Selected data for combination studies with ruxolitinib
| Drug/acronym . | Eligible pts . | Number of pts . | Other findings (eg, MTD) . | Benefits . | Toxicity . |
|---|---|---|---|---|---|
| Ruxolitinib and buparlisib (BKM120) | Intermediate-/high-risk MF spleen >5 cm; both ruxolitinib-naive (arm A) and previously treated (arm B) | Arm A: 22 pts (11 in both escalation and expansion phase) | MTD: ruxolitinib 15 mg twice daily/buparlisib 60 mg daily | Expansion phase at week 24, 45% (5/11) of pts vs 18% (2/11) of pts in arm A and arm B, respectively, achieved a ≥35% reduction from BL in spleen volume | Grade 3/4 nonhematological AEs in >1 pt: anxiety (arm A, n = 2/22), multiorgan failure (arm B, n = 2/20) as a result of AML and progressive disease |
| HARMONY Study74 | Arm B: 20 pts (9 in escalation and 11 in expansion phase) | At week 24, a median (range) change of −3.35 (−26.9 to 2.7) was observed in JAK2V617F allele burden from BL in arm A and 0.60 (−12.6 to 24.7) in arm B at MTD | Grade 3/4 hematologic AEs included anemia (arm A, n = 2/22; arm B, n = 7/20) and thrombocytopenia (arm A, n = 5/22; arm B, n = 6/20) | ||
| Bone marrow fibrosis at 24 wk, 4 pts (n = 3 in arm A; 1 in arm B) and 19 pts (n = 9 in arm A; 10 in arm B) showed an improvement and stabilization, respectively; 2 pts in arm A (0 in arm B) experienced worsening of bone marrow fibrosis | 3 deaths reported at MTD in arm B; 2 deaths attributed to myeloid leukemia and 1 to multiorgan failure secondary to progressive MF | ||||
| Ruxolitinib and sonidegib (LDE225)72 | Intermediate-/high-risk MF spleen >5 cm not previously treated with a JAK inhibitor or HPI | 27 pts were treated at the RP2D | RP2D: sonidegib 400 mg once daily, ruxolitinib 20 mg twice daily | End of week 24, 12 pts (44.4%), ≥35% reduction in spleen volume | 5 pts discontinued treatment as a result of an AE, and 1 pt each as a result of pt decision and death (multiorgan failure unrelated to study treatment occurring 2 d after |
| 15 pts (55.6%) achieved a ≥35% reduction in spleen volume at any time on treatment | |||||
| ≥50% reduction in spleen length at any time achieved by 25 pts (92.6%), with 15 pts (55.6%) having a nonpalpable spleen | Overall, the most common AEs regardless of causality (all grade; grade 3/4) were anemia (52%; 33%) and muscle spasms (48%; 4%) | ||||
| The mean change in JAK2 V617F allele burden was −9.0% (range, −56.5% to 7.0%) from BL to the end of week 24 | AEs requiring dose adjustment or interruption in 17 pts (63%), most common being increased CK (19% [n = 5]) and myalgia (19% [n = 5]) | ||||
| BM fibrosis: 2 pts improved (grade 3 to grade 2), 8 pts remained stable, and 3 pts had a worsening from BL by the end of week 24 | |||||
| Ruxolitinib and panobinostat76 | Intermediate-1, Intermediate-2, or high-risk MF and spleen ≥5 cm by palpation; no prior JAKi | 61 pts (escalation phase, n = 38; expansion phase, n = 23) | RP2D: ruxolitinib 15 mg twice daily, panobinostat 25 mg three times a week | In expansion phase at week 24 (87%; 20/23) and at week 48 (74%; 17/23); 57% (13/23) and 39% (9/23) of pts achieved a ≥35% reduction from baseline in spleen volume | For 34 pts treated at the RP2D, 65% remained on treatment, and 21% discontinued because of AEs |
| BM fibrosis (n = 12 evaluable): 4 had improved fibrosis at wk 48, 6 had no change, and 2 worsened | Most common grade 3/4 hematologic AEs (at RP2D), regardless of causality: | ||||
| JAK2 V617F allele burden (n = 17 evaluable): 5 (29%) had a ≥20% reduction by wk 48 | Anemia (32%), thrombocytopenia (29%) | ||||
| Inflammatory markers (IL-18, MMP-9, and MPO) normalized | Grade 3/4 nonhematologic AEs included diarrhea (18%), asthenia (12%), and fatigue (9%). | ||||
| Three deaths (resulting from progression of underlying disease, myocardial infarction, and hypoxic cardiac arrest) attributed as unrelated | |||||
| Ruxolitinib and interferon COMBI trial70 | PV or MF evidence of active disease | 30 pts, PMF (n=10) OR PV (n=20) ± prior treatment with IFNa2 | Initial therapy was IFNa2 45 μg × 1 sc/week (Pegasys) or 35 μg × 1 sc/week (PegIntron) + ruxolitinib (Jakavi) 20 mg × 2/d | Overall, complete response was achieved as best response in 19 pts (63.3%), and partial response or major response in 8 pts (26.7%); only 3 pts (10%) had no response to treatment | 3 pts discontinued treatment because of an AE; one patient died of transformation to AML shortly after initiation of CT and was not included in this interim analysis |
| Palpable splenomegaly in 7 pts at baseline was significantly reduced by week 2; hct control without phlebotomy was achieved by week 4 in 78% of pts (7 of 9) who at baseline had an elevated hct, only 3 pts required a total of 3 phlebotomies after initiation of CT | Anemia (n = 15, 2 grade 3), granulocytopenia (n = 13, 2 grade 3), or thrombocytopenia (n = 6, 1 grade 3) | ||||
| JAK2V617F% declined significantly | Eleven severe AEs requiring hospitalization: pneumonia (n = 3); fever (n = 2); lipotymia, hematemesis, phlebitis, herpes zoster, angina pectoris, and arterial hypertension (n = 1 pt each) | ||||
| Ruxolitinib and danazol75 | Patients with MF with anemia | 14 patients (9 had prior JAKi) | Ruxolitinib, 10 mg twice-daily or 5 mg twice-daily in combination with tapered danazol up to 200 mg orally three times a day | 4/5 JAKi-naive pts had stable or increasing hgb levels | Nine pts discontinued: 2 progressive disease, 2 adverse event, 2 preference, 1 stem cell transplant, 1 unrelated death, 1 comorbidity. |
| 5/9 pts on prior JAKi, 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels. | Grade ≥3 anemia in 7, neutropenia in 2 leukopenia in 1 and thrombocytopenia in 2 pts | ||||
| Symptoms 4 had at least 50% improvement from baseline on MPN-SAF TSS | Grade ≥3 electrolyte abnormalities in 3, infection in 2, edema in 1, hypertension in 1, and intracranial hemorrhage in 1 pt | ||||
| Overall treatment response: stable disease in 10 pts, clinical improvement in 3, all of which were spleen responses, and progressive disease in 1 |
| Drug/acronym . | Eligible pts . | Number of pts . | Other findings (eg, MTD) . | Benefits . | Toxicity . |
|---|---|---|---|---|---|
| Ruxolitinib and buparlisib (BKM120) | Intermediate-/high-risk MF spleen >5 cm; both ruxolitinib-naive (arm A) and previously treated (arm B) | Arm A: 22 pts (11 in both escalation and expansion phase) | MTD: ruxolitinib 15 mg twice daily/buparlisib 60 mg daily | Expansion phase at week 24, 45% (5/11) of pts vs 18% (2/11) of pts in arm A and arm B, respectively, achieved a ≥35% reduction from BL in spleen volume | Grade 3/4 nonhematological AEs in >1 pt: anxiety (arm A, n = 2/22), multiorgan failure (arm B, n = 2/20) as a result of AML and progressive disease |
| HARMONY Study74 | Arm B: 20 pts (9 in escalation and 11 in expansion phase) | At week 24, a median (range) change of −3.35 (−26.9 to 2.7) was observed in JAK2V617F allele burden from BL in arm A and 0.60 (−12.6 to 24.7) in arm B at MTD | Grade 3/4 hematologic AEs included anemia (arm A, n = 2/22; arm B, n = 7/20) and thrombocytopenia (arm A, n = 5/22; arm B, n = 6/20) | ||
| Bone marrow fibrosis at 24 wk, 4 pts (n = 3 in arm A; 1 in arm B) and 19 pts (n = 9 in arm A; 10 in arm B) showed an improvement and stabilization, respectively; 2 pts in arm A (0 in arm B) experienced worsening of bone marrow fibrosis | 3 deaths reported at MTD in arm B; 2 deaths attributed to myeloid leukemia and 1 to multiorgan failure secondary to progressive MF | ||||
| Ruxolitinib and sonidegib (LDE225)72 | Intermediate-/high-risk MF spleen >5 cm not previously treated with a JAK inhibitor or HPI | 27 pts were treated at the RP2D | RP2D: sonidegib 400 mg once daily, ruxolitinib 20 mg twice daily | End of week 24, 12 pts (44.4%), ≥35% reduction in spleen volume | 5 pts discontinued treatment as a result of an AE, and 1 pt each as a result of pt decision and death (multiorgan failure unrelated to study treatment occurring 2 d after |
| 15 pts (55.6%) achieved a ≥35% reduction in spleen volume at any time on treatment | |||||
| ≥50% reduction in spleen length at any time achieved by 25 pts (92.6%), with 15 pts (55.6%) having a nonpalpable spleen | Overall, the most common AEs regardless of causality (all grade; grade 3/4) were anemia (52%; 33%) and muscle spasms (48%; 4%) | ||||
| The mean change in JAK2 V617F allele burden was −9.0% (range, −56.5% to 7.0%) from BL to the end of week 24 | AEs requiring dose adjustment or interruption in 17 pts (63%), most common being increased CK (19% [n = 5]) and myalgia (19% [n = 5]) | ||||
| BM fibrosis: 2 pts improved (grade 3 to grade 2), 8 pts remained stable, and 3 pts had a worsening from BL by the end of week 24 | |||||
| Ruxolitinib and panobinostat76 | Intermediate-1, Intermediate-2, or high-risk MF and spleen ≥5 cm by palpation; no prior JAKi | 61 pts (escalation phase, n = 38; expansion phase, n = 23) | RP2D: ruxolitinib 15 mg twice daily, panobinostat 25 mg three times a week | In expansion phase at week 24 (87%; 20/23) and at week 48 (74%; 17/23); 57% (13/23) and 39% (9/23) of pts achieved a ≥35% reduction from baseline in spleen volume | For 34 pts treated at the RP2D, 65% remained on treatment, and 21% discontinued because of AEs |
| BM fibrosis (n = 12 evaluable): 4 had improved fibrosis at wk 48, 6 had no change, and 2 worsened | Most common grade 3/4 hematologic AEs (at RP2D), regardless of causality: | ||||
| JAK2 V617F allele burden (n = 17 evaluable): 5 (29%) had a ≥20% reduction by wk 48 | Anemia (32%), thrombocytopenia (29%) | ||||
| Inflammatory markers (IL-18, MMP-9, and MPO) normalized | Grade 3/4 nonhematologic AEs included diarrhea (18%), asthenia (12%), and fatigue (9%). | ||||
| Three deaths (resulting from progression of underlying disease, myocardial infarction, and hypoxic cardiac arrest) attributed as unrelated | |||||
| Ruxolitinib and interferon COMBI trial70 | PV or MF evidence of active disease | 30 pts, PMF (n=10) OR PV (n=20) ± prior treatment with IFNa2 | Initial therapy was IFNa2 45 μg × 1 sc/week (Pegasys) or 35 μg × 1 sc/week (PegIntron) + ruxolitinib (Jakavi) 20 mg × 2/d | Overall, complete response was achieved as best response in 19 pts (63.3%), and partial response or major response in 8 pts (26.7%); only 3 pts (10%) had no response to treatment | 3 pts discontinued treatment because of an AE; one patient died of transformation to AML shortly after initiation of CT and was not included in this interim analysis |
| Palpable splenomegaly in 7 pts at baseline was significantly reduced by week 2; hct control without phlebotomy was achieved by week 4 in 78% of pts (7 of 9) who at baseline had an elevated hct, only 3 pts required a total of 3 phlebotomies after initiation of CT | Anemia (n = 15, 2 grade 3), granulocytopenia (n = 13, 2 grade 3), or thrombocytopenia (n = 6, 1 grade 3) | ||||
| JAK2V617F% declined significantly | Eleven severe AEs requiring hospitalization: pneumonia (n = 3); fever (n = 2); lipotymia, hematemesis, phlebitis, herpes zoster, angina pectoris, and arterial hypertension (n = 1 pt each) | ||||
| Ruxolitinib and danazol75 | Patients with MF with anemia | 14 patients (9 had prior JAKi) | Ruxolitinib, 10 mg twice-daily or 5 mg twice-daily in combination with tapered danazol up to 200 mg orally three times a day | 4/5 JAKi-naive pts had stable or increasing hgb levels | Nine pts discontinued: 2 progressive disease, 2 adverse event, 2 preference, 1 stem cell transplant, 1 unrelated death, 1 comorbidity. |
| 5/9 pts on prior JAKi, 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels. | Grade ≥3 anemia in 7, neutropenia in 2 leukopenia in 1 and thrombocytopenia in 2 pts | ||||
| Symptoms 4 had at least 50% improvement from baseline on MPN-SAF TSS | Grade ≥3 electrolyte abnormalities in 3, infection in 2, edema in 1, hypertension in 1, and intracranial hemorrhage in 1 pt | ||||
| Overall treatment response: stable disease in 10 pts, clinical improvement in 3, all of which were spleen responses, and progressive disease in 1 |
AE, adverse events; hbg, hemoglobin; hct, hematocrit; HPI, hedgehog pathway inhibitor; Int, intermediate; MPN-SAF TSS, myeloproliferative neoplasms symptom assessment form total symptom score; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose; plt, platelets; pt(s), patient(s); sc, subcutaneously.