Table 3.
Summary of selected novel therapies in clinical trials in patients with myelofibrosis.
| Drug/mechanism | Dose | Spleen response | Anemia response | Symptom response | Correlative studies | Toxicity | Current status |
|---|---|---|---|---|---|---|---|
| Pelabresib (CPI-0610) (153–155, 181) | 125 mg daily on days 1–14 of a 21-day cycle | Week 24 | Week 24 | Week 24 | Non-TD cohort | Thrombocytopenia (25.6%), | |
| Bromodomain and Extraterminal Domain Inhibitor (BETi). | SVR≥35% | TD cohort | TSS≥50% | Improvement in fibrosis | Anemia (11.6%), | ||
| Phase II trial (MANIFEST) | Non-TD cohort | 3/14 (21%) | Non-TD cohort | Nausea (32.6%), | |||
| Arm 1 (refractory/intolerant to ruxolitinib). | 5/21(23.8%) | TD-TI | 9/19 (47.4%) | Diarrhea (30.2%), | |||
| Non-TD (n = 27) | TD cohort none | Non-TD cohort | TD cohort | Respiratory tract | |||
| TD (n = 19) | 13/22 (59%), hemoglobin improved ≥1.5 g/dL over 12 weeks | 1/12 (8.3%) | infections (27.9%) | ||||
| Arm 2 (suboptimal response or progression on ruxolitinib) | CPI-0610 + ruxolitinib | Week 24 | TD cohort 13/36 (36%) TD-TI | Week 24 | Not provided | Thrombocytopenia (40%), | |
| TD (n = 52), Non-TD (n = 26). | SVR≥35% | TSS ≥ 50% | Asthenia (32%), | ||||
| TD cohort: 5/24 (20.8%) | Non-TD cohort | TD cohort: 12/26 (46.2%) | Diarrhea (46%), | ||||
| Non-TD cohort: 4/18 (22.2%) | 4/23 (17%) Hb improved ≥1.5 g/dL over 12 weeks. | Nausea (36%), | |||||
| Non-TD cohort: 7/19 (36.8%) | Respiratory infections (32%) | ||||||
| Arm 3: | CPI-0610 + ruxolitinib 10 mg, bid | Week 24 | None | Week 24 | Not provided | Anemia (23.4%), | Phase 3 study CPI-0610 + ruxolitinib vs. placebo + ruxolitinib in JAKi-naïve MF (MANIFEST-2) |
| JAKi-naïve patients | SVR≥35% | TSS≥50% | Thrombocytopenia (20.3%), | ||||
| (n = 64) | 19/30 (63.3%) | 17/29 (58.6%) | Diarrhea (26.6%), | ||||
| Respiratory infections (18.8%), | |||||||
| Nausea (18.8%) | |||||||
| Navitoclax (157, 182) | 50 mg to 300 mg daily + ruxolitinib (>10 mg, bid) | Week 24 | 7/11 (64%) with Hb < 10 g/dL or TD improved ≥ 2 g/dL (n = 6) or TI (n = 1) | Week 24 | Fibrosis reduction | AEs ≥20% | Phase III study navitoclax + ruxolitinib vs. placebo + ruxolitinib in JAKi naïve (TRANSFORM-1) vs. BAT in relapsed/refractory to JAKi. (TRANSFORM-2) |
| Antiapoptotic, binds to B-cell lymphoma 2 (BCL2) | SVR ≥35% 9 (27%) | TSS≥50% 6/20 (30%) | ≥1 grade in 11/33 (33%). | Thrombocytopenia (88%) | |||
| Family, including BCL-XL, BCL2, and BCL-W | Diarrhea | ||||||
| Phase II trial in pts with suboptimal response to ruxolitinib (n = 34) | Anytime SVR ≥35% 15 (44%) | 12/26 (46%) with >10% driver gene VAF reduction. | Fatigue | ||||
| Median duration of SVR- 13.8 months | Median overall survival- not reached 24-month survival- 84% | Anemia | |||||
| Nausea | |||||||
| Dizziness | |||||||
| Confusion | |||||||
| Vomiting | |||||||
| Imetelstat (161) | Imetelstat (9.4 mg/kg or 4.7 mg/kg) i.v. every 3 weeks | Week 24 | None | Week 24 | 41% with ≥1 grade reduction in fibrosis. | Thrombocytopenia (49%), | Phase 3 study 9.4 mg/kg of imetelstat vs. BAT with the exclusion of JAKi in refractory MF |
| Telomerase inhibitor | SVR ≥35% | TSS≥50% | 5/24 (20.8%) with ≥50% reduction in abnormal cytogenetic clones (all with sole 13q) | Anemia (44%), | |||
| Phase II trial (MYF2001) in relapsed/refractory to JAKi, (n = 107) | 6 (10.2%) in 9.4 mg/kg arm with no responses in 4.7 mg/kg arm | 19 (32%) in 9.4 mg/kg arm and 3 (6%) in 4.7 mg/kg arm. | 12/26 (46.2%) in 9.4 mg/kg vs. (4/23) | Neutropenia (36%), | |||
| 17.4% in 4.7 mg/kg arm with ≥20% VAF reduction of any mutated gene | Nausea (34%). | ||||||
| Median overall survival 29.9 months with 9.4 mg/kg. | |||||||
| Luspatercept (159, 160) | 1–1.75 mg/kg s.c. every 21 days | Not provided | Week 24 | Not provided | Not provided | Treatment-related AEs; | Phase 3 study in MF-associated anemia with concomitant JAKi therapy and transfusion needs |
| Binds to TGFβ superfamily ligand, reduces aberrant Smad2/3 signaling and enhances late-stage erythropoiesis. | Cohort 1 (14%) | Hypertension (13%), | |||||
| Phase II trial | Cohort 3a (21%)) | Bone pain (9%), | |||||
| Non-TD without ruxolitinib (n = 22) (Cohort 1) | Cohort 2 | Diarrhea (5%). | |||||
| 2/21 (10%) | 8 (10%) pts had ≥ 1 AE leading to drug discontinuation | ||||||
| With ruxolitinib (n = 14) | Cohort 3b | ||||||
| (Cohort 3a) TD | 6/22 (27%) achieved TI. | ||||||
| Overall | |||||||
| Without ruxolitinib (n = 21) | Cohort 2 | ||||||
| (Cohort 2) | 4/21 (19%) | ||||||
| With ruxolitinib (n = 22) | Cohort 3b | ||||||
| (Cohort 3b) | 8/22 (36%) achieved TI. | ||||||
| Parsaclisib (164) | 10 or 20 mg QD | Week 12 | Hemoglobin remained stable | Week 12 | Not provided | 18%/30% | Phase 3 randomized study ruxolitinib + parsaclisib in JAK- and PI3K-inhibitor treatment-naïve myelofibrosis. |
| PI3Kδ inhibitor | oral for 8 wks | median % change, | median % change | grade 3 thrombocytopenia. | Phase 3 randomized study ruxolitinib + parsaclisib vs. ruxolitinib + placebo in patients with suboptimal responseto ruxolitinib. | ||
| Phase II trial in MF with suboptimal response to ruxolitinib (n = 53) | QW thereafter) or parsaclisib QD (5 or 20 mg QD for 8 wks/5 mg QD thereafter) with stable ruxolitinib dose (5–25 mg bid) | −2.3 and −15.4 | −14.0 in QD/QW | 21%/0% | |||
| Week 24 | −39.6 in QD | grade 4 thrombocytopenia, | |||||
| −2.5 and −25.4 with QD/QW and QD dosing | grade 3/4 events; tuberculosis, | ||||||
| enteritis, fatigue, hypertension, | |||||||
| abnormal liver tests, stomatitis | |||||||
| Bomedemstat (IMG-7289) (163) | Dose uptitrated based on platelet count targeting 50–100k/μL (QD orally). | Week 24 | 72% of evaluable patients (n = 36) with stable or improved hemoglobin >1 g/dl. | Week 24 | Improvement in fibrosis > grade 1 in 26%. | 8 SAEs possibly related: | Ongoing. |
| Lysine-specific demethylase, LSD1 inhibitor | 81% (n = 19) | 85% (n = 13), | Reduction in driver/HMR mutation VAF in 42% | painful splenomegaly, | |||
| Phase II trial in MF resistant to approved therapies. (n = 62) | reduction in spleen volume (mean SVR: -8%). | TSS reduction (mean change -31%). | rectal bleeding, heart failure, | ||||
| 31% with TSS >50% reduction. | headache, vertigo, | ||||||
| GI hemorrhage, | |||||||
| anemia, | |||||||
| pyoderma gangrenosum | |||||||
| Sotatercept (ACE-011) (183) | Single agent 0.75 or 1 mg/kg S/C every 3 weeks (n = 31) and in combination with a stable dose of ruxolitinib (n = 21) | Not provided | Sotatercept alone. | Not provided | Not provided | Hypertension (n = 7), | Ongoing |
| activin receptor type IIA ligand trap | 4 anemia responses (29%); | limb pain (n = 3), | |||||
| Phase II trial in MF pts with anemia, (n = 53) | 3 TD to TI. | headache (n = 1) | |||||
| combination cohort | |||||||
| 5/17 (29%) pts responded, | |||||||
| all non-TD pts | |||||||
| Tagraxofusp (SL-401) (184) | Stage 1 (dose escalation), at 7, 9, or 12 mcg/kg i.v. on days 1–3 every 21 days (cycle 1–4), | Week 24 | None | 3 patients by IWG-MRT | Not provided | hypoalbuminemia (23%), | Ongoing |
| CD123-directed antibody | 28 days (cycles 5–7), | Spleen response by palpation (n = 10, 45%), | 12/26 (46%) with symptom reduction. | headache (17%), | |||
| Phase I/II trial in relapsed/refractory MF (n = 35) | 42 days (cycles 8+). | 2 pts with >50% reduction. | elevated ALT (17%). | ||||
| Stage 2 (expansion), | Capillary leak syndrome in 3 pts (1 grade 4). | ||||||
| recommended phase II dose (12 mcg/kg). |
Abbreviations: ALT, alanine transferase; AEs, adverse events; BAT, best available therapy; BID, twice daily; HMR, high molecular risk mutation; IWG-MRT, International working group-myeloproliferative neoplasms research and treatment; JAKi- Janus kinase inhibitor; MF, myelofibrosis; SAE, serious adverse event; SVR, spleen volume reduction;TSS, total symptom score; TI, transfusion independent; TD, transfusion dependent; VAF, variant allele frequency; QD/QW, once daily/once weekly.