includes data for either del(17p) or TP53 mutated cases for control treatment arm, as del(17p) data alone were not reported.
All data in these comparisons include either del(17p) or TP53 mutations.
PFS: HR, 1.96; 95% CI, 0.92-4.17.
High BCL2 RNA expression.
Absence of a marker includes patients with unknown status.