Myelofibrosis (MF) is a bone marrow malignancy associated with debilitating symptoms, splenic enlargement, and reduced numbers of mature blood cells. Overactivity of the JAK/STAT signaling pathway is a hallmark of the disease, and the JAK1/2 inhibitor ruxolitinib is currently the only FDA-approved therapy for MF. However, many patients with MF receiving ruxolitinib therapy do not achieve complete remission and experience disease progression, and patients who discontinue ruxolitinib therapy have a poor prognosis, with a median survival of just 14 months.1
The oral tyrosine kinase inhibitor pacritinib (PAC), with specificity against JAK2, FLT3, and IRAK1, has recently been investigated for the treatment of MF. In 2 multicenter, randomized, phase 3 clinical trials (PERSIST-1 and PERSIST-2) in advanced MF, PAC showed clinical activity in MF. However, in February 2016, due to concerns about cardiotoxicity and hemorrhage, the FDA placed a clinical hold order on studies involving PAC after reports of patient deaths.
Nevertheless, shortly after placing the order, the FDA allowed patients who were receiving benefit from PAC when the hold was imposed to resume treatment under a single-patient compassionate-use program. In their study, Mascarenhas and colleagues performed a sponsor-independent evaluation of the outcomes of the patients who received PAC on compassionate use.1
The compassionate-use protocol included 33 patients who were approved on an individual basis because they had previously experienced benefit from PAC treatment during the clinical trial. At baseline and every 3 months during PAC treatment, physicians monitored patients for hematologic and cardiac treatment-emergent adverse events (AEs) by performing tests such as a complete blood count, coagulation profile, electrocardiogram, and echocardiogram.1
Of the 33 patients receiving PAC on the compassionate-use program, treating physicians provided complete data for 19 who were followed for a median of 8 months, with a median duration of PAC treatment of 8 months. Before the clinical hold was imposed, these patients had received PAC therapy on the PERSIST clinical trial program for a median of 8.5 months.1 Patients experienced a median PAC treatment interruption of 4 months between the clinical hold order and restarting treatment on compassionate use.1
According to the investigators, PAC retreatment was effective in reducing spleen volume. Mean palpable spleen length was significantly decreased (P = .0009) at months 3 (11.3 cm) and 6 (12.1 cm) compared with baseline (14.3 cm). 1
With regard to safety, from baseline to month 6, the investigators found no significant changes in hematologic parameters in 15 patients. Just 3 patients reported a single grade 3 AE (1 each of epistaxis, QT prolongation, and bradycardia) while receiving PAC, and no patients reported significant treatment-emergent echocardiographic changes. One patient died due to catheter-related sepsis.1
For the 33 patients included in the compassionate-care program, the median duration of PAC treatment was about 1 year, the investigators reported; 42% of patients remained on treatment for more than 18 months.1
In this study, patients received approximately 20 months of cumulative PAC therapy during a combination of the clinical trial program and the compassionate-care protocol. The investigators noted that this amount of time was more favorable for patients with MF than the expected median survival time of 14 months after discontinuing ruxolitinib treatment.
PAC treatment resulted in improvement in patients’ spleen size but no significant changes in hematologic profiles. Overall, PAC was well tolerated, and significant bleeding events were uncommon.1
The authors acknowledged the limitations of this study, including its short follow-up and lack of objective radiographic evaluation of change in spleen volume. Nevertheless, they concluded that PAC offers some benefit by fulfilling an unmet need in the current treatment landscape for some patients with MF.1
Mascarenhas J, Virtgaym E, Stal M, et al. Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study. Ann Hematol. 2018;97(8):1369-1374. doi: 10.1007/s00277-018-3309-6.