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Home , Acute myeloid leukemia, Bone marrow suppression

European Review for Medical and Pharmacological Sciences 2017; 21: 3312-3319 Treatment of patients with using

Q.-L. SONG1, B. ZHANG1, Y. XU1, R.-X. XIA2, X.-H. LU1, Z.-X. PEI1, Q.-W. XU1, W.-Y. LI1, Z.-D. LI1

1Department of , the People’s Hospital of Jiaozuo City, Jiaozuo, Henan Province, China 2Department of Laboratory Medicine, 266 Hospial of PLA, Chengde, Hebei Province, China

Abstract. – OBJECTIVE: Primary myelofibro- of approximately five years. Deaths from PMF are sis (PMF) is a chronic clonal myeloproliferative mainly caused by , bleeding, and disease neoplasm. It is associated with a poor progno- progression to acute myeloid (AML). sis, with a median survival time of approximately Currently, there are no specific targeted drugs five years. Thus far, there are no specific targeted for PMF. Available treatments include immune drugs for PMF. In this study, we evaluated the ef- ficacy and safety of dasatinib, a second-genera- modulators (such as , , tion tyrosine kinase inhibitor, in six PMF patients. and interferons), therapies, hydroxy- PATIENTS AND METHODS: From June 1, 2015 urea, JAK2V617F kinase inhibitors, hematopoi- to February 29, 2016, six patients with PMF in etic stem cell transplantation, experimental new our department were enrolled into this trial. The drugs, , and splenectomy2,3. Out efficacy and safety of 100 mg/d (50 mg twice dai- of these, hematopoietic stem cell transplantation ly) dasatinib were investigated in these patients. RESULTS: For patients who experienced ad- is the only curative treatment for PMF. However, verse drug events, the dose was reduced to 70 its application is limited by the fact that only a or 50 mg/d, whereas for those who tolerated few patients are able to receive the treatment and the drug well, the dosage was increased to 140 its high cost. mg/d (70 mg twice a day). Of the six patients, Dasatinib is a second-generation tyrosine ki- two achieved histologic , nase (TK) inhibitor. Tyrosine kinases regulate a five showed symptomatic improvement, and one wide range of normal cell processes, including reached a stable condition. No severe hemato- logical or non-hematological adverse events metabolism, growth, differentiation, and apopto- were observed thus far. sis. They are key players in various diseases such CONCLUSIONS: Dasatinib treatment may be as , pulmonary arterial hypertension, and beneficial to patients with PMF and resulted in systemic sclerosis4. Using a mouse model of pul- significant improvements in , clini- monary fibrosis, we showed that dasatinib exerted cal symptoms, physical condition, and quality of therapeutic effects in the fibrotic lung. Dasatinib life. Therefore, we regard it as an effective ther- apy for PMF. limited myofibroblast activation and collagen-1 accumulation by inhibiting PDGFR-α (plate- Key Words: let-derived growth factor receptor-α), Src, and Primary myelofibrosis, Dasatinib, Treatment. c-Abl activation5. Moreover, Cruz et al6 reported that dasatinib was effective in inducing macro- phage polarization towards the M2 phenotype Introduction and in reducing lung inflammation and fibrosis. In this study, we evaluated the efficacy and safety Primary myelofibrosis (PMF) is a chronic clon- of dasatinib in six PMF patients. al myeloproliferative neoplasm characterized clinically by anemia, splenomegaly, myelofibro- sis, bone sclerosis, and the presence of immature Patients and Methods and teardrop-shaped erythrocytes. Also, it may be accompanied by symptoms such Patients as , night sweats, , and weight loss1. It From June 1, 2015 to February 29, 2016, has a poor , with a median survival time six patients with PMF in our department were

3312 Corresponding Author: Qing-Lin Song, MD; e-mail: [email protected] Treatment of patients with primary myelofibrosis using dasatinib enrolled into this trial. Bone marrow aspira- Pharmaceutical Group Co, Ltd. (CTTQ: Yinishu, tion, bone marrow biopsy, myeloproliferative produced in Jiangsu Province, China). neoplasm (MPN)-related detection, and Evaluation of drug efficacy was based on cri- analysis was performed. G-banding teria proposed by the European Myelofibrosis was used in for karyotype anal- Network (EUMNET) in 2005. The definition of ysis, and the karyotype was named according the response to treatment in patients was based to the International System for Human Cyto- on hematological, histological, and cytogenetic genetic Nomenclature (ISCN2013). Diagnosis parameters10. The International Working Group criteria were based on the 2008 WHO diagnos- for Myelofibrosis Research and Treatment (IWG- tic criteria for PMF7; the diagnosis met the re- MRT) proposed new efficacy evaluation criteria quirements of three major criteria, as well as in 200611. two minor criteria. The inclusion criteria were: Safety evaluations included assessments of (1) no severe injuries in major organs such as adverse events such as hepatic, renal, and cardi- the heart, liver, and other vital organs; and (2) ac toxicity, monitoring of lung disease, pleural patients and their families gave their informed effusion, gastrointestinal symptoms, vital signs, consent. The exclusion criteria were: (1) pa- weight, and behavioral status, as well as , tients with severe concurrent medical condi- metabolic, and urine analyses. Classification of tions and a short predicted survival time, for adverse events was based on the NCI/NIH com- example, due to another ; (2) women mon toxicity criteria. who were pregnant or currently breastfeeding; and (3) patients and their families who chose to withdraw from the clinical trial. Results

Dasatinib Treatment Patients’ Details All patients signed the informed consent forms Details of the six enrolled patients are shown in and voluntarily participated in this clinical trial. Tables I and II. One patient discontinued dasati- The study protocol was approved by our institu- nib treatment for personal reasons. Subsequently, tion’s Ethics Committee (approval number: ChiE- the disease progressed and the patient died from CRCT-20150071). Patients were administered 100 cachexia, severe diarrhea, and pleural effusions. mg/d (50 mg twice a day) dasatinib. Prognostic The other five patients continued with the treat- stratification of patients was based on DIPSS Plus ment. before the commencement of treatment8. The My- eloproliferative Neoplasm Symptom Assessment Efficacy Assessment Form (MPN10) was used to assess the symptoms9, At the end of the treatment period, dasatinib which included fatigue, inactivity, concentration, markedly reduced volume in all six pa- early satiety, abdominal discomfort, itching, night tients (100%) who received the treatment, but sweats, bone pain (diffuse, non-arthritis or joint did not induce a significant increase in the pe- pain), unintentional in the past six ripheral blood count. The reduction in spleen months, and fever (> 37.8 °C). Symptom severity volume is shown in Figure 1, where the sple- was rated on a 0 (absent/as good as it can be) to nomegaly measurement is represented by line 10 (worst imaginable/as bad as it can be) scale. “1”. One patient tested positive for JAK2V617F Patients received the treatment until the appear- before the treatment, which persisted ance of intolerable side effects or until they chose two months after dasatinib treatment. Before to withdraw from the trial. The follow-up period the treatment, another patient tested positive ended on February 29, 2016. During the treat- for JAK2V617F mutation and 20q-; the patient ment period, dosage adjustments or transient sus- had grade 3 bone marrow fibrosis and eryth- pension of treatment was allowed based on drug roid hypoplasia. Ten weeks after dasatinib tolerability or occurrence of adverse events. The treatment, the patient still tested positive for dosage for patients who developed adverse drug the JAK2V617F mutation and 20q-, but a bone reactions was reduced to 70 or 50 mg/d, whereas marrow biopsy showed that the fibrosis had for those who tolerated the drug well, the dosage reduced to grade 1, and that the bone marrow was increased to 140 mg/d (70 mg twice a day). showed erythroid hyperplasia with primary The dasatinib tablets (20 and 50 mg) used in this cells < 5%. Another patient also tested positive study were manufactured by ChiaTai Tian Qing for the JAK2V617F mutation before treatment

3313 Q.-L. Song, B. Zhang, Y. Xu, R.-X. Xia, X.-H. Lu, Z.-X. Pei, Q.-W. Xu, W.-Y. Li, Z.-D. Li

Table I. Basic clinical information of patients with PMF. Age ECOG Sokal MPN Prognostic Genetic Treatment No. Sex (year) score score score stratification mutation duration (week)

1 Female 55 3 1.54 50 Intermidate-2 JAK2V617F 16 2 Male 58 2 1.08 28 Intermidate-2 JAK2V617F 10 3 Female 64 2 0.66 38 Intermidate-2 JAK2V617F 10 4 Male 60 2 1.38 39 Intermidate-2 JAK2V617F 10 5 Female 69 3 1.64 31 High risk JAK2V617F 11 6 Female 60 2 1.39 32 Intermidate-2 ASXL1, MPLW515 8

and had grade 3 bone marrow fibrosis; the pa- um, potassium, and magnesium tablets, as well tient tested positive for JAK2V617F mutation as hepatoprotective agents. In the event of edema, 11 weeks after treatment with dasatinib, but the pleural effusion, gastrointestinal reactions, and fibrosis had reduced to grade 1 and the primary other adverse reactions, symptomatic treatment cell count was < 5%. One patient tested positive with diuretic, digestive, and antidiarrheal agents for ASXL1 and MPLW515 even eight can help alleviate these conditions. One patient weeks after the treatment; further, bone mar- discontinued dasatinib treatment for personal rea- row biopsy showed that the myelofibrosis grade sons. Thereafter, the disease progressed and the was MF3 as before. Thus far, the histological patient experienced severe diarrhea, effusions, and cytogenetic efficacy of dasatinib treatment hypoproteinemia, and intestinal flora imbalance. in the other patients has not been evaluated. However, symptomatic treatment failed to sig- nificantly alleviate these adverse drug reactions. Hematologic Adverse Events After discontinuation of dasatinib, the patient’s Most of the hematologic adverse events in- spleen became enlarged again and the patient died duced by dasatinib treatment were classified as because of cachexia. grades 1/2, and occasionally as grades 3/4. Grades 3/4 hematologic adverse events occurred in one patient (ID no. 1), whose blood profile showed Discussion the lowest hemoglobin (Hb) concentration (50 g/L) before treatment; treatment with dasatinib PMF is a chronic clonal myeloproliferative did not result in significant difference in the pa- neoplasm, characterized clinically by anemia, tient’s Hb concentration. Furthermore, there was splenomegaly, myelofibrosis, bone sclerosis, and a significant decrease in white (WBC) the presence of immature granulocytes and tear- count, absolute neutrophil count (ANC), and drop-shaped erythrocytes. It may be accompa- count. Patients recovered quickly from nied by constitutional symptoms such as fever, adverse drug reactions after a dose adjustment or night sweats, fatigue, and weight loss. PMF has treatment discontinuation, but some required red a poor prognosis, and so far, there are no specif- blood cell transfusion, , and ic targeted drugs. Hematopoietic stem cell trans- recombinant human colony-stimulat- plantation is currently the only curative treatment ing factor injection (Table III). for primary myelofibrosis, which is suitable for patients with a poor prognosis when a matched Non-hematologic adverse events donor is available. The most common non-hematologic adverse is a first-generation TK inhibitor and events of dasatinib administration included ede- the first-line treatment for chronic myeloid leuke- ma, pleural effusion, fatigue, headache, joint and mia (CML). Besides BCR-ABL tyrosine kinase, muscle pain, rash, gastrointestinal reactions, ele- imatinib can also inhibit the activity of other ki- vated levels of total bilirubin, alanine aminotrans- nases such as PDGFR and c-KIT12. Myeloprolif- ferase (ALT), aspartate aminotransferase (AST), erative disorders are most often associated with and , hypokalemia, hypocal- JAK2V617F and c-KIT mutations. Imatinib has cemia, hypophosphatemia, and hypomagnesemia been evaluated in clinical trials to treat PMF pa- (Tables V and VI). During dasatinib treatment, tients. However, the outcomes were mostly unfa- patients received regular supplements of calci- vorable. Recently, imatinib was used by Robibaro

3314 Treatment of patients with primary myelofibrosis using dasatinib

et al13 in the treatment of a PMF patient; however, the expected hematologic reaction was not ob- served, and the therapy had to be terminated ow- +++ +++ +++ +++ +++ ing to serious interstitial lung disease. Only one ++~+++ previous work has shown that splenomegaly was

Myelofibrosis resolved in four PMF patients (29%) after treat- ment with imatinib14. Systemic (SM) is a rare chronic myeloproliferative neoplasm which is charac- No No No No No Yes terized by abnormal mast cell proliferation. The only therapeutic option for the specific cutaneous Lymph node symptoms is symptomatic therapy: leukotriene antagonists, commonly antihistamines, local im- munosuppressants or local UV radiation, gluco- 21.5 19.5 (cm) 18 10 24.5 20 Line I corticoids, and in selected special cases tyrosine kinase inhibitors (TKIs). However, the role of imatinib mesylate therapy has not been well es- tablished. I. MARTO used imatinib as treatment for a female ISM patient with recurrent cutaneous

Spleen symptoms that impaired her quality of life, even Splenomegaly Splenomegaly Splenomegaly Splenomegaly Splenomegaly Splenomegaly though neither FIP1L1-PDGFRA gene rearrange- ment nor a KIT D816V mutation nor any ima- tinib-sensitive KIT mutation was present15. He

found that shortly after the imatinib the patient’s No No No Yes Yes Liver skin symptoms improved.

Hepatomegaly Dasatinib is a second-generation TK inhibitor. In addition to targeted inhibition of the BCR- ABL1 gene, which could block signaling path- ways activated by BCR-ABL, dasatinib also tar- gets PDGFR, c-Kit, ephrin receptor kinase, and 0 0 0 1 0 0 the Src and Src-related family of kinases. Recent- 16 Blasts and ly, Mohamed et al reported an incidence of CML masquerading as PMF in a patient, and after four immature cells (%) months of dasatinib therapy, bone marrow biopsy

/L) revealed a change in the grade of fibrosis from M3 9 78 58 116 159 103 100

PLT at initial diagnosis to M1. It was also demonstrat- ed that there was a marked regression of myelo- fibrosis upon reduced-dose dasatinib treatment for chronic myelogenous leukemia in the acceler- 57 45 85 50 116 101 Hb 17

(g/L) (×10 ated phase . Dasatinib has not been used for the treatment of PMF in China, and there has been little such research elsewhere. Only one open-la- /L)

9 bel, single-center study was conducted in 2008, 1.0 0.62 2.21 2.8 2.52 35.88

ANC in which the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various myeloid disorders. Among these patients, there were 11 with PMF. No objective clinical responses were /L) (×10 9 observed in 10 patients, and dasatinib was discon- 1.0 3.4 3.4 4.1 2.20 46.6 WBC tinued in one patient due to toxicity. One patient (×10 with systemic mastocytosis-PMF {KIT-D816V negative, FIP1L1-PDGFRα negative, JAK2V617F

positive; complex abnormalities on cytogenet- ic analysis [47, XY, +1, der (1;7) (q10;p10), +9]} 6 5 3 4 2 No. 1

Table II. Basic clinical information of patients with PMF (con’t). achieved complete response that lasted for five

3315 Q.-L. Song, B. Zhang, Y. Xu, R.-X. Xia, X.-H. Lu, Z.-X. Pei, Q.-W. Xu, W.-Y. Li, Z.-D. Li

Figure 1. Reduction in spleen volume after dasatinib treatment. months. However, the patient then progressed to In this paper, all six patients exhibited a re- AML after eight months of dasatinib therapy and duction of about 2/3 in spleen volume com- died18. pared to the baseline value within a week of Ruxolitinib is an oral Janus kinase 1/2 dasatinib treatment. Before the treatment, all (JAK1/2) inhibitor. Several researchers have in- patients experienced early satiety, abdominal vestigated its efficacy against myeloproliferative discomfort, inactivity, and other symptoms due disorders, including PMF, vera, to splenomegaly. After an average of 5-7 days and essential , and found that of dasatinib treatment, the volume of the spleen it exerts significant therapeutic effects in PMF began to decrease, and continued medication patients19. In a study by Harrison et al20, 219 pa- helped to maintain its normal size. Further, the tients with PMF, post– myelo- Eastern Cooperative Group (ECOG) fibrosis, or post-essential thrombocythemia my- score decreased, patients’ quality of life im- elofibrosis were assigned to receive either oral proved significantly, and the disease no longer ruxolitinib (146 patients) or the best available affected the patients’ daily lives. However, no therapy (73 patients). Among the patients in the significant improvement was observed in WBC ruxolitinib group, 28% showed at least a 35% re- count, Hb level, or platelet count in conventional duction in spleen volume at week 48, compared blood tests. To better understand the effects of with 0% in the group receiving the best available dasatinib, bone marrow biopsy was performed therapy; the corresponding percentages at week in two patients, and the results indicated histo- 24 were 32% and 0%. The results of the study logical remission of the bone marrow. Cytoge- demonstrated that continuous ruxolitinib thera- netic abnormalities remained in four patients py was associated with marked and long-lasting after treatment, and they did not achieve a com- reductions in splenomegaly and other disease-re- plete cytogenetic response, probably due to the lated symptoms, improvements in quality of life, short treatment period. Of the six patients, five and modest toxic effects. showed symptomatic improvement, and one was

Table III. in PMF patients caused by dasatinib treatment. Lowest WBC count Lowest ANC count Lowest Hb Lowest PLT count No. (×109/L) (×109/L) (g/L) (×109/L)

1 III III IV III 2 II II II II 3 II I II I 4 0 0 IV II 5 III II II 0 6 III III III 0

3316 Treatment of patients with primary myelofibrosis using dasatinib

in a stable condition. Based on our observations, 0 0 0 II II II we believe that the treatment duration was too

Fever short, and recommend evaluating the efficacy

after every three months of treatment. So far, no severe hematological toxicity was I 0 0 0 0 0 observed. Hematologic toxicities included WBC pain grade 0 (one case), II (two cases), and III (three

Abdominal cases), and ANC grade 0 (one case), I (one case), II (two cases), and III (two cases). The Hb grades I I 0 0 0

III were II (three cases), III (one case), and IV (two

Cough cases). The lowest Hb levels for patients in stages N1 and N3 were 45 g/L and 41 g/L, respectively. I 0 0 0 II II However, these two patients had severe anemia

Vomit before the start of the treatment, so it should not be regarded as a dasatinib-induced hematologic toxicity. The platelet grades were grade 0 (two 0 II II II II III cases), I (one case), II (two cases), and III (one

Infection case). Similarly, no severe non-hematologic adverse 0 0 0 0 0 0 reaction was observed during treatment. Side ef- Pain fects observed in the six patients included edema, rash, nausea, diarrhea, elevated levels of total bil- I I 0 0 0 IV irubin, ALT, AST, and alkaline phosphatase, hy-

Fatigue pokalemia, hypocalcemia, hyperphosphatemia, and hypomagnesemia. These adverse events may be alleviated or ameliorated by treating patients 0 0 0 0 0 II with diuretics, glucocorticoids, hepatoprotective

Bleeding agents, and other therapies, or by correcting the electrolyte imbalance. In this study, dasatinib therapy was associ- I 0 0 II II III ated with a marked reduction in spleen volume difficulty

Breathing and improvement in the quality of life, similar to that induced by the JAK1/2 inhibitor, ruxolitinib. I 0 0 0 0 0 However, the underlying mechanism of its action Rash is not clearly understood. It is not known whether dasatinib targets PDGFR, c-Kit, ephrin kinase, I I I I 0

III Src family of kinases, or other kinase pathways to

Nausea significantly reduce the spleen volume. It is also not understood whether the present findings are specific to this study or if dasatinib has beneficial I I 0 0 0

II effects in other PMF patients. This needs to be further clarified using appropriate study designs

Headache and clinical trials with a large sample size to prop- erly evaluate the drug efficacy and safety. 0 0 II III III IV

Diarrhea Conclusions

We suggest that dasatinib therapy may benefit 0 II II II II IV PMF patients based on the significant improve- Fluid

retention ments in splenomegaly, clinical symptoms, phys- ical condition, and quality of life, and that it is an effective treatment before hematopoietic stem cell 6 No. 3

4 5 1 2

Adverse events in PMF patients treated with dasatinib. Table IV. transplantation.

3317 Q.-L. Song, B. Zhang, Y. Xu, R.-X. Xia, X.-H. Lu, Z.-X. Pei, Q.-W. Xu, W.-Y. Li, Z.-D. Li

Table V. Adverse events in PMF patients treated with dasatinib (Con’t). Elevated Elevated Abnormal No. transaminase bilirubin Hypocalcemia Hypokalemia Hypophosphatemia creatinase

1 0 0 II 0 II 0 2 I I I 0 0 0 3 I 0 I 0 0 0 4 I 0 II 0 0 0 5 I II I 0 0 0 6 0 0 0 0 0 0

Conflict of Interest S, Schouten HC, Sackmann F, Kerguelen Fuentes A, Hernández-Maraver D, Pahl HL, Griesshammer M, All authors declare that they have no conflict of interests in Stegelmann F, Doehner K, Lehmann T, Bonatz K, Re- this paper. iter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Harrison CN, Radia D, Muxi P, Maldona- do N, Besses C, Cervantes F, Johansson PL, Barbui T, References Barosi G, Vannucchi AM, Passamonti F, Andreasson B, Ferrari ML, Rambaldi A, Samuelsson J, Birgegard G, Tefferi A, Mesa RA 1) Yu Q, Xu L, Gao XD, Xu W, Yan H, Wu W, Li J, Shen . Myeloproliferative neoplasm Z. Clinical features and prognostic analysis of 75 (MPN) symptom assessment form total symptom primary myelofibrosis patients. Zhonghua Xue Ye score: prospective international assessment of Xue Za Zhi 2014; 35: 922-925. an abbreviated symptom burden scoring system Zhang DF. among patients with MPNs. J Clin Oncol 2012; 30: 2) Current diagnosis and treatment 4098-4103. progress of primary myelofibrosis: reports from Barosi G, Bordessoule D, Briere J, Cervantes F, the 19th European Hematology Association an- 10) Demory JL, Dupriez B, Gisslinger H, Griessham- nual congress. J Leuk Lymphoma 2014; 23: mer M, Hasselbalch H, Kusec R, Le Bousse-Kerdiles 525-529. MC, Liberato NL, Marchetti M, Reilly JT, Thiele J; 3) He HJ, Chen BA. Research progress of myelopro- European Myelofibrosis Network. Response cri- liferative neoplasms. Zhongguo Shi Yan Xue Ye teria for myelofibrosis with myeloid metaplasia: Xue Za Zhi 2015; 23: 278-284. results of an initiative of the European Myelo- 4) Beyer C, Distler JH, Distler O. Are tyrosine kinase fibrosis Network (EUMNET). Blood 2005; 106: inhibitors promising for the treatment of systemic 2849-2853. sclerosis and other fibrotic diseases? Swiss Med 11) Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Wkly 2010; 140: w13050. Reilly JT, Verstovsek S, Dupriez B, Silver RT, Odeni- 5) Yilmaz O, Oztay F, Kayalar O. Dasatinib attenuat- ke O, Cortes J, Wadleigh M, Solberg LA Jr, Camori- ed bleomycin-induced pulmonary fibrosis in mice. ano JK, Gisslinger H, Noel P, Thiele J, Vardiman JW, Growth Factors 2015; 33: 366-375. Hoffman R, Cross NC, Gilliland DG, Kantarjian H; 6) Cruz FF, Horta LF, Maia Lde A, Lopes-Pache- IWG for Myelofibrosis Research and Treatment (IWG- co M, da Silva AB, Morales MM, Gonçalves-de-Al- MRT). International Working Group (IWG) consen- buquerque CF, Takiya CM, de Castro-Faria-Neto HC, sus criteria for treatment response in myelofibro- Rocco PR. Dasatinib reduces lung inflammation sis with myeloid metaplasia, for the IWG for My- and fibrosis in acute experimental silicosis. PLoS elofibrosis Research and Treatment (IWG-MRT). One 2016; 11: e0147005. Blood 2006; 108: 1497-1503. 7) Tefferi A, Vardiman JW. Classification and diag- 12) Shu LL, Yang M. Imatinib in treatment of thrombo- nosis of myeloproliferative neoplasms: the 2008 cythemia and other myeloproliferative diseases. World Health Organization criteria and point-of- Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012; 20: care diagnostic algorithms. Leukemia 2008; 22: 1507-1512. 14-22. 13) Robibaro B, Kropfmueller A, Prokop M, Haber P, 8) Gangat N, Caramazza D, Vaidya R, George G, Begna Gisslinger H. Imatinib, cytokines and interstitial K, Schwager S, Van Dyke D, Hanson C, Wu W, Par- lung disease in a patient with primary myelofibro- danani A, Cervantes F, Passamonti F, Tefferi A. DIPSS sis. Ann Hematol 2010; 89: 829-831. plus: a refined Dynamic International Prognostic 14) Cortes J, Giles F, O’Brien S, Thomas D, Albitar M, Ri- Scoring System for primary myelofibrosis that in- os MB, Talpaz M, Garcia-Manero G, Faderl S, Let- corporates prognostic information from karyo- vak L, Salvado A, Kantarjian H. Results of imatinib type, platelet count, and transfusion status. J Clin mesylate therapy in patients with refractory or re- Oncol 2011; 29: 392-397. current acute , high-risk myelo- 9) Emanuel RM, Dueck AC, Geyer HL, Kiladjian JJ, dysplastic syndrome, and myeloproliferative dis- Slot S, Zweegman S, te Boekhorst PA, Commandeur orders. Cancer 2003; 97: 2760-2766.

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