Results of selected Jak inhibitor-based combinations for MF
| Agent . | Setting . | Regimen . | Phase . | Study population/sample size . | Clinical responses . | Molecular responses . | BMF reduction . |
|---|---|---|---|---|---|---|---|
| Targeting hematopoietic stem cells | |||||||
| INF-α | First-line | Ruxolitinib + PEG-IFN-α2A | 1/2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 37 (phase 1, N = 18; phase 2, N = 19) | ≥50% reduction in spleen length at 24 wk: 70% | JAK2 V617F VAF decreased from a median of 84% (range, 23%-96%) at baseline to 65% (range, 16-95) and 53% (range, 16-92) after 6 and 12 mo | NR |
| Targeting epigenetic regulators | |||||||
| HMAs | First-line | Ruxolitinib + azacitidine 25-75 mg/m2/d days 1-5 every 4 wk | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 46 | >50% reduction in spleen length at 24 wk: 62% (21/34); best TSS50: 54% (25/46); TI: 20% (1/5) | 81% (13/16) had reduction in JAK2 V617F VAF at 24 wk | 57% (8/14) had BM reticulin fibrosis reduction at 24 wk |
| BET inhibition | First-line | Ruxolitinib + pelabresib | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 84 | SVR35 at 24 wk: 68%; TSS50 at 24 wk: 56%; ≥1.5 g/dL over 12 wk: 24% | NR | 28% evaluable patients had reduction in BMF at 24 wk |
| Second-line | Ruxolitinib + pelabresib | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 86 | SVR35 at 24 wk: 20% (16/81); TSS50 at 24 wk: 37% (30/81) | NR | 26% evaluable patients had reduction in BM reticulin fibrosis at 24 wk | |
| Targeting apoptotic pathways | |||||||
| BCLXL/BCL2 inhibition | First-line | Ruxolitinib + navitoclax | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 32 | SVR35 at 24 wk: 52%; TSS50 at 24 wk: 31%; TI: 55% | 50% and 36% of patients had >20% reduction in JAK2 V617F VAF | 35% had reduction in BM reticulin fibrosis at any time |
| Second-line | Ruxolitinib + navitoclax | 2 | Int-1, int-2, and high-risk MF Suboptimal response to ruxolitinib N = 34 | SVR35 at 24 wk: 26.5%; TSS50 at 24 wk: 30%; TI: 64% | 46% had >10% reduction in VAF of driver gene mutations | 33% had reduction in BM reticulin fibrosis at any time | |
| Selective inhibition of nuclear export | First-line | Ruxolitinib + selinexor | 1/2 | Int-1, int-2, and high-risk MF N = 22 | SVR35 at 24 wk: 64% overall; 79% (11/14) in the 60-mg group and 38% (3/8) in the 40-mg group, respectively; TSS50 at 24 wk: 45% overall; 58% (7/12) in the 60-mg group and 25% (2/8) in the 40-mg group; | 50% (4/8) had >10% reduction in VAF, and 25% (2/8) had >20% reduction in VAF in the 60-mg group | NR |
| Targeting bone marrow microenvironment | |||||||
| Activin receptor IIB ligand trap | Second-line (“add-on”) | Ruxolitinib + luspatercept | 2 | Patients on ruxolitinib ≥16 wk prior to enrollment and TD; N = 38 | 31.6% achieved TI for ≥12 wk over entire treatment period; 50% had ≥50% reduction in transfusions (≥4 units) over 12 wk | NR | NR |
| Agent . | Setting . | Regimen . | Phase . | Study population/sample size . | Clinical responses . | Molecular responses . | BMF reduction . |
|---|---|---|---|---|---|---|---|
| Targeting hematopoietic stem cells | |||||||
| INF-α | First-line | Ruxolitinib + PEG-IFN-α2A | 1/2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 37 (phase 1, N = 18; phase 2, N = 19) | ≥50% reduction in spleen length at 24 wk: 70% | JAK2 V617F VAF decreased from a median of 84% (range, 23%-96%) at baseline to 65% (range, 16-95) and 53% (range, 16-92) after 6 and 12 mo | NR |
| Targeting epigenetic regulators | |||||||
| HMAs | First-line | Ruxolitinib + azacitidine 25-75 mg/m2/d days 1-5 every 4 wk | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 46 | >50% reduction in spleen length at 24 wk: 62% (21/34); best TSS50: 54% (25/46); TI: 20% (1/5) | 81% (13/16) had reduction in JAK2 V617F VAF at 24 wk | 57% (8/14) had BM reticulin fibrosis reduction at 24 wk |
| BET inhibition | First-line | Ruxolitinib + pelabresib | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 84 | SVR35 at 24 wk: 68%; TSS50 at 24 wk: 56%; ≥1.5 g/dL over 12 wk: 24% | NR | 28% evaluable patients had reduction in BMF at 24 wk |
| Second-line | Ruxolitinib + pelabresib | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 86 | SVR35 at 24 wk: 20% (16/81); TSS50 at 24 wk: 37% (30/81) | NR | 26% evaluable patients had reduction in BM reticulin fibrosis at 24 wk | |
| Targeting apoptotic pathways | |||||||
| BCLXL/BCL2 inhibition | First-line | Ruxolitinib + navitoclax | 2 | Int-1, int-2, and high-risk MF Jak inhibitor naive/ N = 32 | SVR35 at 24 wk: 52%; TSS50 at 24 wk: 31%; TI: 55% | 50% and 36% of patients had >20% reduction in JAK2 V617F VAF | 35% had reduction in BM reticulin fibrosis at any time |
| Second-line | Ruxolitinib + navitoclax | 2 | Int-1, int-2, and high-risk MF Suboptimal response to ruxolitinib N = 34 | SVR35 at 24 wk: 26.5%; TSS50 at 24 wk: 30%; TI: 64% | 46% had >10% reduction in VAF of driver gene mutations | 33% had reduction in BM reticulin fibrosis at any time | |
| Selective inhibition of nuclear export | First-line | Ruxolitinib + selinexor | 1/2 | Int-1, int-2, and high-risk MF N = 22 | SVR35 at 24 wk: 64% overall; 79% (11/14) in the 60-mg group and 38% (3/8) in the 40-mg group, respectively; TSS50 at 24 wk: 45% overall; 58% (7/12) in the 60-mg group and 25% (2/8) in the 40-mg group; | 50% (4/8) had >10% reduction in VAF, and 25% (2/8) had >20% reduction in VAF in the 60-mg group | NR |
| Targeting bone marrow microenvironment | |||||||
| Activin receptor IIB ligand trap | Second-line (“add-on”) | Ruxolitinib + luspatercept | 2 | Patients on ruxolitinib ≥16 wk prior to enrollment and TD; N = 38 | 31.6% achieved TI for ≥12 wk over entire treatment period; 50% had ≥50% reduction in transfusions (≥4 units) over 12 wk | NR | NR |
Int-1, intermediate-1 risk by Dynamic International Prognostic Scoring System; Int-2, intermediate-2 risk by Dynamic International Prognostic Scoring System; NR, not reported; PI3K, phosphatidylinositol 3-kinase; RBC, red blood cell.
Data compiled from Kiladjian et al15 ; Masarova et al18 ; Mascarenhas et al21 ; Harrison et al22 ; Passamonti et al25 ; Ali et al29 ; Gerds et al31 ; Harrison et al33 ; Passamonti et al34 ; Passamonti et al35 ; Pemmaraju et al.36