Introduction
Myelofibrosis (MF) is a debilitating myeloproliferative neoplasm that can appear
de novo (primary MF, PMF) or follow polycythemia vera (PV) or essential thrombocythemia (ET) [
1]. Although the most predominant feature of MF is massive splenomegaly, which presents in 89% of patients with PMF, the clinical presentation of MF is also characterized by progressive anemia, leukopenia or leukocytosis, thrombocytopenia, profound remodeling of bone marrow architecture with fibrosis, and multi-organ extramedullary hematopoiesis [
2]. Patients may experience severe constitutional symptoms, sequelae of massive splenomegaly (hepatic obstruction and splenic infarction), dyspnea, pain, limitations of movement, early satiety, hypermetabolic state with cachexia, ineffective hematopoiesis and hematopoietic failure, risk of vascular events (including thrombosis and hemorrhage), progression to leukemia, infections, and premature death [
3]. As a result of these complications, patients with MF have a substantially reduced quality of life (QoL) and life span (median survival, 5 years) [
2].
The discovery of the V617F mutation of the Janus kinase 2 (JAK2) gene in 60% of patients with PMF or post-ET MF and 95% of those with post-PV MF was an important step in the understanding of the pathogenesis of MF [
3–
5]. Dysregulation of the JAK/STAT signaling pathway is a characteristic feature of MF. JAK2 overactivation is widely recognized to contribute to MF pathogenesis and leads to the clinical development of JAK inhibitors, including ruxolitinib [
6]. In two phase III pivotal studies (COMFORT-I and COMFORT-II), ruxolitinib, a potent and selective JAK1/JAK2 inhibitor, led to 28.5% and 41.9% of MF patients achieving≥35% reduction from baseline spleen volume at 48 weeks in COMFORT-II and 24 weeks in COMFORT-I, respectively, but this result was not achieved in patients in placebo arm at either time point. In addition, spleen responses were durable with 80% of patients maintaining response at a median of 12 months of follow-up, which was significantly better than placebo and BAT (best available therapy) group. Furthermore, ruxolitinib treatment was associated with significant relief from disease-related symptoms, improvement in role function and QoL measures compared with BAT; the toxic effects were acceptable [
7,
8]. Notably, long-term ruxolitinib treatment (median, 151 weeks) was associated with significant survival compared with placebo (HR, 0.48; 95% CI, 0.25–0.85;
P = 0.009) [
9] or placebo/best available therapy (HR, 0.65; 95% CI, 0.46–0.90;
P = 0.01) [
10]. Based on the results of these studies, ruxolitinib was approved by the US Food and Drug Administration in November 2011 as the first therapeutic medicine for the treatment of intermediate or high-risk MF [
11].
Despite the well-established favorable clinical benefit–risk ratio of ruxolitinib in patients with MF, its efficacy and safety in Chinese patients have never been studied. Thus, we performed this study in the Chinese population as part of an ongoing multi-national phase II study in Asia (A2202) to evaluate the efficacy and safety of ruxolitinib in patients with intermediate-2 or high-risk PMF, post-PV MF (PPV–MF), or post-ET MF (PET–MF).
Methods
Eligibility criteria
Male or female individuals 18 years of age or older diagnosed with PMF, as defined by World Health Organization, or PPV-MF or PET-MF, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG–MRT) were considered eligible for enrollment. A written informed consent was obtained from each patient before enrollment. The enrolled patients were required to have a palpable spleen measuring 5 cm or greater below the costal margin and have two or more risk factors, as defined by IWG–MRT (age>65 years, constitutional symptom burden, hemoglobin<10 g/dl, white blood cell>25 × 10
9/L, and circulating blasts≥1%) [
12]. Patients who had received prior therapy for MF were included, but those with prior JAK inhibitor treatment were excluded. Patients who were receiving therapy for MF had to discontinue all drugs used to treat MF at least 28 days prior to baseline. The study was conducted according to the ethical principles of the
Declaration of Helsinki.
Study design
This work was part of a multi-center study conducted in Asian countries including China. Ruxolitinib was administered orally using specified dosing schedules. Starting doses of 15 mg and 20 mg bid were selected on the basis of baseline platelet counts. A standardized dosing paradigm was used to determine dose adjustments for safety and efficacy, so that each patient was titrated to their most appropriate dose. Dose increases were permitted at week 4 for patients who demonstrated reduced efficacy as determined by<40% reduction from baseline spleen length. These patients were required to have a platelet count of at least 150 × 109/L and an absolute neutrophil count (ANC) of at least 1 × 109/L at every post-baseline assessment. The study protocol included mandatory dose decreases or interruptions for safety. Dosing was decreased when platelet counts decreased to<100 × 109/L and held when platelet counts decreased to<50 × 109/L, or when ANC decreased to≤0.5 × 109/L while receiving treatment.
Efficacy analyses
Primary efficacy endpoint was defined as the proportion of patients achieving≥35% reduction from baseline in spleen volume at week 24 as assessed by MRI/CT. Symptoms and patient-reported outcomes were assessed using the seven-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score and European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ–C30). Other secondary endpoints included best response rate and duration of spleen response. Best response rate was defined as the percentage of patients who achieved≥35% reduction in spleen volume from baseline at any time during treatment. Loss of response was defined as death,≥25% increase in spleen volume from baseline, splenic irradiation, leukemic transformation (defined as blood blast≥20%), or splenectomy. Transfusion dependency was assessed as exploratory analysis to determine additional efficacy endpoints, such as improvement in peripheral blood.
Safety
We collected all adverse events (AEs) and serious adverse events (SAEs) together with their degree and relationship with the study drug to assess the safety profile of the drug. These examinations included regular monitoring of hematology, blood chemistry, coagulation, and urinalysis results, and regular assessments of vital signs, standard 12-lead ECG monitoring, physical examinations, and body weight.
Results
Patient characteristics
A total of 63 Chinese patients who were enrolled in the study were evaluated for final analysis (cut-off date October 29, 2012). Most of the patients (n = 53, 84.1%) continued to receive treatment, and 10 patients (15.9%) discontinued from the study. The majority of patients were diagnosed with PMF (n = 49, 77.8%), followed by PET–MF (n = 9, 14.3%) and PPV–MF (n = 5, 7.9%). A total of 28 patients (44.4%) had prior history of treatment with hydroxyurea. At baseline, 34 patients (54.0%) had a hemoglobin value<10 g/dl, and 11.1% of all patients were previously transfused. The median baseline hemoglobin value was 9.90 g/dl. Almost all patients had an ECOG PS of 0 (54.0%) or 1 (41.3%). The detailed demographic data are shown in Table 1.
All 63 patients received at least one dose of ruxolitinib. In total, 45 patients (71.4%) were exposed to ruxolitinib treatment for a period of≥6 months. The median duration of exposure (including periods of dose interruptions) was 7.39 months. The median dose intensity was 23.42 mg/d for the 15 mg bid group (n = 25) and 37.82 mg/d for the 20 mg bid group (n = 38). The median relative dose intensity was 78.08% for the 15 mg bid group and 94.54% for the 20 mg bid group.
Efficacy
Overall, 27.0% of all patients (95% CI, 16.0%‒37.9%) met the primary endpoint by achieving≥35% reduction in spleen volume from baseline at week 24 (Fig. 1). The median percent reduction from baseline in spleen volume at week 24 was 25.11% (Table 2). The best response rate was 34.9% (95% CI, 23.1%‒46.7%); most of the patients experienced a decrease in spleen volume (median −29.3%), and only 3 (5.3%) out of 57 patients who had an evaluable post-baseline imaging assessment exhibited an increase in spleen volume as their greatest percentage change from baseline. The median duration of response was not estimated for 22 responders in whom no events were observed.
Kaplan–Meier estimates for time to first reduction (of at least 35%) in spleen volume among responders are shown in Fig. 2. The median time to first event of≥35% spleen volume reduction was 12.36 weeks (95% CI, 12.14‒23.29), which was equal to the time in the first assessment, thus suggesting rapid spleen volume reduction.
The median change (%) from baseline in total symptom score as assessed by seven-day modified MFSAF v2.0 at week 24 was −6.0 (−4.55%). More than half of the patients achieved≥50% improvement in total symptom score from baseline at week 24 (52.9%). The baseline score for Global Health Status/QoL (58.2 out of 100) was the lowest among the EORTC QLQ-C30 functional/QoL scales, thus indicating a reduced QoL and level of functioning prior to study entry. At week 24, the mean change from baseline in the Global Health Status/QoL scale was 7.7, which indicates moderate improvement. Patients reported high baseline individual symptom scores for fatigue (32.1), insomnia (18.0), appetite loss (16.4), pain (16.1), and dyspnea (14.8); the mean change in standardized score from baseline at week 24 was −1.0, 0, −5.7, −1.9, and 4.4, respectively (reduction of symptoms is demonstrated by a negative change in score). As a 10-point difference is equivalent to 10% of the scale (0–100) and considered clinically meaningful, the mean change in EORTC QLQ-C30 of 7.7 did not qualify as apparent and clinically meaningful, but a trend toward improvement was observed. For most of the patients, the ECOG PS remained the same or slightly worsened compared with baseline.
Transfusion dependency was assessed for exploratory analysis. Patients in the study received pRBC transfusions only. Fifteen patients (23.8%) received pRBC transfusions during the first 12 weeks; at week 12 to week 24, 19% of patients received pRBC. The mean number of units of pRBC transfused per month was 0.16 at baseline and increased to 0.26 after treatment with ruxolitinib. However, after week 24, less than 10% patients needed pRBC transfusion. For the remaining duration of the study, the number of patients who received pRBC transfusions was below baseline (11.1%).
Safety
Fifty-nine patients (93.7%) experienced at least one AE during the study. Grade 3 or 4 AEs (52.4%) and AEs requiring dose reduction or interruption (60.3%) were frequently observed. The most common AEs reported in the study were anemia (50.8%), decreased platelet count (34.9%), and thrombocytopenia (22.2%). The most common (n≥5%) grade 3 or 4 AEs were anemia (33.3%), decreased platelet count (7.9%), and lung infection (6.3%). The most frequent AEs suspected to be related to the study drug at a frequency≥20% were anemia (47.6%), decreased platelet count (33.3%), and thrombocytopenia (22.2%). Details of the frequent AEs are shown in Table 3. Overall, 9 patients (14.3%) experienced at least one SAE. SAEs reported in≥2 patients included lung infection (3 patients) and pyrexia (2 patients), whereas all the other SAEs occurred in a single patient. Three patients (4.8%) died during the study (while receiving study treatment or within 30 days of last dose) due to infection, lung infection, or cardiopulmonary failure during the study; one additional patient died 48 days after the last dose of the study drug. None of these deaths were considered by the investigator as related to the study drug. Two patients underwent leukemic transformation.
AEs leading to discontinuation of the study treatment were infrequently reported (6 patients, 9.5%). The most common AEs that necessitated a ruxolitinib dose interruption or reduction were decreased platelet count (31.7%) and thrombocytopenia (22.2%).
New or worsened hematological abnormalities were frequently observed in the study. The most common grade 3/4 hematological abnormalities were decreased hemoglobin (47.1%), absolute decreased lymphocytes (13.1%), and decreased platelets count (9.8%). New or worsened biochemistry abnormalities were infrequent in the study.
Discussion
Although COMFORT studies have established the role of ruxolitinib in the treatment of MF, the clinical status of this new drug is still not clear in the Chinese population in consideration of the fact that Chinese patients may present a slight difference in response compared with western patients. Although generally similar to the patients in the COMFORT studies, Chinese patients in this study had a smaller median spleen volume (2236 cm
3 vs. 2598 cm
3 and 2408 cm
3 in COMFORT-I and-II, respectively) and lower median hemoglobin level at baseline (9.90 g/dl vs. 10.5 g/dl and 10.6 g/dl), and a larger proportion of Chinese patients had PMF (77.8% vs. 45% and 53%) [9,
13–
15]. As part of a multinational, open-label phase II study INC424A2202, which was designed to evaluate the efficacy and safety of treatment in Asian adult patients with MF, this study may be representative of the population of patients with PMF, PPV-MF, and PET-MF in China.
Our study showed a similar efficacy of ruxolitinib in Chinese patients with MF to the patients in the COMFORT studies, as 27.0% of patients achieved significant response (vs. 31.9% in COMFORT-II), and the majority of patients (95%; 54 of 57 evaluable patients) experienced a reduction in spleen size at some time during the study (median: 29% vs. 28% in COMFORT-II) [
9]. The reduction appeared to be rapid and durable as indicated by an estimated time to first reduction equal to the time in the first assessment and by the inestimable median response duration due to no events observed, consistent with the COMFORT-II study. As no MRI assessment was performed until week 12, the actual time to response might possibly be even shorter [
16,
17].
In addition to the reduction of enlarged spleen, ruxolitinib also demonstrated a promising relief of symptom burden as measured by MFSAF v2.0, with more than half of the patients achieving≥50% improvement in total symptom score from baseline at week 24. This finding was also confirmed by EORTC QLQ-C30 with a trend toward improvement for most MF-related symptom scores and moderate improvement in overall QoL. Notably, compared with that in the COMFORT studies, the observed baseline individual subscales of EORTC QLQ-C30 (specifically those for Global Health Status/QoL, role functioning, and physical functioning) showed slightly better conditions for the MF patients enrolled in this study. This result may be attributed to the absence of apparent and clinically meaningful change in EORTC QLQ-C30.
Ruxolitinib treatment was generally well tolerated by the Chinese patients. As expected with its JAK-STAT pathway inhibition mechanism, hematologic AEs were the most commonly reported AEs and treatment-related AEs in this population. Despite the lower baseline median hemoglobin level and lesser in-treatment pRBC transfusion (0.26 units/month vs. 0.92 units/month and 0.86 units/month in COMFORT-I and –II, respectively), the incidence of anemia in the Chinese patients was still comparable with that in the patients from the COMFORT studies (51% vs. 31% and 41%). The incidence of thrombocytopenia events (using standard MedDRA queries) was similar (57.1% vs. 50.0% in COMFORT-II), and the percentage of new or worsened hemoglobin from baseline was similar to those of the COMFORT trials (78% vs. 82%). Notably, grade 3 or 4 anemia was more frequently reported in this study than in the COMFORT studies (36.5% vs. 12.3%), although more patients with baseline hemoglobin<10 g/dl was recruited. In fact, grade 3 or 4 anemia was more frequently observed in patients with baseline hemoglobin counts<10 g/dl (56%) than in those with baseline hemoglobin counts≥10 g/dl (14%) in the study. Less in-treatment pRBC infusion considered as difference in clinical practice also contributed to this higher incidence. Nevertheless, these anemia-related AEs appeared to be easily manageable in the clinical setting of this study as evidenced by the unaffected overall exposure and by the fact that no patient was discontinued because of anemia. Additionally, reports of anemia-related AEs peaked at around week 8 to week 12 and then tapered off thereafter. In general, the safety profiles of ruxolitinib observed in the Chinese population in this study were consistent with the results of the overall study and those of the COMFORT studies, with no new safety concerns identified. As the median duration of follow-up for Chinese patients was 7.39 months, broader interpretations of the stabilization of dose for Chinese patients cannot be made at this time.
In conclusion, the results from this study indicate that ruxolitinib treatment provides a favorable benefit–risk ratio in Chinese patients with MF. Ruxolitinib offers an efficacy profile and a level of safety and tolerability that are similar to those observed in western patients from the COMFORT studies, thus making the drug a valuable therapeutic option for Chinese patients with MF.
Higher Education Press and Springer-Verlag Berlin Heidelberg
PDF
(169KB)
