Pharmacokinetics of ruxolitinib administrated before and after allo-HSCT in patients with myelofibrosis
Maria V. Barabanshikova1, Elena V. Morozova1, Ivan S. Moiseev1, Alena I. Shakirova1, Ildar M. Barkhatov1, Inna I. Ushal2, Gennadij G. Rodionov2, Sergey I. Moiseev2, Julia J. Vlasova1, Tatjana A. Rudakova1, Elena I. Darskaya1, Vadim V. Baykov1, Aleksander L. Alyanskiy1, Sergey N. Bondarenko1, Boris V. Afanasyev1
1 Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
Contact: Dr. Maria V. Barabanshikova
Janus kinase 1 and 2 (JAK1/2) inhibitor ruxolitinib reduces splenomegaly, constitutional symptoms, bone marrow fibrosis and confers survival benefit in some MF-patients and is effectively used for the treatment of acute and chronic graft-versus-host disease (GVHD). However, there is no prospective data on the administration of ruxolitinib as GVHD prophylaxis and relapse prevention.
Patients and methods
Between 2015 and 2018, 20 patients with primary myelofibrosis (PMF), post-essential thrombocythemia (post-ET-MF) and post-polycythemia myelofibrosis (post-PV-MF) were enrolled in the pilot prospective study (NCT02806375, clinicaltrials.gov) in Pavlov First Saint Petersburg State Medical University (Table 1). All the patients were treated with pretransplant ruxolitinib with median time 7.4 months (2.6-22.3) and continued to receive ruxolitinib 45 mg/day from day -7 until day -2. Reduced intensity conditioning was performed with fludarabine 180 mg/m2 and busulfan 10 mg/kg. GVHD prophylaxis included cyclophosphamide (PTCy) 50 mg/kg on days +3, +4 and ruxolitinib 15 mg/day starting day +5 to +100. Peripheral blood was collected from 20 patients at D0, D+3, D+7, D+21, D+30, D+60. A high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method was developed for the determination of ruxolitinib in human plasma in Research Laboratory of Toxicology and Drug Monitoring, The Nikiforov Russian Center of Emergency and Radiation Medicine, EMERCOM of Russia. Analyzes were performed using HPLC Agilent 1200 with triple quadrupole mass-spectrometer Agilent 6460 with ionization – electro spray system (Agilent technology, USA).
The median follow-up was 22 (3-41) months. Primary engraftment was documented in 17 patients. Median time to neutrophil engraftment, on day 27 (18-44); platelet engraftment, day 38 (15-219), RBC transfusion independence, by 59 (20-540) days. Two patients died before engraftment due to severe Pseudomonas aeruginosae sepsis (1) and gastrointestinal bleeding (1). One patient experienced poor graft function (PGF). One patient died at day+115 due to thrombotic microangiopathy and infectious complications after cyclosporine A and steroid therapy, due to acute GVHD grade 3. Fifty-five percent of the patients (11) experienced severe PGF (SPGF), as shown in Fig. 1. In two patients, SPGF resolved without changing ruxolitinib dose. Ruxolitinib dose reduction from 15 to 10 mg/day was performed in eight patients with SPGF. In one of them, SPGF resolved only at day+77, in one another – after ruxolitinib discontinuation at day+100. Three patients required СD34+ boost administration, 3 – donor lymphocyte infusion to treat SPGF.
Figure 1. Incidence of severe poor graft function was assessed after engraftment and was gradually resolved in all cases
Mild veno-occlusive disease (VOD) was observed in one patient. Sepsis was documented in 35% (7) of patients, invasive mycosis – in 1 patient. Forty five percent (9) experienced any type of the viral reactivation or infection (CMV reactivation – 6, HHV type 6 reactivation – 3, HHV type 1,2 – 2, BK – 1, parvovirus B19 – 1). Three patients experienced viral hemorrhagic cystitis. The incidence of acute GVHD grade II-IV was 25% (5), and severe GVHD grade III-IV – 15% (3). The overall rate of chronic GVHD was 40% (8), moderate – 20% (4), mild – 20% (4). All engrafted patients achieved full donor chimerism hematological, molecular remission, splenomegaly regression. Sixty five percent of patients achieved near complete bone marrow fibrosis resolution at day 398 (range 131-748). Molecular and hematological relapse was documented in 1 patient at day+665. Two-year NRM was 15% (95%CI 4-34%), 2-year OS – 85% (95%CI 60-93%), 2-year EFS – 72% (95%CI 45-87%) (Fig. 2).
Figure 2. Two-year overall and event-free survival among our patients treated with ruxolitinib
Analysis of Cthrough concentrations of ruxolitinib demonstrated accumulation of the drug from day +7 (median 17.7 ng/ml) to day +14 (median 43.8 ng/ml, p=0.028) and subsequent stable concentrations (Fig. 3). Therefore, dose reduction from 15 to 10 mg/day might be reasonable after D+20 due to achievement of stable concentration. The anticipated adverse effect of ruxolitinib upon donor stem cells was eliminated by interruption of the drug intake from day -1 to +4. Thereby, ruxolitinib value was not detected at day 0 in all samples.
Figure 3. Time dynamics of ruxolitinib concentration in the patients under study
Replacement of calcineurin inhibitors and mycophenolate mofetil by ruxolitinib as an additional component of PTCy-based prophylaxis resulted in low toxicity, good acute and chronic GVHD control and low relapse incidence. However, relatively high rate of SPGF should be taken in to account, which possibly might be mitigated by ruxolitinib dose reduction.
Myelofibrosis, ruxolitinib, allogeneic hematopoietic stem cell transplantation.
Table 1. Characteristics of the patients