In analyses reported at the 2019 Society of Hematologic Oncology (SOHO) Annual Meeting and published in Clinical Lymphoma, Myeloma & Leukemia, Harrison et al identified response rates to the JAK2 inhibitor fedratinib among patients with myeloproliferative neoplasm–associated intermediate- or high-risk myelofibrosis who had low baseline platelet counts in the phase III JAKARTA and phase II JAKARTA2 trials and presented an updated analysis of the JAKARTA2 study in patients resistant to or intolerant of ruxolitinib (Abstracts MPN-352 and MPN-353).
The JAKARTA trial supported the recent approval of fedratinib in adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. The recommended starting dose is 400 mg daily in patients with platelet counts of at least 50 x 109/L. In the double-blind trial, 290 patients were randomly assigned to receive first-line fedratinib at 500 mg (n = 97) or 400 mg (n = 96) or placebo (n = 96) once daily for at least six 28-day cycles. The single-arm JAKARTA2 trial evaluated fedratinib at 400 mg once daily in 97 patients resistant to or intolerant of ruxolitinib.
Responses in Patients With Low Baseline Platelet Counts
The analysis of outcomes in patients with low baseline platelet counts included 96 patients from the JAKARTA trial and 97 patients from the JAKARTA2 study who received fedratinib at the recommended dose of 400 mg/d in at least six 4-week cycles. A low baseline platelet count was defined as 50 to 100 x109/L. The primary endpoint was spleen volume response rate, with response defined as at least 35% reduction in spleen volume from baseline to the end of cycle 6. Symptom response was defined as at least 50% reduction from baseline total symptom score on the modified myelofibrosis symptom assessment form at the end of cycle 6.
In JAKARTA, 14 of 96 patients (15%) had a low platelet count at baseline. Among these patients, the spleen volume response rate was 36%. Among the 82 patients with platelet counts of at least 100 x 109/L, the spleen volume response rate was 49%. The symptom response rate was 31% among patients with low platelet counts and 42% among those with higher platelet counts.
In JAKARTA2, the median prior ruxolitinib treatment duration among all patients was 10.7 months. In total, 33 of 97 patients (34%) had baseline platelet counts of 50 to 100 x 109/L. The spleen volume response rate was 36% in these patients, compared with 28% among the 64 patients with higher platelet counts. Symptom response rates were 39% and 20%, respectively.
“Patients with myelofibrosis who presented with low baseline platelet counts achieved spleen responses and reduced symptom burden with fedratinib, whether used as first-line or salvage therapy after ruxolitinib failure.”— Harrison et al
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As stated by the investigators, adverse events were generally similar between platelet count groups in both studies. However, a higher incidence of grade 3 or 4 hematologic adverse events was observed among patients in the lower baseline platelet count groups.
The investigators concluded: “Patients with myelofibrosis who presented with low baseline platelet counts achieved spleen responses and reduced symptom burden with fedratinib, whether used as first-line or salvage therapy after ruxolitinib failure.”
Updated Analysis of JAKARTA2
Outcomes of the JAKARTA2 study in patients with myelofibrosis resistant to or intolerant of ruxolitinib therapy were initially reported using a last-observation-carried-forward method in the per-protocol population. The current analysis evaluated outcomes in the intention-to-treat population and in a cohort of patients (cohort 1) who met stringent definitions for ruxolitinib relapsed or refractory disease or ruxolitinib intolerance.
Stringent criteria for ruxolitinib relapsed or refractory disease required that patients had received at least 3 months of prior ruxolitinib with an initial response followed by spleen regrowth or a suboptimal response; ruxolitinib intolerance required at least 28 days of ruxolitinib with development of a red blood cell transfusion requirement or grade ≥ 3 cytopenias. The primary endpoint was spleen volume response rate (≥ 35% spleen volume reduction from baseline to the end of cycle 6). Patients without data from the end of cycle 6 were considered nonresponders.
In the intention-to-treat population, 64 of 97 patients (66%) were resistant to ruxolitinib and 32 (33%) were intolerant of ruxolitinib. The median prior ruxolitinib exposure was 11.7 months in ruxolitinib-resistant patients and 7.0 months in ruxolitinib-intolerant patients. The spleen volume response rates at the end of cycle 6 were 31% among all patients, 33% in ruxolitinib-resistant patients, and 28% in ruxolitinib-intolerant patients.
“Approximately one-third of JAKARTA2 ruxolitinib resistant or intolerant patients had spleen volume responses during fedratinib therapy, regardless of prior ruxolitinib outcomes.”— Harrison et al
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Cohort 1 included 79 patients (81%) who met stringent definitions of relapsed disease (n = 18, 23%), refractory disease (n = 47, 59%), or intolerance (n = 14, 18%); these groups had median ruxolitinib exposure of 11.8, 11.4, and 8.7 months, respectively. The spleen volume response rate at the end of cycle 6 was 30% among all cohort 1 patients, with rates of 28%, 32%, and 29% in the relapsed, refractory, and intolerant groups. The investigators stated that adverse events were generally similar among the ruxolitinib relapsed, refractory, and intolerant groups.
The investigators concluded: “Approximately one-third of JAKARTA2 ruxolitinib resistant or intolerant patients had spleen volume responses during fedratinib therapy, regardless of prior ruxolitinib outcomes.”
DISCLOSURE: For full disclosures of the study authors, visit clinical-lymphoma-myeloma-leukemia.com.