{"paper_id":"abc8f481-851e-4491-9414-04809d1d2ae7","body_text":"Luo et al . Blood Cancer Journal  (2018) 8:9 \nDOI 10.1038/s41408-017-0029-4 Blood Cancer Journal\nARTICLE Open Access\nThalidomide plus prednisone with or\nwithout danazol therapy in myelofibrosis: a\nretrospective analysis of incidence and\ndurability of anemia response\nXueping Luo1,2, Zefeng Xu1,2,B i n gL i1,2, Tiejun Qin1, Peihong Zhang3, Hongli Zhang1,L i w e iF a n g1, Lijuan Pan1,\nNaibo Hu1,S h i q i a n gQ u1, Yue Zhang1,2,G a n gH u a n g4, Robert Peter Gale5 and Zhijian Xiao1,2\nAbstract\nLow-dose thalidomide and prednisone alone or combined are effective therapies in some persons with primary\nmyelofibrosis (PMF) and anemia with or with RBC transfusion dependence. Danazol is also effective in some persons\nwith PMF and anemia. Responses to these drugs are typically incomplete and not sustained. It is unclear whether\nadding danazol to thalidomide and prednisone would improve ef ficacy. We retrospectively compared the outcomes\nof 88 subjects with PMF and anemia receiving thalidomide and prednisone without ( n = 46) or with danazol ( n = 42).\nThe primary end point was anemia response, which was 71% (95% con fidence interval (CI), 57, 85%) in subjects\nreceiving thalidomide/prednisone/danazol compared with 46% (32, 60%; P = 0.014) in those receiving thalidomide/\nprednisone. Response rates in subjects who were RBC transfusion dependent was also higher in the danazol cohort\n(61% (38, 84%)) vs. 25% (6, 44%); P = 0.024). Time to response was rapid (median, 2 months (range, 1 –11 months)) and\nsimilar between the cohorts. Response duration was longer in the thalidomide/prednisone/danazol cohort (HR 2.18\n(1.18–5.42); P = 0.019). Adverse effects were mild and similar between the cohorts. In conclusion, thalidomide/\nprednisone/danazol seems superior to thalidomide/prednisone in persons with PMF and anemia. Our conclusion\nrequires con firmation in a randomized trial.\nIntroduction\nAbout one-third of persons with primary myelo fibrosis\n(PMF) have anemia at diagnosis and it develops in most\nothers as the disease evolves 1,2. Anemia and red blood cell\n(RBC) transfusion dependence are independent adverse\nprognostic variables for survival\n1–3. Erythropoiesis-\nstimulating agents (ESAs), androgenic steroids,\nthalidomide, lenalidomide, splenectomy, and prednisone\nare only modest activity in reversing anemia and\nruxolitinib, pacritinib and fedratinib typically worsen\nanemia\n4–7. New effective therapies are needed.\nThalidomide is active in PMF because of its anti-\nangiogenic, cytokine regulatory, and immune-modulating\nproperties\n8,9. Thalidomide, 100 –400 mg/day, is reported\nto improve anemia in 20 –60% of subjects 10–12. However,\nthese doses are associated with substantial toxicity and are\npoorly tolerated\n10,11. The combination of low-dose thali-\ndomide, 50 mg/day, and prednisone is better tolerated and\nresults in slightly higher responses than thalidomide\nalone13.\nAndrogenic steroids reverse anemia by stimulating\nerythropoietin, increasing iron use and reversing telomere\n© The Author(s) 2018\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution andreproduction\nin any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a lin kt ot h eC r e a t i v eCommons license,and indicate if\nchanges were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicatedotherwise in a credit line to the material. If\nmaterial is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/.\nCorrespondence: Zhijian Xiao ( zjxiao@medmail.com.cn)\n1MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital,\nChinese Academy of Medical Sciences and Peking Union Medical College,\nTianjin, China\n2State Key Laboratory of Experimental Hematology, Institute of Hematology\nand Blood Diseases Hospital, Chinese Academy of Medical Sciences and\nPeking Union Medical College, Tianjin, China\nFull list of author information is available at the end of the article\nXueping Luo, Zefeng Xu, and Bing Li contributed equally to this work.\nBlood Cancer Journal\n12345678901234567890\n\nloss14,15. Danazol, a synthetic androgen with reduced\nmasculinizing activity, is reported to reverse anemia and\nthrombocytopenia in persons with PMF\n16,17. Combining\ntherapies with different mechanisms of action might be\neven more effective in reversing anemia. Herein, we\nreport ef ficacy, safety, and long-time outcome of therapy\nwith low-dose thalidomide and prednisone with or with-\nout danazol in subjects with PMF and anemia with or\nwithout RBC transfusion dependence.\nSubjects and methods\nSubjects\nThis study was approved by the Ethical Committee of\nInstitute of Hematology, CAMS and PUMC according to\nguidelines of the Declaration of Helsinki. From March\n2006 to September 2016, 88 consecutive subjects and\nanemia with or without RBC transfusion dependence\nwere enrolled. Eligibility criteria were: (1) PMF according\nto the WHO 2016 criteria\n18; (2) age ≥ 18 years; (3)\nhemoglobin concentration <100 g/L or RBC transfusion\ndependence19; (4) no exposure to ESAs, androgens, tha-\nlidomide, lenalidomide, or corticosteroids <12 weeks pre-\nenrollment; (5) creatinine ≤2 mg/dL, direct bilirubin <2\ntimes upper limit of normal (ULN) and alanine amino-\ntransferase (ALT)/aspartate aminotransferase (AST) ≤3\nULN. Subjects receiving ruxolitinib during the past sev-\neral years were excluded. Subjects had a pre-therapy\nphysical examination, baseline laboratory assessment of\nserum chemistries and blood hematologic parameters,\nbone marrow aspirate and biopsy, and cytogenetic ana-\nlyses. Prognostic cohort was assigned using the Dynamic\nInternational Prognostic Scoring System (DIPSS)\n2 for all\nsubjects and DIPSS-plus 3 for those with cytogenetics data.\nBone marrow fibrosis was graded using European con-\nsensus guidelines 20.\nTherapy\nSubjects received thalidomide, 50 mg p.o. at bed time\ncontinuously. Prednisone, 0.5 mg/kg/day, was given for\n1 month, 0.25 mg/kg/day, for the next month, 0.125 mg/\nkg/day for the third month and tapered thereafter.\nDanazol, 600 mg/day p.o. was given continuously. Patients\nwith neutrophil count <1.0 × 10E + 9/L and/or platelet\ncount <80 × 10E + 9/L were assigned to thalidomide/\nprednisone/danazol therapy, the others were assigned to\nthalidomide/prednisone therapy. Laboratory studies were\nperformed weekly for 12 weeks. Responders continued on\ntheir assigned therapy, whereas others stopped. Packed\nRBCs were transfused for a hemoglobin concentration\n<60 g/L or symptoms of anemia.\nEvaluation of response and adverse events (AEs)\nThe primary study outcome was anemia response. In\nsubjects with splenomegaly or thrombocytopenia, spleen\nand platelet responses were also analyzed. Anemia and\nspleen responses were assessed according to the revised\nInternational Working Group for Myelo fibrosis Research\nand Treatment (IWG-MRT) consensus criteria\n21.\nThrombocytopenia response was de fined as a platelet\nincrease >50 × 10E + 9/L in subjects with baseline pla-\ntelets <100 × 10E + 9/L. Toxicity was assessed by the\nNational Cancer Institute Common Toxicity Criteria for\nAdverse Events, Version 4\n22.\nStatistical analyses\nFollow-up was to death or 10 June 2017. Quantitative\ndata are expressed as median and range and qualitative\ndata as percent. Baseline variables were compared\nbetween cohorts using χ\n2 test for categorical variables and\nMann–Whitney U-test for continuous variables. Clinical\nresponses were compared between cohorts with χ2 test.\nLogistic regression was used to assess relationships\nbetween baseline variables and outcomes. Variables sig-\nnificant in univariate analyses were included in the mul-\ntivariate analysis. Response duration was de fined as the\ninterval from anemia response to loss of response, change\nof therapy, or death. Response duration was calculated\nusing the Kaplan –Meier method and compared by the\nlog-rank test. P-values are two-sided and statistical sig-\nnificance de fined as P < 0.05. Statistical analyses were\nperformed using the IBM SPSS 22.0 package (SPSS,\nChicago, IL, USA).\nResults\nSubject- and disease-related variables\nEighty-eight subjects with PMF and anemia were eval-\nuated. Forty-six received thalidomide and prednisone and\n42 received thalidomide, prednisone, and danazol. Base-\nline variables were similar (Table 1). Median age was 53\nyears (range, 21 –77 years). Forty-six (52%) were male.\nThirty-eight subjects (43%) were RBC transfusion\ndependent\n19 and 49 (56%) had platelets <100 × 10E + 9/\nL. Median hemoglobin concentration and median white\nblood cell (WBC) and platelet levels were 71 g/L, 3.49 ×\n10E + 9/L and 84 × 10E + 9/L, respectively. Spleens were\npalpable a median of 4 cm (range, 0 –24 cm) below the left\ncostal margin (LCM). Fourteen of 54 subjects (26%) with\nevaluable cytogenetics had unfavorable karyotypes\naccording to DIPSS-plus\n3. Thirty-one of 70 subjects tested\nhad JAK2V617F. Forty- five subjects (51%) were inter-\nmediate-1, 38 (43%) were intermediate-2 and 5 (6%), high-\nrisk according to the DIPSS\n2.\nThirty-one subjects received prior therapy(ies) includ-\ning 9, thalidomide; 20, androgenic steroids; 5, recombi-\nnant human erythropoietin; 3, corticosteroids; 4,\nhydroxyurea; 3, interferon; and 1, melphalan. Median\ninterval from diagnosis to study entry was 0 month (range,\n0–62 months). Althought on-study, nine subjects received\nLuo et al . Blood Cancer Journal  (2018) 8:9 Page 2 of 5\nBlood Cancer Journal\n\nhydroxycarbamide (hydroxyurea) alone ( N = 7) or with\ninterferon ( N = 2) and two received melphalan.\nResponses and outcome\nThe anemia response rate for all subjects was 58% (95%\nconfidence interval (CI) 48, 68%). Subjects receiving\nthalidomide/prednisone/danazol had a signi ficantly\nhigher response rate compared with those receiving tha-\nlidomide/prednisone (71% (57, 85%) vs. 46% (32, 60%); P\n= 0.014). Response rates in subjects who were RBC\ntransfusion dependent were also higher in the danazol\ncohort (61% (38, 84%) vs. 25% (6, 44%); P = 0.024).\nThere is no signi ficant correlations between anemia\nresponse rate and JAK2\nV17F mutation state ( P = 0.238).\nSixty-eight percent (52, 84%) of JAK2V617F subjects\nresponded compared with 54% (38, 70%) JAK2 wild-type\nsubjects ( P = 0.238). In subgroup analysis, 63% (39, 87%)\nof JAK2\nV617F subjects responded compared with 42% (20,\n64%) JAK2 wild-type subjects among patients receiving\nthalidomide/prednisone ( P = 0.229), 73% (51, 95%) of\nJAK2V617F subjects responded compared with 65% (44,\n86%) JAK2 wild-type subjects among patients receiving\nthalidomide/prednisone/danazol ( P = 0.875).\nIn multivariate analyses, only thalidomide/prednisone/\ndanazol therapy (odds ratio (OR) = 3.39 (1.29, 8.89); P =\n0.013) and not being RBC transfusion dependent (OR =\n2.90 (1.11, 7.61); P = 0.03) were signi ficantly associated\nwith response (Table 2). Responses occurred rapidly:\nmedian time to response was 2 months (range,\n1–11 months) and did not differ between the cohorts.\nInterval to response varied: 61% of responders did so by\n3 months, 94% by 6 months and only 6% after 6 months.\nThe minimum duration of treatment was 3 months,\nwith a median of 25 months (range 3 –117+ months).\nSubjects receiving thalidomide/prednisone/danazol had\nsignificantly longer response durations than those\nTable 1 Baseline characteristics of patients\nVariable Thalidomide/\nprednisone\nThalidomide/\nprednisone/\ndanazol\nP-value\nNo. 46 42\nAge (years) 53 (21, 77) 53 (26, 72) 0.776\nMale n (%) 24 (52.2%) 22 (52.3%) 0.985\nPrevious therapy 13 (28.3%) 18 (42.9%) 0.152\nSpleen size below\nleft costal margin\n(cm)\n3 (0,18) 5 (0, 24) 0.606\nConstitutional\nsymptoms\n18 (39.1%) 11 (26.2%) 0.197\nHemoglobin (g/L) 71 (31, 99) 71 (38, 99) 0.854\nWBC counts (×10\n9/L) 4.07 (0.75, 22.36) 3.22 (1.51, 25.63) 0.335\nPlatelets counts\n(×109/L)\n100 (3, 1064) 80 (14, 540) 0.631\nSerum EPO (mU/mL) 504 (21, 774) 652 (76, 774) 0.845\nRBC transfusion\ndependency\n20 (43.5%) 18 (42.9%) 0.953\nBlood blasts% 0 (0,17) 0 (0, 2) 0.100\nMarrow blasts% 0 (0,7) 0 (0,5) 0.202\nBone marrow\nfibrosis\n0.328\nMF-2 35 (76.1%) 28 (66.7%)\nMF-3 11 (23.9%) 14 (33.3%)\nCytogeneticsa 0.777\nUnfavorable 9 (27.3%) 5 (23.8%)\nFavorable 24 (72.7%) 16 (76.2%)\nJAK2V6A7F mutationb 0.810\nPositive 16 (46%) 15 (43%)\nNegative 19 (54%) 20 (57%)\nDIPSS risk group 0.217\nIntermediate-1 20 (43.5%) 25 (59.5%)\nIntermediate-2 22 (47.8%) 16 (38.1%)\nHigh 4 (8.7%) 1 (2.4%)\nWBC white blood cell, EPO erythropoietin, DIPSS Dynamic International\nPrognostic Scoring System\naCytogenetic information was available in 54 patients\nbJAK2V6A7F mutation status was available in 70 patients\nTable 2 Multivariate analysis of anemia response\nVariable OR (95% CI) Multivariate analysis,\nP\nTreatment group 0.013\nThalidomide/prednisone 1\nThalidomide/prednisone/\ndanazol\n3.39 (1.29 –8.89)\nGender 0.161\nMale 1\nFemale 2.01 (0.76 –5.31)\nRBC transfusion dependent 0.03\n≥6U/12W 1\n<6U/12W 2.90 (1.11 –7.61)\nPalpable spleen length 0.225\nLCM <5 cm 1\nLCM ≥5 cm 1.82 (0.69 –4.79)\nOR odds ratio, CI confidence interval, LCM left costal margin\nLuo et al . Blood Cancer Journal  (2018) 8:9 Page 3 of 5\nBlood Cancer Journal\n\nreceiving thalidomide/prednisone (hazard ratio (HR) 2.18,\n95%CI (1.18 –5.42), P = 0.019; Fig. 1). Median response\nduration was 27 months (95% CI, 15 –39 months) overall,\n30 months (10 –49 months) in the thalidomide/pre-\ndnisone/danazol cohort compared with 11 months\n(0–30 months) in the thalidomide/prednisone cohort.\nTwenty-two of 49 subjects (45% (31, 59%)) with baseline\nplatelets <100 × 10E + 9/L had an increase of >50 × 10E\n+ 9 L including 58% (39, 77%) of subjects receiving tha-\nlidomide/prednisone/danazol vs. 30% (11, 49%; P = 0.06)\nof subject in the thalidomide/prednisone cohort. Median\ntime to platelet response was 3 months (range,\n<1–9 months) and was similar between the cohorts as was\nresponse duration (21 months (95% CI, 7 –35 months)).\nThere was a spleen response in 16 of 41 evaluable subjects\n(39% (24, 54%)) with similar response rates between the\ncohorts.\nAdverse events\nAEs were dose dependent and reversible with similar\nincidences (save ALT/AST increases) and severities in the\ncohorts. No subject discontinued therapy because of\ndrug-related AEs. Leukocytosis and thrombocytosis\noccurred in 19% (11, 27%) and 24% (15, 33%) of subjects.\nThere was no thrombo-embolic event. The most frequent\nnon-hematologic AE was increased ALT/AST in 19% (8,\n31%) of subjects receiving thalidomide/prednisone/dana-\nzol compared with 4% (3, 22%; P = 0.07) of subjects\nreceiving thalidomide/prednisone. Other non-\nhematologic AEs were less frequent and did not differ\nsignificantly between the cohorts (Table 3) including\nincreased bilirubin in four, constipation in six, hypergly-\ncemia in six; rash in five; edema in six, neurological\nsymptoms in seven; abdominal distention in four; hyper-\ntension in three, somnolence in two, and creatinine ele-\nvation in two. There was no case of prostate cancer or\nhepatic adenoma.\nDiscussion\nEfficacy of low-dose thalidomide/prednisone in persons\nwith PMF and anemia was studied in relatively small\nseries of subjects with variable response criteria and\nresponse rates\n13,23,24. We con firmed the ef ficacy of thali-\ndomide/prednisone using the current IWG-MRT cri-\nteria\n21. Importantly, adding danazol signi ficantly\nincreased response. In another recent study, danazol alone\nwas reported to have a response rate of 30% (17, 43%) 17.\nThese data suggest therapy with thalidomide/prednisone/\ndanazol is better than any component therapy.\nPrevious studies reported lower serum EPO levels,\nsmaller spleen size, and lower RBC transfusion frequency\nwere associated with higher anemia response rates\n17,25,26.\nWe found such an association only for RBC transfusion\ndependence, and independence. We also found an\nFig. 1 Response duration according to the treatment groups\nTable 3 Toxicity of the therapeutic regimen\nAdverse events Thalidomide/\nprednisone ( n=46)\nThalidomide/\nprednisone/danazol\n(n=42)\nHyper-bilirubinemia 1 3\nConstipation 4 2\nEdema 3 3\nHyperglycemia 3 3\nRash 3 2\nNeurological\nsymptoms\n52\nAbdominal\ndistention\n22\nHypertension 1 2\nSomnolence 2 0\nCreatinine elevation 0 2\nLuo et al . Blood Cancer Journal  (2018) 8:9 Page 4 of 5\nBlood Cancer Journal\n\nadvantage for combined therapy in subjects who were\nRBC transfusion dependent. Anemia responses occurred\nquickly and similarly in the two groups. Median time to\nresponse was shorter in our study than a previous study of\ndanazol\n17 suggesting thalidomide/prednisone may have\naccelerated danazol responses.\nOur data suggest adding danazol to thalidomide/pre-\ndnisone improves response rates, prolongs response\nduration in persons with PMF and anemia with and\nwithout RBC transfusion dependence. The major limita-\ntion of our study is that it was a retrospective analysis and\nnot randomized, and that although the cohorts were\nsimilar for known predictive variables we cannot be cer-\ntain they were comparable for unknown predictive vari-\nables. As such, our conclusions require con firmation in a\nrandomized trial.\nAcknowledgements\nThis study was supported in part by National Natural Science Funds (no.\n81530008, no. 81370611, no. 81270585, and no. 81470297), Program for Peking\nUnion Scholars and Innovative Research Team and PUMC Youth Fund and\nFundamental Research Funds for the Central Universities (no. 3332016089). R.P.\nG. acknowledges support from the National Institute of Health Research (NIHR)\nBiomedical Research Centre funding scheme.\nAuthor details\n1MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital,\nChinese Academy of Medical Sciences and Peking Union Medical College,\nTianjin, China. 2State Key Laboratory of Experimental Hematology, Institute of\nHematology and Blood Diseases Hospital, Chinese Academy of Medical\nSciences and Peking Union Medical College, Tianjin, China.\n3Department of\nPathology, Institute of Hematology and Blood Diseases Hospital, Chinese\nAcademy of Medical Sciences and Peking Union Medical College, Tianjin,\nChina.\n4Divisions of Experimental Hematology and Cancer Biology, Cincinnati\nChildren’s Hospital Medical Center, Cincinnati, OH, USA. 5Haematology Section,\nDivision of Experimental Medicine, Department of Medicine, Imperial College\nLondon, London, UK\nCompeting interests\nR.P.G. is a part-time employee of Celgene Corp.\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in\npublished maps and institutional af filiations.\nReceived: 6 September 2017 Revised: 10 October 2017 Accepted: 13\nOctober 2017\nReferences\n1. 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T s i a r a ,S .N . ,C h a i d o s ,A . ,B o u r a n t a s ,L .K . ,K a p s a l i ,H .D .&B o u r a n t a s ,K .L .\nRecombinant human erythropoietin for the treatment of anemia in patients\nwith chronic idiopathic myelofibrosis. Acta Haematol. 117,1 5 6–161 (2007).\nLuo et al . Blood Cancer Journal  (2018) 8:9 Page 5 of 5\nBlood Cancer Journal","source_license":"CC0","license_restricted":false}