Therapeutic effects of rituximab combined with cyclophosphamide on refractory idiopathic thrombocytopenic purpura

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: , 2019 Therpeutic effects of rituximb combined with cyclophosphmide on refrctory idiopthic thrombocytopenic purpur JIUHE WANG 1, BIN WANG 2, ZHONGHUI SUN 3 nd KEZENG XUE 2 1 Deprtment of Hemtology, Qingdo Hiser Medicl Group; 2 Wrd Phrmcy, Qingdo Municipl Hospitl; 3 Deprtment of Phrmcy, The Eighth People's Hospitl of Qingdo, Qingdo, Shndong , P.R. Chin Received June 11, 2018; Accepted Jnury 16, 2019 DOI: /etm Abstrct. Therpeutic effects of rituximb combined with cyclophosphmide on refrctory idiopthic thrombocytopenic purpur (ITP) were investigted. We retrospectively nlyzed 249 ptients with refrctory ITP who were dmitted to Qingdo Hiser Medicl Group between Mrch 2013 nd Mrch Curtive effects of ptients treted with rituximb, cyclophosphmide, nd combintion therpy were observed nd the chnges of pltelet count, PA IgG, nd lymphocyte CD20 before nd fter tretment, s well s the incidence of dverse rections fter tretment, were compred. There ws no significnt difference in the expression of lymphocyte CD20, PA IgG nd pltelet count mong the three groups of refrctory ITP ptients before tretment (P>0.05). After tretment, the expression levels of CD20 nd PA IgG in lymphocytes were significntly downregulted, nd pltelet counts significntly incresed in the three groups (P<0.05). After tretment, CD20 nd PA IgG levels in combined therpy group were significntly lower, nd pltelet count ws significntly higher, thn those in the rituximb nd cyclophosphmide groups (P<0.05). Also, fter rituximb tretment, the expression levels of CD20 nd PA IgG in lymphocytes were significntly lower thn those in cyclophosphmide group (P<0.05), nd pltelet count ws higher thn tht in cyclophosphmide group (P<0.05). After tretment, the totl effective rte in combined therpy group ws higher thn tht in the rituximb nd cyclophosphmide group (P<0.05). Totl effective rte of rituximb group ws significntly higher thn tht of cyclophosphmide group (P<0.05). The incidence of dverse rections in combined therpy group ws 14.29% (12/84), which ws significntly lower thn tht in cyclophosphmide group (40.70%, 35/86, P<0.05) nd rituximb group (29.11%, 23/79, P<0.05). The ppliction of rituximb combined with cyclophosphmide in Correspondence to: Dr Kezeng Xue, Wrd Phrmcy, Qingdo Municipl Hospitl, 1 Jiozhou Rod, Qingdo, Shndong , P.R. Chin E mil: kjf32v@163.com Key words: rituximb, cyclophosphmide, combined therpy, refrctory idiopthic thrombocytopenic purpur, efficcy the tretment of refrctory ITP cn improve ptient's clinicl symptoms. The efficcy of this technique is promising with no serious dverse rections. This technique should be populrized in clinicl prctice. Introduction Idiopthic thrombocytopenic purpur (ITP) is hemorrhgic disese, induced by the dysfunction of the immune system, which cuses mturtion disorder or thrombocytopeni. ITP is sometimes ccompnied by n increse of bone mrrow megkryocytes nd its incidence is reltively high in children (1). Clinicl mnifesttions of ITP re chills, fever, nd even sudden spontneous mucosl bleeding in the skin (2). Non specific tretment with lrge doses of γ globulin, glucocorticoids, nd splenectomy is effective in 70% of ptients with ITP, while the efficcy in the remining 30% of ptients is low (3). Refrctory ITP predominntly occurs in women, nd high dose hormonl drugs, such s immunosuppressnt nd γ globulin, re frequently used. Immunosuppressive gents hve low rte of remission nd my be ssocited with myelosuppression nd secondry tumors. Remission rte of γ globulin is high, s well s the cost, nd the durtion of curtive effect is short (4). In recent yers, ttention hs been pid to the tretment of refrctory ITP, nd some new immunotherpy methods hve been introduced (5). At present, cyclophosphmide nd rituximb re frequently used in the tretment of ptients with refrctory ITP. Although the efficcy of cyclophosphmide in the tretment of refrctory ITP ptients is stisfctory, the incidence of dverse rections, such s gstrointestinl rections, bone mrrow suppression, hir loss or even myocrdil dmge, is high (6). Rituximb cn cuse disorders, such s rrhythmis or hypotension (7). Mrtinez et l (8) hve stted tht the efficcy of rituximb in combintion with cyclophosphmide in the tretment of ptients with refrctory ITP is superior to trditionl single gent therpy. However, studies on the efficcy nd clinicl significnce of rituximb in combintion with cyclophosphmide in the tretment of refrctory ITP ptients re reltively rre. In this study, clinicl dt of ptients with refrctory ITP were retrospectively nlyzed to compre the tretment efficcies of the single nd combined therpy. This study provides reference for the tretment of refrctory ITP.

2 2138 WANG et l: EFFECTS OF RITUXIMAB COMBINED WITH CYCLOPHOSPHAMIDE ON PURPURA Tble I. Bsic informtion of 249 ptients with refrctory ITP [n (%)]. Rituximb Cyclophosphmide Combined therpy Fetures group (n=79) group (n=86) group (n=84) χ 2 test P vlue Sex Mle 26 (32.91) 30 (34.88) 35 (41.67) Femle 53 (67.09) 56 (65.12) 49 (58.33) Age (yers) <30 42 (53.16) 47 (54.65) 46 (54.76) (46.84) 39 (45.35) 38 (45.24) Hemturi Yes 23 (29.11) 31 (36.05) 28 (33.33) No 56 (70.89) 55 (63.95) 56 (66.67) Hemtemesis or hemoptysis Yes 31 (39.24) 34 (39.53) 35 (41.67) No 48 (60.76) 52 (60.47) 49 (58.33) Epistxis Yes 46 (58.23) 50 (58.14) 52 (61.90) No 33 (41.77) 36 (41.86) 32 (38.10) Pltelet count (x10 9 /liter) (30.38) 25 (29.07) 30 (35.71) >50 43 (54.43) 40 (46.51) 39 (46.43) <20 12 (15.19) 21 (24.42) 15 (17.86) ITP, idiopthic thrombocytopenic purpur. Ptients nd methods Ptient informtion. Clinicl dt of 249 ptients with refrctory ITP dmitted to Qingdo Hiser Medicl Group (Qingdo, Chin) from Mrch 2013 to Mrch 2017 were retrospectively nlyzed. Among them, 79 ptients were treted with rituximb, including 26 mles nd 53 femles, ged yers, with men ge of 31.54±4.78 yers; 86 ptients were treted with cyclophosphmide, including 30 mles nd 56 femles, ged yers, with men ge of 33.17±3.64 yers; nd 84 ptients were treted with both (combined therpy), including 35 mles nd 49 femles, ged yers, with men ge of 32.92±5.24 yers. No significnt differences in the bsic informtion were found mong the three groups of ptients (Tble I). Exclusion nd inclusion criteri. Inclusion criteri: ptients who met the refrctory ITP dignostic criteri (9); ptients >18 yers of ge; ptients who did not receive ny relevnt medicl tretment in other hospitls. Exclusion criteri: ptients who did not cooperte with the exmintion; ptients with other secondry thrombocytopeni; ptients with llergic rection to the drugs used in the present study; ptients during pregnncy nd lcttion; ptients with cute gstrointestinl bleeding or other serious diseses; ptients with communiction nd cognitive disorders. All prticipnts or their fmily members signed n informed consent nd cooperted with the medicl stff to complete the relevnt medicl tretment. The study ws pproved by the Ethics Committee of Qingdo Hiser Medicl Group. Methods. In rituximb group, 100 mg of rituximb (stte pprovl no. J ; Roche Phrmceuticl Co., Ltd., Shnghi, Chin) were dissolved in 100 ml of sline nd infusion ws performed once week t rte of 50 ml/h for 4 weeks. Intrvenous injection of 40 mg of methylprednisolone (Pfizer Mnufcturing Belgium NV, Puurs, Belgium) ws performed to prevent relted dverse rections. In cyclophosphmide group, intrvenous injection of cyclophosphmide (stte pprovl no. H ; Yngtze River Phrmceuticl Group; Jingsu HiCi Biologicl Phrmceuticl Co., Ltd., Jingsu, Chin) t dose of 0.8 g ws performed every week, nd orl intke of cyclophosphmide t dose of 2 mg/(kg dy) ws performed every dy, for time period of 3 months. Both rituximb nd cyclophosphmide were used in the combined tretment group using the sme methods. Tretment ws pplied for 2 months. The curtive effects of the three groups of ptients were observed. Lymphocyte CD20 ws detected by ELISA using the Humn CD20 ELISA kit obtined from Jining Industril Co., Ltd. (Shnghi, Chin). Pltelet ntibody IgG ws detected using humn nti pltelet ntibody IgG kit purchsed from Beyotime Institute of Biotechnology (Shnghi, Chin). Chnges in pltelet counts were monitored using Beckmn Coulter DxH2400 hemtology nlyzer (Beckmn Coulter, Inc., Bre, CA, USA). Occurrence of dverse rections, such s dizziness or hedche, nuse nd vomiting, bnorml liver

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: , Tble II. Lymphocyte CD20 before nd fter tretment in three groups of ptients (%). Groups Before tretment After tretment t test P vlue Rituximb group (n=79) 28.6± ± <0.001 Cyclophosphmide group (n=86) 27.8± ± <0.001 Combined therpy group (n=84) 28.1± ±2.3,b 34.5 <0.001 F vlue P vlue <0.001 P<0.05, compred with rituximb group; b P<0.05, compred with cyclophosphmide group. Tble III. Chnges of PA IgG before nd fter tretment in three groups of refrctory ptients (%). Groups Before tretment After tretment χ 2 test P vlue Rituximb group (n=79) 83±12 46± <0.001 Cyclophosphmide group (n=86) 84±12 50± <0.001 Combined therpy group (n=84) 83±14 33±9,b <0.001 F vlue P vlue <0.001 P<0.05, compred with rituximb group; b P<0.05, compred with cyclophosphmide group. nd kidney function, nd lung infection, fter tretment were recorded. Curtive effects. Curtive effects were evluted ccording to relevnt stndrds (10). Completely effective: if pltelet count increses significntly to >100x10 9 /liter, no bleeding occurs, nd efficcy lsts >2 months. Prtilly effective: if pltelet count increses significntly to x10 9 /liter, no bleeding bsiclly occurs, nd efficcy lsts >2 months. Miniml effective: when pltelet count level fluctutes within 20 49x10 9 /liter, bleeding symptoms re improved nd durtion is >2 months. Ineffective: if pltelet count is <20x10 9 /liter, no improvement or even worsening bleeding is observed. Totl efficiency: completely effective + prtilly effective. Sttisticl nlysis. SPSS 19.1 softwre [AsiAnlytics, Corp. (formerly SPSS Chin), Shnghi, Chin] ws used for dt processing. Mesurement dt, such s lymphocyte CD20, PA IgG, nd pltelet counts before nd fter tretment, were ll expressed s men ± stndrd devition. One wy nlysis of vrince ws used to compre continuous dt mong multiple group,s with Dunnett's test used s post hoc test, nd t test ws used for the comprison between two groups. Count dt, such s ptient bsic dt, efficcy evlution, nd incidence of dverse rections were ll expressed s rtes, nd comprisons between groups were nlyzed using Chi squre test. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Chnges of CD20 expression in lymphocytes of three groups of refrctory ITP ptients before nd fter tretment. There ws no significnt difference in the CD20 expression mong the three groups of ptients before tretment (P>0.05). After tretment, the CD20 expression levels were lower thn those before tretment (P<0.05). Also, fter tretment, CD20 expression level in combined therpy group ws lower thn tht in rituximb nd cyclophosphmide groups (P<0.05), nd CD20 expression level in rituximb group ws lower thn tht in cyclophosphmide group (P<0.05) (Tble II). Chnges of PA IgG before nd fter tretment in three groups of refrctory ITP ptients. Before tretment, there ws no significnt difference in PA IgG mong the three groups of refrctory ITP ptients (P>0.05). After tretment, there ws sttisticlly significnt difference in PA IgG mong the three groups (P<0.05). PA IgG level ws lower in combined therpy group thn in rituximb nd cyclophosphmide groups (P<0.05), nd PA IgG level in rituximb group ws lower thn tht in cyclophosphmide group (P<0.05) (Tble III). Chnges of pltelet count before nd fter tretment in three groups of refrctory ITP ptients. There ws no significnt difference in pltelet counts mong the three groups of refrctory ITP ptients before tretment (P>0.05). After tretment, the pltelet counts of the three groups were higher thn those before tretment (P<0.05). Pltelet counts were higher in combined therpy group thn in rituximb nd cyclophosphmide groups (P<0.05), nd pltelet counts were lso higher in rituximb group thn tht in cyclophosphmide group (P<0.05) (Tble IV). Comprison of curtive effects fter tretment in three groups of ptients. After tretment, the totl effective rte in

4 2140 WANG et l: EFFECTS OF RITUXIMAB COMBINED WITH CYCLOPHOSPHAMIDE ON PURPURA Tble IV. Pltelet counts before nd fter tretment in three groups of ptients (x10 9 /liter). Groups Before tretment After tretment t test P vlue Rituximb group (n=79) 12.3± ± <0.001 Cyclophosphmide group (n=86) 12.6± ± <0.001 Combined therpy group (n=84) 12.5± ±9.8,b <0.001 F vlue P vlue <0.001 P<0.05, compred with rituximb group; b P<0.05, compred with cyclophosphmide group. Tble V. Comprison of curtive effects fter tretment in three groups of ptients [n (%)]. Completely Prtilly Miniml Totl effective Groups effective effective effective Ineffective rte Rituximb group (n=79) 33 (41.77) 25 (31.65) 14 (17.72) 7 (8.86) 58 (73.42) Cyclophosphmide group (n=86) 13 (15.12) 36 (41.86) 23 (26.74) 14 (16.28) 49 (56.98) Combined therpy group (n=84) 58 (69.05),b 17 (20.24) b 7 (8.33) b 2 (2.38) b 75 (89.29),b F vlue P vlue < <0.001 P<0.05, compred with rituximb group; b P<0.05, compred with cyclophosphmide group. Tble VI. Comprison of the incidence of dverse rections fter tretment in the three groups of ptients [n (%)]. Rituximb Cyclophosphmide Combined therpy Adverse rections group (n=79) group (n=86) group (n=84) χ 2 test P vlue Dizziness or hedche 8 (10.13) 12 (13.95) 5 (5.95) Vomit 12 (15.19) 15 (17.44) 6 (7.14) Liver nd kidney dysfunction 2 (2.53) 5 (5.81) 1 (1.19) Lung infection 1 (1.27) 3 (3.49) 0 (0.00) Incidence of dverse rections 23 (29.11) 35 (40.70) 12 (14.29) <0.001 combined therpy group ws higher thn tht in rituximb nd cyclophosphmide groups (P<0.05). Totl effective rte in the rituximb group ws higher thn tht in cyclophosphmide group (P<0.05) (Tble V). Comprison of the incidence of dverse rections fter tretment in the three groups of ptients. After tretment, the incidence of dverse rections in the three groups ws significntly different from ech other (P<0.05). Symptoms such s dizziness or hedche, nuse, nd vomiting were mostly self relieving. In the rituximb group, 1 cse of liver function bnormlity, 1 cse of renl function, nd 1 cse of lung infection occurred. In cyclophosphmide group, there were 2 cses of bnorml liver function, 3 cses of renl function, nd 3 cses of pulmonry infection. In combined therpy group, there ws 1 cse of renl function, which ws relieved fter trgeted tretment. No cute nd lte toxic rections were observed (Tble VI). Discussion ITP is liquid immune medited systemic immune disese. In ptients with ITP, pltelet utontibodies bind to pltelet membrne glycoproteins nd re phgocytosed by mcrophges vi Fc receptors (11). Tretment of ITP is imed t reducing pltelet destruction nd controlling bleeding, while overtretment should be voided (12). The most common drug for the tretment of ITP is glucocorticoids, but some ptients with ITP re insensitive or intolernt to glucocorticoids, which cuses ITP ptients to become refrctory fter glucocorticoid tretment (13). With the dvncement of modern medicine, refrctory ITP cn be llevited, but it is still difficult to chieve full rehbilittion, the incidence is high nd the tretment cycle is long (14,15). Therefore, the use of proper drugs for timely tretment is the key to control the deteriortion of the disese (16). Rituximb is CD20 monoclonl ntibody tht binds to Fc receptors on bnorml B cells to initite complement medited

5 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: , killing of cytotoxic ntibodies. The killing effect leds to the solubiliztion of CD20 on B lymphocytes, inhibited production of ntibodies by B lymphocytes, nd reduced destruction of pltelets. Rituximb hs been widely used in the tretment of utoimmune hemtologicl diseses (17). Cyclophosphmide cn not only block the prolifertion of B cells, but lso inhibits the production of ntibodies, which cn be used to ssist immunodsorption therpy (18). Gödel et l (19) hve shown tht cyclophosphmide cn tret utoimmune diseses by limiting the non specific killing of smll lymphocytes, inhibiting cell prolifertion, nd limiting the trnsformtion of virl cells into immune mother cells. It is worth noting tht cyclophosphmide interferes with the production of DNA nd RNA nd even cross links with DNA, which in turn inhibits the immune response nd prolifertion nd division of immune lymphocytes nd impedes the deposition of immune complexes. Cyclophosphmide hs been widely used in the tretment of lymphtic systemic nd utoimmune diseses (20). This study investigted the efficcy nd clinicl significnce of rituximb in combintion with cyclophosphmide for the tretment of refrctory ITP ptients. There ws no significnt difference in the expression levels of CD20 nd PA IgG, nd the pltelet counts mong the three groups of ptients with refrctory ITP before tretment (P>0.05). After tretment, the expression levels of CD20 nd PA IgG in lymphocytes of three groups were lower thn those before tretment, nd the pltelet counts were higher (P<0.05). After tretment, CD20 nd PA IgG levels in combined therpy group were lower thn those in rituximb nd cyclophosphmide groups (P<0.05), while pltelet count ws higher (P<0.05). Also, fter rituximb tretment, the expression levels of CD20 nd PA IgG in lymphocytes were lower thn those in cyclophosphmide group (P<0.05), while pltelet count ws higher (P<0.05). After tretment, totl effective rte in combined therpy group ws higher thn tht in rituximb nd cyclophosphmide groups (P<0.05). Totl effective rte of rituximb group ws significntly higher thn tht of cyclophosphmide group (P<0.05). The dt showed tht the combined use of rituximb nd cyclophosphmide intermittently results in the decrese of CD20 nd PA IgG nd increse of pltelet count in some ptients, which restores the bnorml immune function nd significntly improves the qulity of life. It hs been reported (21) tht rituximb is humn mouse chimeric ntibody tht reduces the production of utontibodies nd the combintion with cyclophosphmide cn increse the immunosuppressive effect. In the present study, it ws found tht the incidence of dverse rections in combined therpy group is 14.29% (12/84), which is significntly higher thn tht in cyclophosphmide group (40.70%, 35/86, P<0.05) nd rituximb group (29.11%, 23/79, P<0.05). Symptoms such s dizziness or hedche, nuse, nd vomiting were mostly self relieving. In the rituximb group, 1 cse of liver function bnormlity, 1 cse of renl function, nd 1 cse of lung infection occurred. In cyclophosphmide group, there were 2 cses of bnorml liver function, 3 cses of renl function, nd 3 cses of pulmonry infection. In combined therpy group, there ws 1 cse of renl function, which ws relieved fter trgeted tretment. Al Askr et l (22) hve shown tht cyclophosphmide is toxic nd combined tretment cn reduce the dosge of cyclophosphmide, which in turn reduces the dverse rections of cyclophosphmide nd the dmge to the body, nd increse ptient's complince. This study is limited by the smll smple size. Future studies re required to confirm our conclusions. In conclusion, ppliction of rituximb combined with cyclophosphmide in the tretment of refrctory ITP cn improve ptient's clinicl symptoms. The efficcy of this technique is promising with no serious dverse rections. This technique should be populrized in clinicl prctice. Acknowledgements Not pplicble. Funding No funding ws received. Avilbility of dt nd mterils The dtsets used nd/or nlyzed during the present study re vilble from the corresponding uthor on resonble request. Authors' contributions JW collected nd nlyzed the generl informtion of ptients. BW nd ZS performed ELISA. KX nlyzed the curtive effects. All uthors red nd pproved the finl mnuscript. Ethics pprovl nd consent to prticipte The study ws pproved by the Ethics Committee of Qingdo Hiser Medicl Group (Qingdo, Chin). Ptients who prticipted in this reserch, signed n informed consent nd hd complete clinicl dt. Signed informed consents were obtined from the ptients or the gurdins. Ptient consent for publiction Not pplicble. Competing interests The uthors declre tht they hve no competing interests. References 1. 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