Clinical efficacy and safety of ruxolitinib in the management of myelofibrosis: A single institution experience in Taiwan.

OBJECTIVE: Myelofibrosis (MF) is a pathologic entity of myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms that severely affect the quality of life accompanied with the risk of leukemia development. Conventional treatment is usually ineffective and has limited impact on prolongation of survival. Dysregulated Janus kinase (JAK) signaling is common in MPN. In two randomized controlled trials, ruxolitinib, a potent pan-JAK inhibitor, has been shown to be highly effective in patients with intermediate- and high-risk MF. METHOD: We retrospectively analyzed the therapeutic outcome of 10 MF patients treated with ruxolitinib in our institute. Basic clinical data, JAK2V617F mutational status and Myelofibrosis Symptoms Assessment Form (MF-SAF) to evaluate disease-related symptoms were recorded initially, and at every visit. RESULT: Among these patients, only half of the patients harbored JAK2V617F mutation. After treatment with ruxolitinib, all patients had reduction of splenic size and reached nadir by week 24. Nine patients had body weight increment, and four of them had body weight increment more than 10%. Seven patients had their total symptom score reduced by more than 50% after therapy. The efficacy of ruxolitinib was irrelevant to JAK2V617F mutational status. Adverse events were mainly hematological and easily manageable. DISCUSSION AND CONCLUSION: Ruxolitinib is both safe and efficacious in a cohort of Asian patients with MF. The efficacy of ruxolitinib is irrelevant to the mutational status of JAK2V617F.

Frequency and allele burden of CALR mutations in Chinese with essential thrombocythemia and primary myelofibrosis without JAK2(V617F) or MPL mutations.

CALR mutations are detected in about 50% of persons of predominately European descent with essential thrombocythemia (ET) or primary myelofibrosis (PMF) with wild-type alleles of JAK2 and MPL. We studied 1088 Chinese with diverse myeloproliferative neoplasms including ET (N=234) and PMF (N=50) without JAK2(V617F) or MPL exon 10 mutations. CALR mutation was detected in 53% (95% CI, 46-60%) of subjects with ET and 56% (95% CI, 41-70%) of subjects with PMF. 152 CALR mutations were identified clustering into 15 types including deletions (N=8), insertions (N=3) and complex indels (N=4). We also identified 9 new mutations. Mean (±SD) mutant allele burden was 31±12% (range, 0.5-69%). Persons with PMF had higher CALR mutant allele burdens than those with ET (38±8% vs. 29±12%; P<0.001). Amongst persons with CALR mutations, those with PMF had different clinical features from those with ET. These data may be useful for diagnosing ET and PMF in Chinese who are about 40% of all persons with ET and PMF and for monitoring therapy-response. They also highlight similarities and differences in CALR mutations between Chinese and persons of predominately European descent with these diseases.

Cytogenetic studies and their prognostic contribution in 565 Chinese patients with primary myelofibrosis.

To study the feature and prognostic contribution of cytogenetic information in Chinese patients with primary myelofibrosis (PMF), we analyzed cytogenetic data from 565 patients with PMF. One hundred and sixty-two subjects (29%) had abnormal karyotypes, including trisomy 8 (45; 28%), deletion of 20q (25; 15%), deletion of 13q (13; 8%), deletion of 11q (12; 7%), and abnormal chromosome 1 (21; 13%); balanced translocations (14; 9%); a complex karyotype (CK; 30; 19%), and a monosomal karyotype (MK; 19; 12%). Using these data, we showed that the Dynamic International Prognostic Scoring System (DIPSS)-plus, which includes cytogenetic information, is a better survival predictor than the DIPSS. We next used our data to construct the following two cytogenetic-based cohorts: (1) favorable karyotype-subjects with a normal karyotype, a CK that is not a MK, +8 only or a balanced translocation only and (2) unfavorable karyotype-all others. The median survival times were not reached and were 52 month (95% CI, 32-72 months; P = 0.01) in patients with favorable and unfavorable karyotypes, respectively. These data provided the detailed cytogenetic information in Chinese patients with PMF and confirmed the impact of cytogenetic abnormalities on survival in Chinese patients.

JAK2V617F allele burden is associated with transformation to myelofibrosis.

The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV.

The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries.

Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.