Investigators Identify Starting Dose of Ruxolitinib in MF Patients with Thrombocytopenia


A phase Ib dose-finding study has established the maximum safe starting dose of ruxolitinib to be 10 mg twice daily in treating myelofibrosis in patients with low initial platelet counts.

Alessandro M. Vannucchi, MD

Alessandro M. Vannucchi, MD

A phase Ib dose-finding study has established the maximum safe starting dose (MSSD) of ruxolitinib (Jakafi) to be 10 mg twice daily in treating myelofibrosis (MF) in patients with low initial platelet counts.1

“The tolerability of ruxolitinib in this previously unstudied patient population with MF with low platelet counts at baseline was acceptable at doses of 10 mg BID in both strata,” the study authors, led by Alessandro M. Vannucchi, MD, of the University of Florence, Florence, Italy, wrote inHaematologica. “The findings to date from the 48-week follow-up analysis of EXPAND provide evidence to support a starting dose of ruxolitinib at 10 mg BID for patients with MF with low baseline platelet counts of 75 to 99×109/L (Stratum 1) but are less conclusive for baseline platelet counts of 50 to 74×109/L (Stratum 2).”

The open-label EXPAND study consisted of dose-escalation and safety-expansion phases. Key secondary objectives included safety and efficacy.

The authors previously published preliminary findings from the dose-escalation and safety-expansion phases of EXPAND at the preplanned interim analysis point of 24 weeks.2

Based on dose-limiting toxicities (DLTs) during the first treatment cycle, Vannucchi et al initially set the MSSD for stratum 1 patients at 15 mg BID. However, once they reviewed the safety and efficacy data from the interim analysis, they lowered the MSSD for stratum 1 to 10 mg BID. Stratum 2’s 10 mg MSSD remained unchanged.

EXPAND enrolled adult patients who had been diagnosed with intermediate-1, intermediate-2, or high-risk MF (primary MF, post—polycythemia vera MF, or post– essential thrombocythemia MF) and had a palpable spleen at 5 or more cm from the costal margin.

In addition to having an ECOG status of 0, 1, or 2, patients&rsquo; platelet counts must have been within the prespecified range of 75 to 99x109/L for stratum 1 or 50 to 74x109/L for stratum 2. A history of platelet dysfunction, platelet counts <45&times;109/L within 30 days prior to screening, or recent platelet transfusion were the key exclusion criteria.

At the time of week 48 data cutoff in December 2017, EXPAND&rsquo;s overall enrollment consisted of 69 patients, 44 in stratum 1 and 25 in stratum 2. Fourteen stratum 1 patients (31.8%) were still receiving ruxolitinib, while 3 stratum 2 patients (12.0%) were. That means that nearly one-quarter of patients (24.6%, 17 of 69) were still receiving treatment at data cutoff.

Stratrum 1 patients received a median exposure to ruxolitinib of 51.4 weeks (range, 0.9-210.0 weeks). Their stratum 2 counterparts had a median exposure of 67.4 weeks (range, 4.4-161.1 weeks).

The MSSD cohort was smaller, with 20 patients in stratum 1 and 18 patients in stratum 2. Among this cohort, 70.0% (14 of 20) of stratum 1 patients were still on ruxolitinib at data cutoff. In stratum 2, 16.7% (3 of 18) of patients were still on treatment.

Reasons for treatment discontinuation were varied. In stratrum 1, adverse events (AEs) and physician decision led to discontinuation for 1 patient each (5.0%), while disease progression accounted for 3 discontinuations each (15.0%). No patients in stratum 1 completed treatment or died.

In stratum 2, AEs led 4 patients (22%) to stop treatment, followed by treatment completion and physician decision for 3 patients each (16.7%). Disease progression caused 1 patient (5.6%) to discontinue, and 2 patients died (11.1%).

Among the MSSD cohort, median ruxolitinib exposure in stratum 1 was 54.8 weeks (range, 4.3-210.0 weeks). Median exposure for stratum 2 patients was 83.2 weeks (range, 4.4-161.1 weeks). As expected, dose reductions and interruptions were much more common in stratum 2 vs stratum 1, affecting 16 patients (88.9%) and 9 patients (45.0%), respectively.

As observed in the interim analysis, anemia and thrombocytopenia (all grades) were the most common hematologic AEs in both strata. In stratum 1, 9 patients (45%) had anemia, while 8 patients (40%) had thrombocytopenia. In stratum 2, 8 patients (44.4%) had anemia and 14 (77.8%) experienced thrombocytopenia.

In stratum 1, 14 of 20 patients (70%) experienced grade 3 or 4 AEs. These AEs led to treatment discontinuation in 3 stratum 1 patients (15%).

In stratum 2, nearly all patients suffered from grade 3 or 4 AEs (16 of 18; 88.9%). One-third of these patients (6 of 18; 33.3%) stopped treatment as a result, with thrombocytopenia cited as the main cause (n = 3, 16.7%).

Thrombocytopenia was the primary reason for dose adjustment/interruption in both strata (S1, n = 4 [20.0%]; S2, n = 12 [66.7%]). Notably, grade 4 thrombocytopenia (related to ruxolitinib) was the only DLT reported in both strata at 10 mg BID (1 patient in stratum 1; 2 patients in stratum 2). Nearly 40% of stratum 2 patients exhibited grade 4 worsening from the baseline platelet count (n = 7, 38.9%), while only 1 stratum 1 patient did (5.0%).

In stratum 1, one-third of patients displayed at least a 50% spleen length reduction at week 48 (n = 5, 33.3%; 95% CI: 11.8, 61.6), while 40% of patients displayed a spleen response at any time (n = 8; 95% CI: 19.1, 63.9). Spleen response at week 48 was achieved in 30% of stratum 2 patients (n = 3; 95% CI: 6.7, 65.2), while response at any time was seen in two-thirds of this group (n = 18, 66.7%; 95% CI: 41.0, 86.7).

Vannucchia et al noted that FDA approval for ruxolitinib for the treatment of MF in intermediate- and high-risk patients with normal platelet counts was based on the COMFORT studies.3-7&ldquo;Findings from a post hoc analysis of COMFORT-I showed that patients with cytopenias at baseline could be effectively managed with ruxolitinib dose adjustments and that doses of &ge;10 mg bid yielded clinically meaningful reductions in spleen volume and symptom improvement,&rdquo; they wrote. &ldquo;These findings support the use of ruxolitinib as a therapeutic option for patients with MF with low baseline platelet counts.&rdquo;

The EXPAND study is ongoing and further evaluations will be performed at the end of the study to confirm the safety and efficacy of ruxolitinib in the study cohorts, according to Vannucchia et al.


  1. Vannucchi AM, te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis.Haematologica. 2018;103:xxx doi:10.3324/haematol.2018.204602
  2. Vannucchi AM, Gisslinger H, Harrison CN, et al. EXPAND: A phase 1b, open-label, dose-finding study of ruxolitinib in patients with myelofibrosis (MF) and low platelet counts (50 &times; 109/L to 99 &times; 109/L) at baseline.Blood. 2015;126(23):2817.
  3. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.N Engl J Med. 2012;366(9):787-798. EXPAND: 48-week follow-up analysis
  4. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis.Leukemia. 2016;30(8):1701-1707.
  5. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebocontrolled, phase 3 COMFORT-I trial.J Hematol Oncol. 2017;10(1):55.
  6. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.N Engl J Med. 2012;366(9):799-807.
  7. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes.Onco Targets Ther. 2013;7:13-21.
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