ALBERT

Description: BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable reductions in splenomegaly and MF-related symptoms and improved survival compared with placebo and best available therapy in the 2 large phase 3 COMFORT studies. Those studies required baseline platelet (PLT) counts ≥ 100 × 109/L, limiting safety and efficacy data in patients (pts) with lower PLTs; however, thrombocytopenia is frequent in MF. Ongoing phase 2 clinical trials in pts with low PLTs have shown ruxolitinib to be generally well tolerated and to provide efficacy benefits for these pts. To gather additional safety and efficacy data in pts with low PLTs, recruitment for JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients), a phase 3b expanded-access trial for countries with no access to ruxolitinib outside a clinical trial, was extended to pts with baseline PLT counts ≥ 50 × 109/L. Here, we present safety and efficacy data from a planned interim analysis of ruxolitinib in pts with baseline PLT count ≥ 50 to 〈 100 × 109/L. METHODS: Eligible pts had high-, intermediate-2, or intermediate-1-risk MF, with a palpable spleen (≥ 5 cm from the costal margin) and baseline PLT counts ≥ 50 × 109/L. The starting doses of ruxolitinib was 5 mg bid for pts with baseline PLTs ≥ 50 to 〈 100 × 109/L. The primary endpoint was assessment of safety and tolerability of ruxolitinib based on the frequency, duration, and severity of adverse events (AEs). An interim analysis of the safety and efficacy of ruxolitinib in pts with PLTs ≥ 50 to 〈 100 × 109/L at baseline (low-PLT group) was planned for when the first 50 low-PLT pts had completed 6 mo of therapy; this analysis includes results from the first 6 mo of treatment. The final analysis will be performed after all pts have completed 24 mo of treatment or ended treatment due to commercial availability. RESULTS: At data cutoff (01 January 2014), 50 pts with low PLTs had been treated for 6 mo and are included in this analysis. Pt characteristics were median age, 68.5 years; median palpable spleen length, 15.5 cm below the costal margin; and female, 50.0%. Median (range) baseline hemoglobin (Hb) was 98 g/L (57-149 g/L) and PLT count was 87 × 109/L (68 to 98 × 109/L). Most pts (76.0%) remained on or completed treatment as per protocol at the time of data cutoff. The primary reasons for discontinuation included adverse events (AEs; n = 9) and disease progression (n = 2). The median daily dose was 11.8 mg/day (range, 5.9-40.0 mg/day). Of evaluable pts at week 24, 38.2% (13/34 pts) achieved a ≥ 50% reduction from baseline in palpable spleen length; 38.2% had reductions of ≥ 25% to 〈 50%. Overall, 44.7% of pts achieved a ≥ 50% reduction from baseline in spleen length at any time. Clinically meaningful improvements in symptoms, as assessed using the FACT-Lymphoma Total Score (the range for the minimally important difference is 6.5 to 11.2 points), were seen as early as week 4 (mean change from baseline, 8.2) and were durable through week 12 (9.6). The most common hematologic grade ≥ 3 AEs were anemia (28.0%) and thrombocytopenia (30%; 4% grade 4); 3 pts discontinued due to thrombocytopenia and 1 due to anemia. Four pts had grade 1/2 hemorrhages (1 conjunctival, 1 gastric, and 2 epistaxis) and 2 pts had grade 3/4 (1 intestinal and 1 esophageal varices). PLT counts decreased slightly from baseline (mean change at nadir, −5.9 × 109/L); 3 pts required PLT transfusions. The mean change from baseline to nadir in Hb was −13.4 g/L. Rates of nonhematologic grade ≥ 3 AEs were low overall (1 pt each), with the exception of pyrexia (6.0%), septic shock (4.0%), and arthralgia (4.0%); 44.0% of pts had ≥ 1 dose modification and 28.0% had ≥ 1 dose interruption. CONCLUSIONS: In this cohort of pts with low PLTs, ruxolitinib demonstrated an AE profile consistent with that previously reported in pts with normal PLTs. As compared to a previous analysis of pts with median baseline PLT counts of 248 × 109/L from this same study (Al-Ali et al. EHA 2014), pts in this low-PLT cohort experienced similar improvements in symptoms (mean change from baseline at week 12, 9.6 vs 11.8) but lower achievement of a ≥ 50% reduction from baseline in spleen length within the first 24 weeks of treatment (44.7% vs 69%), likely due to the lower median daily dose (11.8 mg/day vs 36.8 and 24.0 mg/day for pts with starting doses of 20 and 15 mg bid, respectively). Taken together, these data suggest that low-dose ruxolitinib is generally safe and efficacious in pts with PLTs ≥ 50 to 〈 100 × 109/L. Disclosures Griesshammer: Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Shire: Honoraria; Amgen: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. le Coutre:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Foltz:Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy. Bouard:Novartis: Employment. Perez Ronco:Novartis: Employment. Ghosh:Novartis: Employment.

Description: BACKGROUND: Ruxolitinib is a potent JAK1/JAK2 inhibitor that has proved superior to placebo and best available therapy in the phase 3 COMFORT studies for patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF). Ruxolitinib-treated pts demonstrated improvements in splenomegaly and MF-related symptoms as well as improved overall survival. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of ruxolitinib in pts with MF and includes those with no access to ruxolitinib outside of a clinical trial. Here, we report updated safety and efficacy findings for the full enrollment of JUMP, which includes 2233 pts in 26 countries. METHODS: Eligible pts had Int-2- or high-risk MF, with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of ruxolitinib based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to 〈 100 × 109/L], 15 mg bid [100 to 200 × 109/L], 20 mg bid [〉 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores. The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 2233 pts (primary MF, 59.4% [n = 1326]) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2016). At baseline, median age was 67 y (range, 18-89 y); 54.5% were male; median palpable spleen length was 12 cm below the costal margin; median time since diagnosis was 25.8 months. Median hemoglobin (Hb) was 106 g/L, and 38.3% of pts had Hb levels ˂ 100 g/L; median platelet count was 254 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.9 and 33.4, respectively. At data cutoff, 15.8% of pts (353/2233) remained on treatment and 45.1% (1006/2233) completed treatment per protocol (ie, transitioned to commercial ruxolitinib). The primary reasons for treatment discontinuation were adverse events (AEs; 17.7%), disease progression (8.6%), and death (4.1%). Median exposure was 12.4 months; the median average daily dose of ruxolitinib was 23.1 mg for pts starting at 15 mg bid (n = 647 [29.0%]) and 36.5 mg for pts starting at 20 mg bid (n = 1384 [61.9%]). Overall 66.7% of pts had dose modifications and 26.3% had a dose interruption. Grade (G) 3/4 hematologic AEs included anemia (34.1%), thrombocytopenia (16.3%), and neutropenia (4.5%), which led to discontinuation in 1.5%, 2.7%, and 0.1% of pts, respectively. Nonhematologic AEs were primarily G1/2, and the most common (≥ 10%) were pyrexia (15.6%; G3/4, 2.3%), asthenia (14.9%; G3/4, 2.2%), and diarrhea (12.0%; G3/4, 1.1%). Rates of other G3/4 AEs were low (≤ 2%), except pneumonia (4.3%), which led to discontinuation in 10 pts (0.5%). Rates of infections were generally low; all-grade infections in ≥ 5% of pts included pneumonia (6.8%), urinary tract infection (5.6%), and nasopharyngitis (5.0%). Herpes zoster was reported in 4.6% of pts (G3/4, 0.5%), tuberculosis in 0.2% (G3/4, 0.04%) and hepatitis B in 1 pt (G3/4, 0.04%). At wk 24 and 48, 56.6% (874/1545) and 61.6% (658/1069) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 23.3% (360/1545) and 18.9% (202/1069) had 25% to 50% reductions, respectively. Most pts (70.2% [1441/2054]) experienced a ≥ 50% reduction at any time; 23.7% had complete resolution of splenomegaly (Figure). At wk 24 and 48, 97.1% (67/69) and 92.3% (48/52) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (42.4% [596/1406]; 46.6% [675/1447]) and wk 48 (42.9% [404/941]; 45.4% [434/957]). Overall, 221 patients received ESAs to manage anemia (G1, 7.2%; G2, 49.8%; G3, 38.9%; G4, 4.1%), and the majority had improved (32.6%) or resolved (31.7%) anemia (worsened, 16.3%; no change, 19.5%). CONCLUSIONS: This study includes the largest cohort of pts with MF treated with ruxolitinib to date. Consistent with findings from other studies, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the COMFORT studies. Disclosures Foltz: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Le Coutre:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel, accomodations, expenses; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: travel, accomocations, expenses, Research Funding. Vannucchi:Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Bouard:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Khanna:Novartis Healthcare Pvt. Ltd: Employment. Zaritskey:Janssen: Consultancy; Novartis: Consultancy.

Description: Background: The ENESTop study (NCT01698905) evaluates treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with sustained deep molecular response following second-line (2L) treatment with nilotinib (NIL). In the primary analysis, 57.9% of pts remained in TFR 48 weeks after stopping NIL and previous analysis at ≥3.7 years showed durability of TFR. The present analysis first assessed long-term TFR outcomes at ≥5 years and then a post-hoc analysis evaluated rates of regain of molecular response following NIL re-initiation in pts with loss of major molecular response (MMR) or confirmed loss of MR4.0 at a follow-up of 5 years. Methods: Eligible pts had received ≥3 years of treatment (including 〉4 weeks of imatinib followed by ≥2 years of NIL) and had achieved MR4.5 (BCR-ABL1IS ≤0.0032%) on NIL. Pts without confirmed loss of MR4.5 after 1 year of consolidation treatment (CONS) could attempt TFR. NIL was re-initiated upon loss of MMR (BCR-ABL1IS 〉0.1%) or confirmed loss of MR4.0 (BCR-ABL1IS 〉0.01% in 2 consecutive assessments). By data cut-off (29 Jan 2020) pts had completed ≥5 years of TFR, resumed NIL, or discontinued the study. Results: At the data cut-off, of the 126 pts who entered TFR, 52 remained in TFR, 59 had resumed NIL and 15 had discontinued the study. At 5 years, the TFR rate was 42.9% (54/126; 95% CI, 34.1-52.0). Compared with pts in TFR at the end of the 3.7-year follow-up, an additional 4 pts were not in TFR at the 5-year follow-up, none due to loss of response: 2 pts discontinued TFR due to pt/guardian decision, 1 pt had an ischemic stroke and died in the post-treatment follow-up phase, and 1 pt was lost to follow-up. The MR4.5 rate at 5 years after starting TFR was 37.3% (47/126, 95% CI: 28.9-46.4). 11 pts with MR4.5 at 5 years had a temporary loss of MR4.5 while 36/126 (28.6%) maintained stable MR4.5 for 5 years. The estimated treatment-free survival (TFS) rate at 5 years was 49.4% (95% CI: 40.3-57.9). Of the 59 pts who resumed NIL, 58 (98.3%) regained MMR. The only pt who did not regain MMR stopped retreatment at 20 weeks and withdrew from the study. 56 (94.9%) pts regained MR4.0 and 55 (93.2%) regained MR4.5 (Figure). The median time to regain MR4.5 was 2.9 months (range: 0.9-22.5). Baseline characteristics between pts who resumed NIL due to loss of MMR (n=34) or confirmed loss of MR4.0 (n=25)were similar; more pts with loss of MMR had a low Sokal relative risk score at diagnosis (44.1% vs 16.0%) and pts with loss of MMR had a shorter median time from achievement of MR4.5 until TFR entry (27.9 vs 40.1 months). In pts with confirmed loss of MR4.0, 25/25 (100.0%) and 24/25 (96.0%) regained MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. In pts with loss of MMR, 33/34 (97.1%), 31/34 (91.2%) and 30/34 (88.2%) regained MMR, MR4.0 and MR4.5 within the first 48 weeks of NIL re-initiation, respectively. The median time to regain MR4.5 for pts who resumed NIL due to confirmed loss of MR4.0 or loss of MMR was 2.0 months (range: 0.9-4.6) and 3.6 months (range: 1.6-22.5), respectively. There were no cases of disease progression or death due to underlying CML. For pts remaining in TFR 〉3.7 years (n=58), the rates of all-grade adverse events (AEs) were 50.0% in the fifth 48 weeks of TFR compared with 55.2% in the fourth 48 weeks. The musculoskeletal pain AE rate was high during the first 48 weeks of TFR (53.4%) but by the fifth 48 weeks of TFR was lower (6.9%) than during CONS (10.3%). In pts who resumed NIL (n=59), the rate of all-grade AEs was higher (94.9%) than during CONS (77.9%, n=163). Overall all-grade AE rates were similar between pts re-initiating NIL due to loss of MMR (94.1%) or confirmed loss of MR4.0 (96.0%), with the most common AEs being hypertension (26.5% vs 32.0%), arthralgia (20.6% vs 8.0%), constipation (11.8% vs 20.0%) and hyperglycemia (26.5% vs 0%). Conclusions: These results illustrate the long-term (up to 5 years) durability and safety of TFR in pts with CML-CP following 2L NIL. The majority of pts requiring NIL re-treatment rapidly regained MMR, MR4.0 or MR4.5. The faster rate of regain in pts resuming NIL due to confirmed loss of MR4.0 likely reflects earlier intervention but could also suggest a slower tempo of relapse and possibly more favorable biology. Subgroup analysis should be interpreted with caution due to small base sizes. No new or unexpected safety signals were observed. Disclosures Mahon: ARIAD: Honoraria; Novartis Pharma: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Honoraria. Clementino:EMS: Other: Financial support for congress. Fominykh:Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Pfizer Japan Inc.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kim:Sun Pharma.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Current Employment, Current equity holder in publicly-traded company, Research Funding. Tiwari:Novartis: Current Employment. Bouard:Novartis: Current Employment. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.